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.

Methionine, an essential sulfur-containing amino acid, plays a critical role in methyl metabolism, folate metabolism, polyamine synthesis, redox homeostasis maintenance, epigenetic modification and signaling pathway regulation, particularly during embryonic development. Animal and human studies have increasingly documented that methionine deficiency or excess can negatively impact metabolic processes, translation, epigenetics, and signaling pathways, with ultimate detrimental effects on pregnancy outcomes. However, the underlying mechanisms by which methionine precisely regulates epigenetic modifications and affects signaling pathways remain to be elucidated. In this review, we discuss methionine and the metabolism of its metabolites, the influence of folate-mediated carbon metabolism, redox reactions, DNA and RNA methylation, and histone modifications, as well as the mammalian rapamycin complex and silent information regulator 1-MYC signaling pathway. This review also summarizes our present understanding of the contribution of methionine to these processes, and current nutritional and pharmaceutical strategies for the prevention and treatment of developmental defects in embryos.

Elevated levels of homocysteine in the blood plasma (hyperhomocysteinemia, HHCY) positively correlate with migraine symptoms in patients. Experimental studies show a higher sensitivity of rats with prenatal HHCY (pHHCY) to migraine symptoms like allodynia, photophobia, anxiety, and a higher excitability of meningeal trigeminal afferents. In the present study, the roles of purinergic mechanisms in the homocysteine-induced hyperexcitability of the trigeminal ganglion (TG) system using electrophysiological recordings from the trigeminal nerve, Ca2+ imaging of cells isolated from TG, and mast cell staining in meninges were investigated. Experiments were performed using rats with pHHCY born from females fed with a high-methionine-containing diet before and during pregnancy. Firstly, we found that lower concentrations of 4-aminopyridine, a K+-channel blocker, were able to induce an increase in the nociceptive activity of trigeminal afferents, supporting the hypothesis of the higher excitability of the trigeminal nerve of rats with pHHCY. Trigeminal afferents of rats with pHHCY were more sensitive to the exogenous application of the nonspecific agonist of purinergic ATP receptors. In neurons and satellite glial cells of TG of rats with pHHCY ATP, ADP (an agonist of metabotropic P2Y receptors) and BzATP (an agonist of ionotropic P2X with especially high potency for the P2X7 receptor) induced larger Ca2+ transients. The incubation of TG neurons in homocysteine for 24 h increased the ratio of neurons responding simultaneously to ATP and capsaicin. Moreover, rats with pHHCY exhibit a higher rate of degranulation of mast cells and increased response to the agonist of the P2X7 receptor BzATP application. In addition, higher levels of calcitonin gene-related peptide (CGRP) were found in rats with pHHCY. Our results suggest that chronic elevated levels of homocysteine induce the upregulation of ionotropic or metabotropic ATP receptors in neurons, satellite glial cells, and mast cells, which further provide inflammatory conditions and the sensitization of peripheral afferents underlying pain.

The association between plasma homocysteine (Hcy) levels and short-term mortality in sepsis patients remains unclear. This meta-analysis aimed to clarify this potential relationship. Following PRISMA 2020 and Cochrane Handbook guidelines, we conducted a comprehensive literature search in the PubMed, Embase, and Web of Science databases up to June 24, 2024. We included cohort studies that assessed the association between plasma Hcy levels and all-cause mortality in adult sepsis patients. Standardized mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model to account for potential heterogeneity. Nine cohort studies involving 771 sepsis patients were included. Overall, no significant difference in plasma Hcy levels was observed between survivors and non-survivors (SMD: -0.23, 95% CI: -0.84 to 0.37, P = 0.45), with substantial heterogeneity (I² = 86%). Subgroup analysis revealed lower plasma Hcy levels among survivors in Chinese patients (SMD: -1.56, 95% CI: -1.98 to -1.13, P < 0.001) but not in non-Asian patients. Plasma Hcy levels were not significantly associated with all-cause mortality (OR per 1-unit increment: 1.03, 95% CI: 0.95 to 1.11, P = 0.51), with notable heterogeneity (I² = 72%). However, a significant association was found in Chinese patients (OR: 1.09, 95% CI: 1.03 to 1.15, P = 0.003), but not in non-Asian patients. In conclusion, plasma Hcy levels were not generally associated with short-term mortality in sepsis patients. However, significant associations were observed in Chinese patients, suggesting potential ethnic differences that warrant further investigation.

Given the essential roles of homocysteine (Hcy) and the interference of cysteine in effectively monitoring human health, this study proposed a synergistic effect strategy that combines the unique structural and functional properties of nanoporous gold (NPG) with the selective recognition capability of a recombinant cystathionine β-synthase (CBS) for the sensitive and specific detection of Hcy. The CBS protein with specific catalytic activity for Hcy was successfully produced in recombinant Escherichia coli BL21 (pET-30a-cbs) using the cbs gene from Pseudomonas aeruginosa PAO1. The electrochemical mechanism demonstrated that the electrooxidation of H2S, a catalytic product of the CBS, was an irreversibly surface-controlled process on the CBS/NPG/GCE electrode surface. The electrochemical detection of Hcy exhibited excellent linearity, with a high sensitivity reaching 10.43 µA mM-1 cm-2 and a low detection limit of 1.31 µM. Furthermore, the CBS/NPG/GCE biosensor was successfully used to detect Hcy in urine samples with strong anti-interference capability and high selectivity (relative standard deviation less than 2.81%), while effectively reducing the interference from cysteine. These results confirmed that the proposed CBS/NPG/GCE electrochemical sensor achieved specific, sensitive, and reliable rapid detection of homocysteine, making it highly promising for practical applications in clinical treatment and health assessment.

Prenatal hyperhomocysteinemia (HCY) is associated with neurodevelopmental deficits, yet its long-term impact on hippocampal synaptic function remains poorly understood. This study examines the effects of moderate maternal HCY on excitatory synaptic transmission in the CA1 region of the dorsal hippocampus in rat offspring at juvenile (P21) and adult (P90) stages. Using field postsynaptic potential (fPSP) recordings, electron microscopy, and Western blot analysis, we observed a significant age-dependent decline in the efficiency of excitatory synaptic transmission in HCY-exposed rats. Electron microscopy revealed structural alterations, including synaptic vesicle agglutination in the stratum radiatum, suggesting impaired neurotransmitter release. Additionally, a significant reduction in pyramidal neuron density was observed in the CA1 region, although seizure susceptibility remained unchanged. Western blot analysis showed altered expression of Synapsin I, indicating presynaptic dysfunction. These findings suggest that moderate prenatal HCY leads to persistent deficits in synaptic transmission and structural integrity, potentially contributing to cognitive impairments in adulthood. Our results highlight the importance of maternal homocysteine levels in shaping hippocampal function and could offer insights into neurodevelopmental disorders associated with metabolic disturbances.

