Homocysteine Metabolism Research Articles

The Influence of Atorvastatin Treatment on Homocysteine Metabolism and Oxidative Stress in an Experimental Model of Diabetic Rats

Objective: In our experimental study, we evaluated the influence of treatment with atorvastatin on the antioxidant activity of intracellular and extracellular systems factors, homocysteine levels (Hcy), and lipid profiles in obese and diabetic rats. Method: Twenty-one male Wistar rats, aged 6 months, 450–550 g, were allocated into three groups. From the beginning of the study, the first group (G-I, control) received only standard food, while the second and third groups (G II—obese, G III—diabetic) were administered a high-fat diet (HFD) with 2% cholesterol. After 2 weeks of accommodation, the specimens in G-III were injected intraperitoneal (i.p.) streptozotocin (35 mg of body weight, pH 4.5), intervention followed by the onset of type 2 diabetes mellitus. Following confirmation of diabetes onset, the specimens in G III were administered concomitantly with the HFD a daily gavage of atorvastatin 20 mg of body weight/day for 20 days. We measured, at the beginning and the end of the study, the Hcy levels, lipid profile, vitamin B12, B6, folic acid, and various parameters of oxidative stress (OS)—total antioxidant status (TAS), glutathione peroxidase (GPX) and superoxide dismutase (SOD). Results: After treatment with atorvastatin, the lipid profile in G III significantly improved compared to the other two groups, but enzymatic markers of oxidative stress did not closely parallel this trend. However, after the treatment of statin, we observed an important reduction in Hcy values. Conclusion: Our results demonstrate that treatment with atorvastatin can be used not only for its lipid-lowering properties and antioxidant effects but also to reduce Hcy concentration in this experimental model of diabetic rats. Moreover, atorvastatin therapy improves lipid profiles, reduces inflammation, suppresses oxidation, and decreases Hcy levels, potentially preventing major adverse cardiovascular events.

Hydrogen sulfide: A whiff of trouble for cancer cell survival

Hydrogen sulfide (H2S) can regulate biological processes by post-translational persulfidation of proteins at select cysteine residues. In this issue of Molecular Cell, Zheng etal.1 identify the enzyme SAHH as an H2S substrate, which upon persulfidation disrupts homocysteine metabolism and sensitizes lung cancer cells to ferroptosis.

Effects of four-week lasting aerobic treadmill training on hepatic injury biomarkers, oxidative stress parameters, metabolic enzymes activities and histological characteristics in liver tissue of hyperhomocysteinemic rats.

Disruptions in homocysteine (Hcy) metabolism may increase the liver's susceptibility to developing conditions such as alcoholic liver disease, viral hepatitis, hepatocellular carcinoma (HCC), and cirrhosis. The aim of this study was to examine effects of aerobic treadmill training on hepatic injury biomarkers in sera, oxidative stress parameters, the activity of metabolic enzymes, and histological characteristics in the liver tissue of rats with experimentally induced hyperhomocysteinemia. Male Wistar albino rats were divided into four groups (N = 10, per group): C-saline 0.2mL/day sc. 2×/day for 14days + saline 0.5mL ip.1×/day for 28days; H-homocysteine 0.45µmol/g b.w. 2×/day for 14days + saline 0.5mL ip.1×/day for 28days; CPA-saline 0.2mL/day sc. 2×/day for 14days + aerobic treadmill training for 28days; and HPA-homocysteine 0.45µmol/gb.w. 2×/day for 14days + aerobic treadmill training for 28days. The serum albumin concentration was decreased in both physically active (PA) groups compared to sedentary groups. Concentration of malondialdehyde in liver tissue homogenates was lower in both PA groups compared to the H group. The total lactate dehydrogenase and malate dehydrogenase activities were significantly elevated in the HPA group compared to the C and H groups. Activities of aminotransferases in sera samples, and activities of catalase and superoxide dismutase in liver tissue did not significantly differ between groups. No significant histological changes were found in liver tissue in groups. This study demonstrated that aerobic treadmill training can reduce lipid peroxidation in liver tissue under hyperhomocysteinemic conditions, providing a protective effect. However, hyperhomocysteinemia can alter energy metabolism during aerobic exercise, shifting it toward anaerobic pathways and leading to elevated lactate dehydrogenase activity in the liver. Given that conditions like hyperhomocysteinemia are associated with an increased risk of cardiovascular diseases and liver damage, understanding how exercise influences these dynamics could guide therapeutic approaches.