In our practice, testing hypo-fertile patients for circulating homocysteine (Hcy) and the two principal MTHFR SNPs (677C > T and 1298A > C) has been routine for the past 7 years. Couples carrying a genetic background known to be associated with the disease were proposed treatment regimens consisting of 5-methyl tetrahydrofolate (5-MTHF) together with nutritional support of the one-carbon cycle (1-CC). Some patients preferred to continue with folic acid (FA) as prescribed by their referring gynecologist/obstetrician: this gave us the opportunity to compare outcomes between the two groups of patients.

After successful live birth deliveries, we compared health characteristics and circulating Hcy in the offspring from ages 2 to 6 years, i.e., after cessation of breastfeeding and before puberty. Follow-up included children of 21 couples who were treated with FA vs 36 couples treated with 5-MTHF.

In the FA-treated group, we found two children with autism spectrum disorder (ASD) syndrome, one child with significantly elevated circulating Hcy (19 µM at the age of 2 years), and one child affected by oculo-auriculo-vertebral spectrum (OAVS), a syndrome known to be linked to DNA methylation. No pathology of any kind was detected in children of the 5-MTHF treatment group.

Treatment with 5-MTHF is safe and effective for both males and females. It should be implemented in order to avoid disruption of methylation linked to folate metabolism during oocyte maturation and pregnancy, and subsequently in the offspring. This type of treatment should be considered to avoid metabolic diseases linked to elevated homocysteine.

Introduction Obsessive-compulsive disorder (OCD) is a persistent psychiatric condition that causes significant clinical and functional impairments. Recent research suggests a link between deficiencies in micronutrients, particularly vitamin B12, folic acid, and elevated homocysteine, and the development of OCD. This study investigates the blood levels of these micronutrients and their relationship to OCD severity, with an emphasis on potential gender differences. Methods This cross-sectional study included 300 drug-free OCD patients. Serum levels of vitamin B12, folic acid, and homocysteine were measured using established biochemical methods. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was used to assess clinical severity. Data were examined to determine relationships between micronutrient levels and OCD severity and differences between male and female patients. Results This study found that women had higher levels of vitamin B12 (405.3 ± 15.1 vs. 360.4 ± 14.3) and folic acid (7.18 ± 0.27 vs. 5.76 ± 0.25) but lower levels of homocysteine (9.35 ± 0.64 vs. 14.4 ± 0.60) compared to men. Higher folic acid levels were linked to study participants having higher levels of education (at a college or university, where subjects are studied at an advanced level) compared to those with primary-level education. Lower vitamin B12 levels were linked to family mental health history and noncommunicable diseases. Women exhibited lower levels of substance use but higher rates of self-harm and suicide attempts. Elevated homocysteine levels were linked to longer illness duration and more severe OCD symptoms. Conclusion These findings suggest that imbalances in micronutrients, particularly vitamin B12, folic acid, and homocysteine, may contribute to OCD severity and treatment resistance. Gender-specific variations in micronutrient levels could provide valuable insights into personalized OCD therapy choices. Further longitudinal studies are needed to understand these relationships and their potential as therapeutic targets.

Metabolomics provide a promising tool for understanding dementia pathogenesis and identifying novel biomarkers. This study aimed to identify amino acid biomarkers for Alzheimer's Disease (AD) and Vascular Dementia (VD). By amino acid metabolomics, the concentrations of amino acids were determined in the serum of AD and VD patients as well as age-matched healthy controls. Several differences in the concentration of amino acids were observed in AD patients compared to both healthy controls and VD patients. However, no significant distinction was found between healthy controls and VD patients. Considering comorbidities, cystine levels were higher in AD than in VD among non-diabetic patients, but not in those with diabetes. Notably, creatine, spermidine, cystine, and tyrosine demonstrated favorable results in decision curve analyses and good discriminative performances, suggesting their potential for clinical application. These fundings give novel perspectives of serum amino acids for predicting metabolic pathways in AD and VD pathogenesis.

One-carbon metabolism (OCM) is a series of connected pathways involving the methionine-folate cycles, transsulfuration, polyamine synthesis, nucleotide synthesis, free-radical scavenging, and energy metabolism. These pathways functionally depend upon amino acids (methionine, glycine, and serine), vitamins (folate, B2, B6, and B12), and minerals (sulfur, cobalt, and zinc). Growing bodies of research indicate that in beef cattle, physiological stage, nutritional plane, diet, species (Bos taurus vs. indicus), rumen protected vs. not, individual vs. combination supplementation and method of delivery all affect the efficacy of one-carbon metabolite supplementation. Infusion studies showed that supplementing methionine to growing steers improved N retention and altered hepatic activity of methionine synthase; however, only supplementing methionine without folate decreased folate concentrations in circulation. When heifers were supplemented with methionine, choline, folate, and B12 for the first 63 d of gestation, metabolomic analysis revealed increasing OCM analytes to the heifer, but a buffering effect to the fetus with minimal changes seen in hepatic metabolite abundance. Methionine supplementation to heifers during the periconceptual period increased circulating methionine but shifted fetal hepatic metabolism toward the transsulfuration pathway. Periconceptual methionine supplementation to cows increased gain and total-tract digestibility in calves post-weaning. In vitro supplementation of choline to beef cattle embryos results in calves of increased birth and weaning weight. Overall, these data demonstrate that OCM is altered in those cattle receiving one-carbon metabolites, and that a metabolic programming response is elicited in offspring receiving supplements in vitro or during early gestation. Research should be considered to maximize efficiency of beef cattle production at all stages by identifying limiting metabolites or enzymes to maximize efficiency of OCM in beef cattle, as well as to understand the concerted effects of multiple one-carbon metabolites to balance the stoichiometry of the pathway.

Research on elemental changes in tissues and organs provides valuable information enabling better understanding of the physiological processes occurring in a living organism, as well as the pathogenesis and course of various diseases. They may also contribute to the development of new, more effective, and safer therapeutic strategies. So far, they have been carried out mainly on male individuals because of the easier planning and conducting of experiments as well as the lower variability of the results in comparison with studies involving females.

The significance of incorporating both sexes in research concerning elemental alterations of tissues may be unveiled by data concerning the influence of sex on the physiological levels of selected elements in various rat organs. Therefore, here we determined and compared the levels of P, S, K, Ca, Fe, Cu, Zn, and Se in brains, hearts, kidneys, livers, and spleens taken from male and female rats. To measure the concentrations of the elements in digested tissue samples, ICP-OES and TXRF methods were utilized.

Significant differences between male and female rats were found for all the organs examined, and the concentrations of most of the tested elements were higher in males than females. The exception was Fe, the level of which in the kidneys and liver was higher in female rats. Sex influenced the elemental composition of spleen the most. For the brain, heart, kidneys, and liver, differences were sparse and were found mainly for the heavier elements.

Homocysteine (Hcy) is a metabolic intermediate product derived from methionine. Hyperhomocysteinemia is a condition associated with various diseases. Hcy is recognized as a risk factor for cardiovascular disease (CVD). Ferroptosis, a novel form of cell death, is primarily characterized by substantial iron accumulation and lipid peroxidation. Recent research indicates a close association between ferroptosis and the pathophysiological processes of tumors, neurological diseases, CVD, and other ailments. However, limited research has been conducted on the impact of Hcy on ferroptosis. Therefore, this paper aimed to investigate the potential roles and mechanisms of homocysteine and ferroptosis in the context of cardiovascular disease. By conducting comprehensive literature research and analysis, we aimed to summarize recent advancements in understanding the effects of homocysteine on ferroptosis in cardiovascular diseases. This research contributes to a profound understanding of this critical domain.

Psoriasis is a chronic, systemic, immune-mediated, inflammatory skin disease associated with significant comorbidities. Globally, there are an estimated 60 million people living with psoriasis (PLwP). There is a growing body of evidence on the role of diet in psoriasis management, and demand for dietary advice is high. However, there are no specific, evidence-based dietary guidelines. This scoping review summarises the literature on use and effectiveness of diet in the management of psoriasis to improve understanding of the evidence and assist PLwP and healthcare professionals (HCPs) to discuss diet. The findings were categorised into three themes: (1) dietary intakes of PLwP, (2) the perceived role of diet in psoriasis management and (3) dietary approaches to manage psoriasis symptoms. In cross-sectional studies PLwP were reported to have higher fat and lower fibre intakes compared with controls, and lower psoriasis severity was associated with higher fibre intake. However, research is limited. PLwP perceive diet to have an impact on symptoms and make dietary modifications which are often restrictive. Systematic reviews and RCTs found certain dietary approaches improved symptoms, but only in specific populations (e.g. PLwP with obesity and PLwP with coeliac disease), and evidence for supplement use is inconclusive. The grey literature provides limited guidance to PLwP; focusing on weight loss and associated comorbidities. Larger, controlled trials are required to determine dietary approaches for psoriasis management, especially in PLwP without obesity and non-coeliac PLwP. Further understanding of diet modification, information acquisition and experiences among PLwP will enhance holistic care for psoriasis management.

Hyperhomocysteinemia can be due to various abnormalities of the complex interaction of methionine, folate and vitamin B12. It has been known to be a cardiovascular risk factor. This study aims to review the clinical presentation, underlying causes and clinical outcome in paediatric patients diagnosed with significant hyperhomocysteinemia in Malaysia.

Data were obtained from the medical records and the laboratory information system. Paediatric patients with significant hyperhomocysteinemia were identified from a selective high-risk screening of 96,721 patients, performed between 2010 and 2022. Inclusion criteria for the study were paediatric patients with significant hyperhomocysteinemia (>40 µmol/L).

Sixteen patients were identified. The average total homocysteine (tHcy) and methionine were 269 µmol/L and 499 µmol/L in cystathionine β-synthase deficiency (CBS), 127 µmol/L and 29 µmol/L in patients with remethylation defects and 390 µmol/L and 4 µmol/L in congenital B12 deficiency. We found c.609G>A as the most prevalent mutation in MMACHC gene and possible novel mutations for CBS (c.402del, c.1333C>T and c.1031T>G) and MTHFR genes (c.266T>A and c.1249del). Further subclassification revealed CBS was 5/16 patients (31 %), remethylation defects was 9/16 (56 %) and congenital B12 deficiency was 2/16 (13 %). All patients received standard treatment and regular monitoring of the main biomarkers. The average age at the time of diagnosis were 9.2 years (CBS) and 1.2 years (remethylation defects). Congenital B12 deficiency had slight delay in milestones, remethylation defects had mild to moderate learning disabilities, CBS had variable degree of intellectual disability, delayed milestones, ophthalmological abnormalities, and thrombosis at an early adolescent/adulthood.

The majority of significant hyperhomocysteinemia in Malaysian children was due to remethylation defects. Screening for hyperhomocysteinemia in Malaysian children is recommended for earlier treatment and improved clinical outcome.

Stress is an independent risk factor for cognitive impairment, with elevated plasma homocysteine (HCY) levels playing a crucial role in stress-induced cognitive decline. While the rise in plasma HCY levels is linked to abnormal peripheral catabolism, the impact of stress on HCY catabolism in the brain remains unclear. This study investigated the effect of stress on HCY metabolism in the brain by analyzing HCY and its metabolic enzymes in the hippocampus and prefrontal cortex. The results showed a significant decrease in enzymes MS (methionine-synthase), CBS (cystathionineβ-synthase), and CSE (cystathionine γ-lyase) in these brain regions of mice subjected to 3 weeks of restraint stress, leading to HCY accumulation. Additionally, the enzyme MTHFR (methylenetetrahydrofolate reductase) remained unchanged. Immunofluorescence double-labeling revealed the downregulation of HCY metabolic enzymes in neurons of stressed mice. The transcription factor KLF4 (Kruppel-likefactor4), known for its inhibitory role, increased after stress or glucocorticoid treatment and suppressed the expression of MS, CBS, and CSE, contributing to elevated HCY levels in the brain. These findings offer new insights into the impairment of HCY catabolism in the stressed brain, suggesting that the downregulation of HCY metabolic enzymes may underlie HCY accumulation and exacerbate stress-induced cognitive dysfunction.

Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. Reviews indicated a positive relationship between exposure to pesticides and the development of cancers. In the present study, we have estimated the level of oxidative stress markers in serum samples of pesticide exposure and unexposed cancer patients as compared to normal control. We have found a significant decrease in peroxygenase (PON) and arylesterase (ARE) activity and substantial increases in homocysteine levels in both cancer groups. The level of heme biosynthesis rate-limiting enzymes delta-aminolevulinic acid dehydratase (δ-ALA-D) also significantly decreased compared to control. The statistical comparison between the cancer groups does not show significant changes. We concluded the involvement of oxidative stress in carcinogenesis in both cancer group patients. However, more study is needed to put homocysteine as a novel marker for a variety of diseases on a single platform.

Aim: To investigate the association between serum homocysteine (HCY) levels, red blood cell folate (RCF) levels, methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and infertility.Materials & methods: Serum HCY and RCF levels and C677T polymorphism of MTHFR gene were analyzed in 149 infertile patients and 223 women of normal reproductive age with healthy childbirth history.Results: The HCY level of MTHFR C677T TT genotype infertility patients was higher than that of women of normal reproductive age, while the RCF level was not significantly different between the two groups.Conclusion: Serum HCY levels increased in infertility patients, and the MTHFR C677T TT genotype in childbearing-aged women are associated with a higher risk of infertility. The results showed that HCY level and MTHFR C677T genotype were closely related to infertility.

Folate has an important role in the functioning of the musculoskeletal system, including modulation of inflammation, immunity, cartilage regeneration, prevention of osteoporosis, and maintenance of muscle strength, but evidence on the association between folate intake and knee pain, functional scores, and radiographic progression in patients with knee osteoarthritis (OA) is still limited.

Our population-based cohort was extracted from the osteoarthritis initiative (OAI), focusing on individuals with prevalent radiographic knee OA (with a Kellgren-Lawrence score ≥2). Folate consumption was determined using the food frequency questionnaire. Data regarding the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores and radiographic readings were collected over 48 months. We analyzed the compiled data using generalized additive mixed models.