Serum Vitamin B12 Levels as a Risk Factor and Prognostic Marker in Patients With Acute Ischemic Stroke at a Tertiary Care Center in Northern India: A Case-Control Study.

Objective Stroke is a leading cause of death and disability globally, with its incidence, prevalence, and mortality rising significantly over the past decades. Beyond traditional risk factors, vitamin B12 has garnered attention for its role in stroke prevention due to its influence on homocysteine metabolism. Deficiencies in vitamin B12 are linked to hyperhomocysteinemia, which increases the risk of ischemic stroke. This study aims to compare vitamin B12 and homocysteine levels in stroke patients versus control subjects. Methodology This observational case-control study was conducted at King George's Medical University (KGMU), Lucknow, involving 75 acute ischemic stroke patients and 75 age- and sex-matched controls. Serum vitamin B12 and homocysteine levels were measured, and stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) score. The modified Rankin scale (MRS) evaluated functional outcomes at discharge. Statistical analysis was performed to identify associations between vitamin B12 levels, stroke severity, and patient outcomes. Results Stroke patients had significantly lower vitamin B12 levels (194.24 ± 91.11 pmol/L) and higher homocysteine levels (16.33 ± 3.29 µmol/L) compared to controls (271.13 ± 91.19 pmol/L and 9.76 ± 4.55 µmol/L, respectively). Vitamin B12 levels were lower, and homocysteine levels were higher in patients who died during the study. Additionally, vitamin B12 levels were negatively correlated with MRS scores at discharge and 28 days post-discharge, and positively correlated with NIHSS scores, indicating worse outcomes in patients with lower vitamin B12 levels. Conclusions This study demonstrates a significant association between vitamin B12 deficiency and the occurrence and severity of ischemic stroke. Lower vitamin B12 levels correlated with higher stroke severity and poorer functional outcomes, highlighting the potential role of vitamin B12 in stroke management. Further research is needed to explore the therapeutic implications of vitamin B12 supplementation in reducing stroke risk and improving patient outcomes.

Hydrogen sulfide-mediated persulfidation regulates homocysteine metabolism and enhances ferroptosis in non-small cell lung cancer

Hydrogen sulfide (H₂S), a metabolite of the transsulfuration pathway, has been implicated in ferroptosis, a unique form of cell death caused by lipid peroxidation. While the exact mechanisms controlling ferroptosis remain unclear, our study reveals that H₂S sensitizes human non-small cell lung cancer (NSCLC) cells to this process, particularly when cysteine levels are low. Combining H₂S with cystine depletion significantly enhances the effectiveness of ferroptosis-based cancer therapy. Mechanistically, H₂S persulfidates the 195th cysteine on S-adenosyl homocysteine hydrolase (SAHH), reducing its enzymatic activity. This leads to decreased homocysteine levels, subsequently lowering cysteine and glutathione concentrations under cystine depletion conditions. These changes ultimately increase the vulnerability of NSCLC cells to ferroptosis. Our findings establish H₂S as a key regulator of homocysteine metabolism and a critical factor in determining NSCLC cell susceptibility to ferroptosis. These results highlight the potential of H₂S-based therapies to improve the efficacy of ferroptosis-targeted cancer treatments for NSCLC.

Relationship between Sources of Dietary Fiber Intake and Homocysteine Metabolism in Relation to Serum Homocysteine Concentrations

While homocysteine is produced as an intermediate metabolite during methionine metabolism, increased blood homocysteine levels are associated with various diseases. In a previous cross-sectional study, we reported a significant negative association between the serum concentrations of homocysteine in 227 young women and their dietary fiber intake. In the present study, we examined the relationship between dietary fiber intake from food sources and serum levels of homocysteine and its metabolites. Homocysteine and its metabolites 5-methyltetrahydrofolate (5MTHF), cystathionine, glycine, methionine, and S-adenosyl-methionine were measured using LC-MS/MS. The soluble, insoluble, and total fiber intake from fruits and mushrooms was significantly inversely correlated with the homocysteine concentrations. Furthermore, the soluble, insoluble, and total fiber intake from fruits was significantly positively associated with the serum 5MTHF concentrations, while the fiber intake from mushrooms was positively correlated with the cystathionine concentration and negatively correlated with the methionine and glycine concentrations. These results suggest that ingesting dietary fiber in the form of fruits and mushrooms maintains a low concentration of homocysteine by activating two different homocysteine-scavenging metabolic pathways.