Our cohort consisted of 1472 OA patients (626 men and 846 women, mean [SD] age 62.35 [8.92]). At the 48-month follow-up, we observed a significant correlation between higher folate intake and a slower progression of knee pain and functional scores, as evidenced by a statistically significant decrease in the WOMAC total score, WOMAC pain subscale score, and WOMAC function/disability subscale score (p < .05). The fully adjusted models estimated a reduction of -0.028 points per 50 μg/1000 kcal of daily folate intake on the WOMAC pain subscale, -0.117 points on the WOMAC function subscale, and -0.160 points on the total WOMAC scale. Furthermore, our nonparametric fit analysis suggested that a higher intake of folate might decelerate the radiographic progression of OA. Stratified analyses indicated that an increase in folate consumption might particularly benefit men, older adults, overweight and obese individuals, and those with a higher dietary fiber intake.

Higher folate intake is correlated with improved knee function and reduced pain in patients with knee OA and might deter the radiographic progression of OA. The benefits appear to be more pronounced in men, older adults, overweight and obese individuals, and those with a higher dietary fiber intake.

l-Homocysteine, formed from S-adenosyl methionine following demethylation and adenosine release, accumulates when the methionine recycling pathway and other pathways become impaired, thus leading to hyperhomocysteinemia, a biomarker in cardiovascular diseases, neurological/psychiatric disorders, and cancer. The partial oxidation of the l-homocysteine thiol group and its decarboxylation on C-alpha lead to the formation of l-homocysteinesulfinic acid (l-HCSA) and homohypotaurine (HHT), respectively. Both compounds are not readily available from commercial suppliers, which hinders the investigation of their biological activities. Herein, the chemical synthesis of l-HCSA, from l-homocystine, was the starting point for establishing the bio-based synthesis of HHT using recombinant Escherichia coli glutamate decarboxylase (EcGadB), an enzyme already successfully employed for the bio-based synthesis of GABA and its phosphinic analog. Prior to HHT synthesis, kcat (33.92 ± 1.07) and KM (38.24 ± 3.45 mM) kinetic constants were determined for l-HCSA on EcGadB. The results of our study show that the EcGadB-mediated synthesis of HHT can be achieved with good yields (i.e., 40% following enzymatic synthesis and column chromatography). Purified HHT was tested in vitro on primary human umbilical vein endothelial cells and rat cardiomyoblasts and compared to the fully oxidized analog, homotaurine (OT, also known as tramiprosate), in widespread pharmaceutical use. The results show that both cell lines display statistically significant recovery from the cytotoxic effects induced by H2O2 in the presence of HHT.

Cell activation and nutrient dysregulation are common consequences of atherosclerosis and its preceding risk factors, such as hypertension, dyslipidemia, and diabetes. These diseases may also impact cellular metabolism and consequently cell function, and the other way around, altered cellular metabolism can impact disease development and progression through altered cell function. Understanding the contribution of altered cellular metabolism to atherosclerosis and how cellular metabolism may be altered by co-morbidities and atherosclerosis risk factors could support the development of novel strategies to lower the risk of CVD. Therefore, we briefly review disease pathogenesis and the principles of cell metabolic pathways, before detailing changes in cellular metabolism in the context of atherosclerosis and comorbidities. In the hypoxic, inflammatory and hyperlipidemic milieu of the atherosclerotic plaque riddled with oxidative stress, metabolism shifts to increase anaerobic glycolysis, the pentose-phosphate pathway and amino acid use. We elaborate on metabolic changes for macrophages, neutrophils, vascular endothelial cells, vascular smooth muscle cells and lymphocytes in the context of atherosclerosis and its co-morbidities hypertension, dyslipidemia, and diabetes. Since causal relationships of specific key genes in a metabolic pathway can be cell type-specific and comorbidity-dependent, the impact of cell-specific metabolic changes must be thoroughly explored in vivo, with a focus on also systemic effects. When cell-specific treatments become feasible, this information will be crucial for determining the best metabolic intervention to improve atherosclerosis and its interplay with co-morbidities.

Nonalcoholic fatty liver disease (NAFLD) is a serious threat to public health, but its underlying mechanism remains poorly understood. In screening important genes using Gene Importance Calculator (GIC) we developed previously, ribosomal modification protein rimK-like family member A (RIMKLA) was predicted as one essential gene but its functions remained largely unknown. The current study determined the roles of RIMKLA in regulating glucose and lipid metabolism. RIMKLA expression was reduced in livers of human and mouse with NAFLD. Hepatic RIMKLA overexpression ameliorated steatosis and hyperglycemia in obese mice. Hepatocyte-specific RIMKLA knockout aggravated high-fat diet (HFD)-induced dysregulated glucose/lipid metabolism in mice. Mechanistically, RIMKLA is a new protein kinase that phosphorylates betaine-homocysteine S-methyltransferase 1 (BHMT1) at threonine 45 (Thr45) site. Upon phosphorylation at Thr45 and activation, BHMT1 eliminated homocysteine (Hcy) to inhibit the activity of transcription factor activator protein 1 (AP1) and its induction on fatty acid synthase (FASn) and cluster of differentiation 36 (CD36) gene transcriptions, concurrently repressing lipid synthesis and uptake in hepatocytes. Thr45 to alanine (T45A) mutation inactivated BHMT1 to abolish RIMKLA's repression on Hcy level, AP1 activity, FASn/CD36 expressions, and lipid deposition. BHMT1 overexpression rescued the dysregulated lipid metabolism in RIMKLA-deficient hepatocytes. In summary, RIMKLA is a novel protein kinase that phosphorylates BHMT1 at Thr45 to repress lipid synthesis and uptake. Under obese condition, inhibition of RIMKLA impairs BHMT1 activity to promote hepatic lipid deposition.

The etiology of Alzheimer's disease (AD) is multifactorial. The most important challenge of research is the identification of potential biomarkers associated with AD pathogenesis that may significantly contribute to early diagnosis of the disease. We aim to explore an eventual association of the C677T and A1298C genetic polymorphisms in the MTHFR gene with AD risk in an Algerian population.

This case-control study involved comparing a group of 106 patients that had developed AD to another group of 104 non-demented individuals. The MTHFR genotypes were determined using PCR-RFLP method. Additionally, the homocysteine level was evaluated.

Genotypes analysis did not show an association for both MTHFR677CT and 677TT variants with AD risk (OR = 1.12; p = 0.66; OR = 1.76; p = 0.09) respectively. As expected, the 677CC wild type genotype showed a protective role against AD (OR = 0.52; p = 0.03). For 1298AC MTHFR variant, the distribution of different genotypes did not show a statistical significant difference between the two cohorts. However the silmutaneous carrier, CT/AC presented association with AD (OR = 5.96; p = 0.05). On the other hand, carrier-state of MTHFR T allele showed a relationship with AD (OR = 1.98; p = 0.02). Additionally, hyperhomocysteinemia seems to be a risk factor for AD (OR = 1.08; p = 0.02).

Our exploration reveals that the silmutaneous carrier, CT/AC, carrier-state of MTHFR T allele, and hyperhomocysteinemia seem to be risk factors for AD.

Homocysteine (Hcy) is a sulphur-containing nonessential amino acid derived from the intermediate metabolites of methionine. Methionine is obtained from dietary proteins, such as poultry, meat, eggs, seafood, and dairy products. Abnormalities in Hcy metabolic pathways, deficiencies in dietary methionine, folate, and vitamins B12, B6, and B2 and genetic defects, polymorphisms, or mutations in Hcy metabolism-related enzymes may lead to an increase in plasma Hcy levels. Generally, a plasma Hcy level higher than 10 or 15 μmol/L has been defined as hyperhomocysteinemia (HHcy). An individual with essential hypertension complicated with HHcy is considered to have H-type hypertension (HTH). Currently, HHcy is considered a novel independent risk factor for various cardiovascular diseases. To provide a useful reference for clinicians, the research progress on Hcy, HHcy, and HTH in recent years was systematically reviewed here, with a focus on the source and metabolic pathways of Hcy, plasma Hcy levels and influencing factors, detection methods for plasma Hcy levels, relationship between Hcy concentration and hypertension, pathogenesis of HTH, cardiovascular complications of HTH, and treatment of HTH.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and repetitive behaviors. Metabolomic profiling has emerged as a valuable tool for understanding the underlying metabolic dysregulations associated with ASD.

To comprehensively explore metabolomic changes in children with ASD, integrating findings from various research articles, reviews, systematic reviews, meta-analyses, case reports, editorials, and a book chapter.

A systematic search was conducted in electronic databases, including PubMed, PubMed Central, Cochrane Library, Embase, Web of Science, CINAHL, Scopus, LISA, and NLM catalog up until January 2024. Inclusion criteria encompassed research articles (83), review articles (145), meta-analyses (6), systematic reviews (6), case reports (2), editorials (2), and a book chapter (1) related to metabolomic changes in children with ASD. Exclusion criteria were applied to ensure the relevance and quality of included studies.

The systematic review identified specific metabolites and metabolic pathways showing consistent differences in children with ASD compared to typically developing individuals. These metabolic biomarkers may serve as objective measures to support clinical assessments, improve diagnostic accuracy, and inform personalized treatment approaches. Metabolomic profiling also offers insights into the metabolic alterations associated with comorbid conditions commonly observed in individuals with ASD.

Integration of metabolomic changes in children with ASD holds promise for enhancing diagnostic accuracy, guiding personalized treatment approaches, monitoring treatment response, and improving outcomes. Further research is needed to validate findings, establish standardized protocols, and overcome technical challenges in metabolomic analysis. By advancing our understanding of metabolic dysregulations in ASD, clinicians can improve the lives of affected individuals and their families.

Blood homocysteine (Hcy) level has become a sensitive indicator in predicting the development of cardiovascular disease. Studies have shown an association between individual mineral intake and blood Hcy levels. The effect of mixed minerals' intake on blood Hcy levels is unknown.

Data were obtained from the baseline survey data of the Shanghai Suburban Adult Cohort and Biobank(SSACB) in 2016. A total of 38273 participants aged 20-74 years met our inclusion and exclusion criteria. Food frequency questionnaire (FFQ) was used to calculate the intake of 10 minerals (calcium, potassium, magnesium, sodium, iron, zinc, selenium, phosphorus, copper and manganese). Measuring the concentration of Hcy in the morning fasting blood sample. Traditional regression models were used to assess the relationship between individual minerals' intake and blood Hcy levels. Three machine learning models (WQS, Qg-comp, and BKMR) were used to the relationship between mixed minerals' intake and blood Hcy levels, distinguishing the individual effects of each mineral and determining their respective weights in the joint effect.

Traditional regression model showed that higher intake of calcium, phosphorus, potassium, magnesium, iron, zinc, copper, and manganese was associated with lower blood Hcy levels. Both Qg-comp and BKMR results consistently indicate that higher intake of mixed minerals is associated with lower blood Hcy levels. Calcium exhibits the highest weight in the joint effect in the WQS model. In Qg-comp, iron has the highest positive weight, while manganese has the highest negative weight. The BKMR results of the subsample after 10,000 iterations showed that except for sodium, all nine minerals had the high weights in the joint effect on the effect of blood Hcy levels.

Overall, higher mixed mineral's intake was associated with lower blood Hcy levels, and each mineral contributed differently to the joint effect. Future studies are available to further explore the mechanisms underlying this association, and the potential impact of mixed minerals' intake on other health indicators needs to be further investigated. These efforts will help provide additional insights to deepen our understanding of mixed minerals and their potential role in health maintenance.

Homocysteine (Hcy) is an independent cardiovascular disease (CVD) risk factor, whose mechanisms are poorly understood. We aimed to explore mild hyperhomocysteinemia (HHcy) effects on oxidative status, inflammatory, and cholinesterase parameters in aged male Wistar rats (365 days old). Rats received subcutaneous Hcy (0.03 μmol/g body weight) twice daily for 30 days, followed by euthanasia, blood collection and heart dissection 12 h after the last injection. Results revealed increased dichlorofluorescein (DCF) levels in the heart and serum, alongside decreased antioxidant enzyme activities (superoxide dismutase, catalase, glutathione peroxidase), reduced glutathione (GSH) content, and diminished acetylcholinesterase (AChE) activity in the heart. Serum butyrylcholinesterase (BuChE) levels also decreased. Furthermore, nuclear factor erythroid 2-related factor 2 (Nrf2) protein content decreased in both cytosolic and nuclear fractions, while cytosolic nuclear factor kappa B (NFκB) p65 increased in the heart. Additionally, interleukins IL-1β, IL-6 and IL-10 showed elevated expression levels in the heart. These findings could suggest a connection between aging and HHcy in CVD. Reduced Nrf2 protein content and impaired antioxidant defenses, combined with inflammatory factors and altered cholinesterases activity, may contribute to understanding the impact of Hcy on cardiovascular dynamics. This study sheds light on the complex interplay between HHcy, oxidative stress, inflammation, and cholinesterases in CVD, providing valuable insights for future research.

The risk of venous thromboembolism in patients with mental illness has been insufficiently addressed. This study aimed to assess the correlation between hyperhomocysteinemia and venous thromboembolism prevalence among this population.

Patients with a diagnosis of mental illness and concurrent venous thromboembolism, admitted to Sir Run Run Shaw Hospital at Zhejiang University School of Medicine between January 2014 and December 2021, were included in the venous thromboembolism group. The control group, approximately twice the size, comprised individuals with mental illness but without venous thromboembolism. Basic clinical data were gathered for both cohorts.