Exploring the association of hyperhomocysteinemia with early pregnancy losses: A retrospective case-control study in a tertiary clinic in Türkiye.

A disturbance in the metabolism of homocysteine in both the mother and the fetus has been implicated in several placental vasculopathy-related disorders, including pregnancy loss. This study aimed to provide insights into the potential role of homocysteine, Vitamin B12, and folic acid in early pregnancy losses, with a specific focus on the Turkish population. The results of 93 pregnant women who experienced miscarriage between 5 and 14 gestational weeks and 93 healthy pregnant women at the same gestational weeks were compared. The demographic and pregnancy characteristics of all pregnant women were recorded. Vitamin B12, folic acid, and homocysteine levels were measured in serum samples obtained from the groups at similar gestational weeks. In addition, any associations between these biomarkers and different types of pregnancy loss, such as spontaneous abortion and missed abortion, were evaluated. Vitamin B12 and folic acid serum levels were significantly lower in women with miscarriages (P = .019, P < .001, respectively). Homocysteine levels were higher in the patient group (P < .001). Logistic regression analysis showed that a higher homocysteine level was the only predictive factor of miscarriage (P = .001, odds ratio = 0.596); however, folic acid and Vitamin B12 were not predictive factors. There was no significant difference in homocysteine and micronutrient levels between women with missed abortions and women with spontaneous abortions (P > .05). Our results support the continuing evidence of a link between maternal homocysteine levels and fetal loss. However, in exploring the shared pathways in the underlying mechanisms causing the 2 forms of pregnancy loss, maternal blood analysis showed no relationship.

Vitamin B12 (cobalamin) deficiency in gastroenterological diseases - review

Introduction: Vitamin B12 is a water-soluble vitamin found primarily in animal-derived products such as red meat, dairy, and eggs. An essential substance for its absorption is the intrinsic factor, produced by the parietal cells of the stomach. After absorption in the distal ileum, cobalamin acts as a coenzyme in DNA synthesis and the metabolism of fatty acids and homocysteine. In addition to its well-known influence on the nervous system, it has been associated with gastrointestinal diseases according to numerous authors. Objective: The objective of this study is to gather and analyze literature regarding the associations between vitamin B12 deficiency and gastrointestinal diseases, including gastroesophageal reflux disease (GERD), gastritis, inflammatory bowel disease (IBD), small intestinal bacterial overgrowth (SIBO), and hepatitis C (HCV). Materials and Methods: A literature review was conducted using the PubMed database with the following search terms: vitamin B12, cobalamin, deficiency, gastrointestinal diseases, GERD, IBD, SIBO, HCV. Current Knowledge: Vitamin B12 deficiency can be caused by autoimmune factors, dietary insufficiencies, toxin exposure, and malabsorption disorders related to gastrointestinal diseases. Gastrointestinal conditions such as GERD and IBD can both lead to and be exacerbated by cobalamin deficiency. Furthermore, vitamin B12 deficiency may be worsened by prolonged use of proton pump inhibitors (PPIs) and Helicobacter pylori infection. Conclusions: An adequate amount of vitamin B12 is crucial for gastrointestinal health. Deficiency can significantly impact the course and symptoms of many gastrointestinal diseases. Therefore, monitoring and supplementation of vitamin B12 should be an integral part of managing patients with gastrointestinal conditions.