In psychiatric patients, elevated D-dimer levels(OR=5.60,95% CI 3.28-10.00), hyperhomocysteinemia (OR=2.37,95% CI 1.10-5.14), and hyperprolactinemia(OR= 2.68,95% CI 1.12-6.42)were significant risk factors for venous thromboembolism. According to further subgroup analyses, hyperhomocysteinemia is a significant risk factor associated with pulmonary embolism, with an OR of 5.08 (95% CI 1.20-21.48). An interaction effect between gender and homocysteine level was found, with a p-interaction of 0.022. A subsequent analysis confirmed the association between hyperhomocysteinemia and venous thromboembolism in female psychiatric patients, with an OR of 3.34 (95% CI 1.68-6.65), indicating that hyperhomocysteinemia is a significant risk factor for venous thromboembolism in women.

Patients with psychiatric disorders were found to have an elevated risk of venous thromboembolism, which was associated with increased levels of D-dimer, hyperprolactinemia, and hyperhomocysteinemia. A strong correlation between hyperhomocysteinemia and pulmonary embolism was identified in patients with mental illnesses. Furthermore, the study revealed that female psychiatric patients with hyperhomocysteinemia constituted a high-risk group for venous thromboembolism. This finding holds significant clinical implications, suggesting that early preventative measures could be implemented for this high-risk population to reduce the incidence of thromboembolic events during hospitalization for psychiatric patients.

Alterations in the level of neurotransmitters are evident in patients with major depressive disorder (MDD). Vitamin B12 mediates the synthesis of neurotransmitters, and hence, vitamin B12 deficiency could be associated with depression.

To assess the levels of serum vitamin B12, homocysteine (Hcy), and haematological profiles in patients of MDD.

Fifty-nine patients with MDD were recruited based on ICD-10 criteria. Severity of depression was assessed by HAM-D scale. Vitamin B12, Hcy levels, and haematological profiles were analysed.

Vitamin B12 was deficient or depleted in all patients with MDD. The median level of vitamin B12 in serum was 164.2 pg./ml and significantly lower in patients with severe MDD. The mean value of Hcy was 18.34 μmol/L, which was high compared to the normal reference range. The red cell distribution width (RDW-CV) varied significantly between the three groups of MDD patients. Patients consuming non-vegetarian food had a significantly higher median value of serum vitamin B12.

Vitamin B12 deficiency is found in patients with MDD and varies inversely with severity of MDD. Hcy is found to be higher in patients with MDD. The manifestation of depressive symptoms precedes the more commonly known haematological manifestations of vitamin B12 deficiency in this study.

Investigation of chronic homocysteine action on the excitability and N-methyl-D-aspartate (NMDA) sensitivity of the peripheral trigeminovascular system of rats.

Migraine is a neurological disease that affects 15%-20% of the general population. Epidemiological observations show that an increase of the sulfur-containing amino acid homocysteine in plasma-called hyperhomocysteinemia-is associated with a high risk of migraine, especially migraine with aura. In animal studies, rats with hyperhomocysteinemia demonstrated mechanical allodynia, photophobia, and anxiety, and higher sensitivity to cortical spreading depression. In addition, rats with hyperhomocysteinemia were more sensitive in a model of chronic migraine induced by nitroglycerin which indicated the involvement of peripheral nociceptive mechanisms. The present work aimed to analyze the excitability of meningeal afferents and neurons isolated from the trigeminal ganglion of rats with prenatal hyperhomocysteinemia.

Experiments were performed on male rats born from females fed with a methionine-rich diet before and during pregnancy. The activity of meningeal afferents was recorded extracellularly in hemiskull preparations ex vivo and action potentials were characterized using cluster analysis. The excitability of trigeminal ganglion neurons was assessed using whole-cell patch clamp recording techniques and calcium imaging studies. Meningeal mast cells were stained using toluidine blue.

The baseline extracellular recorded electrical activity of the trigeminal nerve was higher in the hyperhomocysteinemia group with larger amplitude action potentials. Lower concentrations of KCl caused an increase in the frequency of action potentials of trigeminal afferents recorded in rat hemiskull ex vivo preparations. In trigeminal ganglion neurons of rats with hyperhomocysteinemia, the current required to elicit at least one action potential (rheobase) was lower, and more action potentials were induced in response to stimulus of 2 × rheobase. In controls, short-term application of homocysteine and its derivatives increased the frequency of action potentials of the trigeminal nerve and induced Ca2+ transients in neurons, which are associated with the activation of NMDA receptors. At the same time, in rats with hyperhomocysteinemia, we did not observe an increased response of the trigeminal nerve to NMDA. Similarly, the parameters of Ca2+ transients induced by NMDA, homocysteine, and its derivatives were not changed in rats with hyperhomocysteinemia. Acute incubation of the meninges in homocysteine and homocysteinic acid did not change the state of the mast cells, whereas in the model of hyperhomocysteinemia, an increased degranulation of mast cells in the meninges was observed.

Our results demonstrated higher excitability of the trigeminal system of rats with hyperhomocysteinemia. Together with our previous finding about the lower threshold of generation of cortical spreading depression in rats with hyperhomocysteinemia, the present data provide evidence of homocysteine as a factor that increases the sensitivity of the peripheral migraine mechanisms, and the control of homocysteine level may be an important strategy for reducing the risk and/or severity of migraine headache attacks.

Aromatic l-amino acid decarboxylase deficiency (AADC-DY) is caused by one or more mutations in the DDC gene, resulting in the deficit in catecholamines and serotonin neurotransmitters. The disease has limited therapeutic options with relatively poor clinical outcomes. Accumulated evidence suggests the involvement of neurodegenerative mechanisms in the etiology of AADC-DY. In the absence of neurotransmitters' neuroprotective effects, the accumulation and the chronic presence of several neurotoxic metabolites including 4-dihydroxy-L-phenylalanine, 3-methyldopa, and homocysteine, in the brain of subjects with AADC-DY, promote oxidative stress and reduce the cellular antioxidant and methylation capacities, leading to glial activation and mitochondrial dysfunction, culminating to neuronal injury and death. These pathophysiological processes have the potential to hinder the clinical efficacy of treatments aimed at increasing neurotransmitters' synthesis and or function. This review describes in detail the mechanisms involved in AADC-DY neurodegenerative etiology, highlighting the close similarities with those involved in other neurodegenerative diseases. We then offer novel strategies for the treatment of the disease with the objective to either reduce the level of the metabolites or counteract their prooxidant and neurotoxic effects. These treatment modalities used singly or in combination, early in the course of the disease, will minimize neuronal injury, preserving the functional integrity of neurons, hence improving the clinical outcomes of both conventional and unconventional interventions in AADC-DY. These modalities may not be limited to AADC-DY but also to other metabolic disorders where a specific mutation leads to the accumulation of prooxidant and neurotoxic metabolites.

An increased homocysteine level is a risk factor for cardiovascular disease, venous thromboembolism, cerebrovascular disease, and chronic kidney disease. In addition, vitamin D deficiency is associated with coronary artery disease and metabolic disorders. The present study included data from 1375 adults (895 men and 480 women) with a mean age of 52.62 ± 9.94 years who visited the Health Promotion Center of the University Hospital in Gyeonggi-do, Republic of Korea from January 2018 to December 2022 for routine checkups that included assessments of their homocysteine and vitamin D levels. Homocysteine levels were positively associated with age, a history of hypertension, a history of diabetes, current smoking habits, and levels of low-density lipoprotein cholesterol, creatinine, uric acid, and high-sensitivity C-reactive protein. By contrast, vitamin D levels were negatively associated with serum levels of homocysteine after adjusting for covariates (β = -0.033, p < 0.001). Additional long-term prospective studies are needed to elucidate the presence of a causal relationship between vitamin D status and serum levels of homocysteine in asymptomatic Korean adults. An intervention trial is warranted to determine whether the administration of vitamin D is helpful for the primary prevention of cardiovascular disease by lowering the homocysteine level in this population.

In the present study, we investigated the effects of N-homocysteine thiolactone (tHcy) modification on expressed and purified tau protein and the synthesized VQIVYK target peptide. The modified constructs were subjected to comprehensive validation using various methodologies, including mass spectrometry. Subsequently, in vivo, in vitro, and in silico characterizations were performed under both reducing and non-reducing conditions, as well as in the presence and absence of heparin as a cofactor. Our results unequivocally confirmed that under reducing conditions and in the presence of heparin, the modified constructs exhibited a greater propensity for aggregation. This enhanced aggregative behavior can be attributed to the disruption of lysine positive charges and the subsequent influence of hydrophobic and p-stacking intermolecular forces. Notably, the modified oligomeric species induced apoptosis in the SH-SY5Y cell line, and this effect was further exacerbated with longer incubation times and higher concentrations of the modifier. These observations suggest a potential mechanism involving reactive oxygen species (ROS). To gain a deeper understanding of the molecular mechanisms underlying the neurotoxic effects, further investigations are warranted. Elucidating these mechanisms will contribute to the development of more effective strategies to counteract aggregation and mitigate neurodegeneration.

Vascular dementia (VaD) is the second most common type of dementia. VaD is synonymous with ageing, and its symptoms place a significant burden on the health and wellbeing of older people. Despite the identification of a substantial number of risk factors for VaD, the pathological mechanisms underpinning this disease remain to be fully elucidated. Consequently, a biogerontological imperative exists to highlight the modifiable lifestyle factors which can mitigate against the risk of developing VaD. This review will critically examine some of the factors which have been revealed to modulate VaD risk. The survey commences by providing an overview of the putative mechanisms which are associated with the pathobiology of VaD. Next, the factors which influence the risk of developing VaD are examined. Finally, emerging treatment avenues including epigenetics, the gut microbiome, and pro-longevity pharmaceuticals are discussed. By drawing this key evidence together, it is our hope that it can be used to inform future experimental investigations in this field.

Chronic total coronary occlusion is among the most complex coronary artery diseases. Elevated homocysteine is a risk factor for coronary artery diseases. However, few studies have assessed the relationship between homocysteine and chronic total coronary occlusion.

1295 individuals from Southwest China were enrolled in the study. Chronic total coronary occlusion was defined as complete occlusion of coronary artery for more than three months. Homocysteine was divided into quartiles according to its level. Univariate and multivariate logistic regression models, receiver operating characteristic curves, and subgroup analysis were applied to assess the relationship between homocysteine and chronic total coronary occlusion.

Subjects in the higher homocysteine quartile had a higher rate of chronic total coronary occlusion (P < 0.001). After adjustment, the odds ratio for chronic total coronary occlusion in the highest quartile of homocysteine compared with the lowest was 1.918 (95% confidence interval 1.237-2.972). Homocysteine ≥ 15.2 μmol/L was considered an independent indicator of chronic total coronary occlusion (odds ratio 1.53, 95% confidence interval 1.05-2.23; P = 0.0265). The area under the receiver operating characteristic curve was 0.659 (95% confidence interval, 0.618-0.701; P < 0.001). Stronger associations were observed in elderly and in those with hypertension and diabetes.

Elevated homocysteine is significantly associated with chronic total coronary occlusion, particularly in elderly and those with hypertension and diabetes.

This case report discusses the intricate diagnostic and therapeutic challenges faced by a 23-year-old Indian male who presented with altered consciousness, a holo-cranial headache, right-sided hemiparesis, and subsequent neurological symptoms. The patient's dietary habits, leading to vitamin B12 and folic acid deficiencies resulting in hyperhomocysteinemia, along with binge alcohol drinking leading to dehydration, were identified as the main causes of cerebral venous sinus thrombosis (CVST) in this case. The case was complicated by an additional cerebral hemorrhage. The patient received a comprehensive treatment regimen involving antiepileptic medications, intravenous fluids, and anticoagulation therapy. A decline in the Glasgow Coma Scale score prompted further interventions. Collaborative decision-making, involving neurologists, neurosurgeons, and the patient's relatives, steered the treatment course, ultimately favoring continued medical management over decompression surgery. Notably, the patient exhibited remarkable progress in mobility, achieving the ability to walk with support by the end. This case report contributes valuable insights to the understanding of CVST, emphasizing the significance of nutritional considerations, especially in vegetarians, and underscoring the importance of thorough diagnostic evaluations in complex clinical scenarios.

Manic depressive psychosis (MDP) or bipolar disorder, a prevalent psychiatric condition globally and in the Indian population, has been attributed to various pathological mechanisms. Hydrogen sulphide (H2S), a member of the gasotransmitter family, may be linked to the development of bipolar disorder because it plays a crucial role in maintaining proper neuronal function in terms of excitability, plasticity, and homeostatic functions. There is very little data regarding the role of the gasotransmitter H2S in MDP in terms of its association, diagnostic ability, and severity prediction, which led us to conduct this study among MDP patients in the Sub-Himalayan region of West Bengal.

This was an observational case-control study performed in the Department of Biochemistry, North Bengal Medical College and Hospital, Siliguri, West Bengal, India, from January 2022 to December 2022. Fifty diagnosed MDP patients and 50 healthy age- and sex-matched control subjects satisfying the inclusion and exclusion criteria were studied. The H2S level in the blood was assayed using the standardised spectrophotometric methylene blue method. The severity of depression was assessed by Hamilton Depression Rating Scale (HAM-D) scoring.

Of the 50 MDP patients, 45 (90%) were in the depressive phase, and five (10%) were in the manic phase. Of the 45 depressive patients, eight (17.8%) had mild depression, 12 (26.7%) had moderate depression, 19 (42.2%) had severe depression, and six (13.3%) had very severe depression. The mean H2S level in MDP patients (41.98±18.88 μmol/l) was significantly (P<0.05) lower than that in control subjects (99.20± 15.20 μmol/l). It was also observed that the mean H2S level in MDP patients decreased with the duration of the disease but was not statistically significant. The mean H2S levels in the different depression severity groups were found to be significantly different (P<0.001). Receiver operating characteristic (ROC) curve analysis revealed that a cut-off value of H2S <78.5 μmol/l was associated with MDP, with a sensitivity of 96% and a specificity of 88%, and a cut-off value of H2S < 53 μmol/l predicted the severity of depression with a sensitivity of 89.3% and a specificity of 76.5%.

The significant association of the gasotransmitter H2S in MDP patients and its role as a diagnostic and severity predictive marker can help us to employ proper measures for better management of MDP and improving quality of life.

Background: In the antiretroviral therapy (ART) era, HIV-associated neurocognitive disorders (HAND) remain a considerable challenge for people with HIV, yet not all such disorders can be attributed to HIV alone. This study aimed to: (1) identify factors influencing neurocognitive impairment (NCI) utilizing the NIH Toolbox Cognition Battery (NIHTB-CB) as per the revised research criteria for HAND; (2) ascertain the moderating role of high homocysteine levels in the association between NCI and HIV; and (3) assess the mediating effect of elevated homocysteine levels on this association.Methods: We analyzed data from 788 adults (≥45 years) participating in a study on HIV-related comorbidities in underserved Baltimore communities, using NIHTB-CB to gauge neurocognitive performance. Special attention was given to results from the Dimensional Change Card Sort (DCCS) test within the executive function domain during causal mediation analysis.Results: Overall, HIV was not associated with NCI presence. However, HIV was associated with NCI among individuals with homocysteine >14 μmol/L. Furthermore, HIV was both directly and indirectly associated with NCI in DCCS test scores. Notably, the mediating role of elevated homocysteine in DCCS scores was only observable among individuals who had never used cocaine or had used it for ≤ 10 years, suggesting that extended cocaine use may have a substantial influence on cognitive performance.Conclusions: The findings from this study suggest elevated homocysteine levels may moderate and mediate the association between HIV and neurocognitive impairment.

The aim of this study was to investigate the effects of aerobic treadmill training regimen of four weeks duration on oxidative stress parameters, metabolic enzymes, and histomorphometric changes in the colon of hyperhomocysteinemic rats. Male Wistar albino rats were divided into four groups (n = 10, per group): C, 0.9% NaCl 0.2 mL/day subcutaneous injection (s.c.) 2x/day; H, homocysteine 0.45 µmol/g b.w./day s.c. 2x/day; CPA, saline (0.9% NaCl 0.2 mL/day s.c. 2x/day) and an aerobic treadmill training program; and HPA, homocysteine (0.45 µmol/g b.w./day s.c. 2x/day) and an aerobic treadmill training program. The HPA group had an increased level of malondialdehyde (5.568 ± 0.872 μmol/mg protein, p = 0.0128 vs. CPA (3.080 ± 0.887 μmol/mg protein)), catalase activity (3.195 ± 0.533 U/mg protein, p < 0.0001 vs. C (1.467 ± 0.501 U/mg protein), p = 0.0012 vs. H (1.955 ± 0.293 U/mg protein), and p = 0.0003 vs. CPA (1.789 ± 0.256 U/mg protein)), and total superoxide dismutase activity (9.857 ± 1.566 U/mg protein, p < 0.0001 vs. C (6.738 ± 0.339 U/mg protein), p < 0.0001 vs. H (6.015 ± 0.424 U/mg protein), and p < 0.0001 vs. CPA (5.172 ± 0.284 U/mg protein)) were detected in the rat colon. In the HPA group, higher activities of lactate dehydrogenase (2.675 ± 1.364 mU/mg protein) were detected in comparison to the CPA group (1.198 ± 0.217 mU/mg protein, p = 0.0234) and higher activities of malate dehydrogenase (9.962 (5.752-10.220) mU/mg protein) were detected in comparison to the CPA group (4.727 (4.562-5.299) mU/mg protein, p = 0.0385). Subchronic treadmill training in the rats with hyperhomocysteinemia triggers the colon tissue antioxidant response (by increasing the activities of superoxide dismutase and catalase) and elicits an increase in metabolic enzyme activities (lactate dehydrogenase and malate dehydrogenase). This study offers a comprehensive assessment of the effects of aerobic exercise on colonic tissues in a rat model of hyperhomocysteinemia, evaluating a range of biological indicators including antioxidant enzyme activity, metabolic enzyme activity, and morphometric parameters, which suggested that exercise may confer protective effects at both the physiological and morphological levels.

Alzheimer's Disease (AD) is a multifactorial neurodegenerative disease and there is still no definitive treatment today. Early diagnosis of the disease is important, but there are almost no biomarkers that can be used in early diagnosis. The cerebrospinal fluid used in the diagnosis of the disease is not sufficient and is very difficult to obtain. Therefore, blood biomarkers that are less costly, less invasive, easily accessible, and can be used in long-term studies would be a better alternative. The aim of this study is to determine the relationship between Alzheimer's Disease and P301L MAPT gene mutation, homocysteine, folate and uric acid. 101 Alzheimer's patients and 101 healthy individuals were included in this study. Mutation analysis was performed using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method with blood samples taken from the subjects. There was no significant difference between the patient and control groups in terms of homocysteine (p = 0.771), folate (p = 0.366) and uric acid (p = 0.860). When the genotypes were compared between the patient and control groups in terms of MAPT gene mutation (P301L), no statistically significant difference was detected (p = 0.081). There are very few studies in the literature investigating the relationship between Alzheimer's disease and P301L MAPT gene mutation. Additionally, there is no study investigating the relationship between Alzheimer's disease and homocysteine, folate, uric acid and P301L MAPT mutation in the Turkish population. We believe that this study has shed light on future studies.

There is very few data regarding homocysteine's influence on the formation and rupture of intracranial aneurysms.

To compare homocysteine levels between patients with ruptured and unruptured intracranial aneurysms, and to evaluate possible influences of this molecule on vasospasm and functional outcomes.

This is a retrospective, case-control study. We evaluated homocysteinemia differences between patients with ruptured and unruptured aneurysms; and the association of homocysteine levels with vasospasm and functional outcomes. Logistic regressions were performed.

A total of 348 participants were included: 114 (32.8%) with previous aneurysm rupture and 234 (67.2%) with unruptured aneurysms. Median homocysteine was 10.75µmol/L (IQR = 4.59) in patients with ruptured aneurysms and 11.5µmol/L (IQR = 5.84) in patients with unruptured aneurysms. No significant association was detected between homocysteine levels and rupture status (OR = 0.99, 95% CI = 0.96-1.04). Neither mild (>15µmol/L; OR = 1.25, 95% CI 0.32-4.12) nor moderate (>30µmol/L; OR = 1.0, 95% CI = 0.54-1.81) hyperhomocysteinemia demonstrated significant correlations with ruptured aneurysms. Neither univariate (OR = 0.86; 95% CI 0.71-1.0) nor multivariable age-adjusted (OR = 0.91; 95% CI = 0.75-1.05) models evidenced an association between homocysteine levels and vasospasm. Homocysteinemia did not influence excellent functional outcomes at 6 months (mRS≤1) (OR = 1.04; 95% CI = 0.94-1.16).

There were no differences regarding homocysteinemia between patients with ruptured and unruptured intracranial aneurysms. In patients with ruptured aneurysms, homocysteinemia was not associated with vasospasm or functional outcomes.