THE ROLE OF FOLATE, VITAMIN B12 AND B6 IN HYPERHOMOCYSTEINEMIA AS THE RISK FACTOR OF CARDIOVASCULAR DISEASE: NARRATIVE REVIEW

Cardiovascular disease (CVD), encompassing ailments affecting the heart and vascular system, is estimated to contribute to one-third of global mortality, and its prevalence is continuously rising. The etiology of this condition is multifactorial, making it challenging to identify a singular causative factor. Homocysteine, a factor identified in the 1990s, is known to contribute to the development of atherosclerotic vascular disease and hypercoagulability. Although there is a definite connection, the assessment and management of this condition are still a subject of debate due to inconsistent research findings on its impact in lowering the risk of cardiovascular disease. B vitamins are a collection of chemical compounds that play a crucial role in physiological function. However, the body does not produce them naturally and they need to be obtained from dietary intake. Vitamins B6, B9, and B12 are crucial in the metabolism of homocysteine. The cause of hyperhomocysteinemia is believed to be a deficiency of certain vitamins, particularly folate, B12, and B6, which are important for effectively recycling homocysteine in the methionine cycle. Vitamin B is intricately linked to both the homocysteine and cardiovascular disease (CVD) pathways.

Geographical distribution of MTHFR C677T gene polymorphisms among the reproductive-age women in Chinese Han populations: based on migration

BackgroundMethylenetetrahydrofolate reductase (MTHFR) is essential for the metabolism of folic acid and homocysteine. The MTHFR C677T polymorphism is associated with several disorders. Our study aims to explore the geographical distributions of the MTHFR C677T polymorphism of women in China and how migration affected the polymorphism in Suzhou.MethodsA total of 7188 women of reproductive age were recruited in Suzhou of the study. Subjects were classified according to their native places after data extraction. MTHFR C677T gene polymorphisms were detected by quantitative PCR with genomic DNA isolated from blood samples.ResultsThe frequencies of the 677T allele and 677TT genotype were higher in northern China than that in southern China and decreased in geographical gradients from north to south. The frequencies were considerably higher in the migrant population than that in the indigenous population of Suzhou. The migrant population have gradually changed the prevalence in Suzhou.ConclusionsOur study suggested that the prevalence of MTHFR C677T polymorphisms among women varied across different geographical regions in Chinese Han populations. The 677T allele frequencies of the northern populations were significantly higher than those of the southern populations. The migrant population gradually changed the prevalence of the MTHFR C677T polymorphism in Suzhou.

Homocysteine Metabolism, Subclinical Myocardial Injury, and Cardiovascular Mortality in the General Population

BackgroundHomocysteine (Hcy) is a recognized cardiovascular disease (CVD) risk factor linked with atherosclerosis. However, the association between Hcy and myocardial injury is little known. ObjectivesThis study aimed to examine the associations between Hcy metabolism, subclinical myocardial injury, and cardiovascular mortality. MethodsWe included 10,871 participants without diagnosed CVD. Generalized linear regression was used to investigate the relationship between Hcy-related indicators (plasma total Hcy [tHcy], vitamin B12, and folate) and myocardial injury biomarkers (high-sensitivity troponin T [hs-cTnT], high-sensitivity troponin I [hs-cTnI] measured using 3 assays [Abbott, Siemens, and Ortho], and N-terminal pro–B-type natriuretic peptide [NT-proBNP]). ResultsAmong 10,871 participants, the weighted mean levels for tHcy, folate, and vitamin B12 were 8.58 μmol/L, 32.43 nmol/L, and 447.08 pmol/L, respectively. Plasma tHcy levels were positively associated with elevated hs-cTnT, hs-cTnI, and NT-proBNP, whereas folate and vitamin B12 were not inversely related to myocardial injury biomarkers. Multivariable-adjusted odds ratios for elevated hs-cTnT (19 ng/L) and NT-proBNP (125 pg/mL) per doubling of tHcy were 2.80 (95% CI: 1.17-6.73; P < 0.001) and 1.58 (95% CI: 1.20-2.08; P < 0.001), respectively. The associations of tHcy levels with elevated hs-cTnI (Abbott: 28 ng/L; Siemens: 46.5 ng/L; Ortho: 11 ng/L) were consistent. Indirect effects of tHcy on cardiovascular mortality risk via hs-cTnT and NT-proBNP explained up to 26.6% and 12.3% of the total effect, respectively. ConclusionsPlasma tHcy, not folate or vitamin B12, is significantly associated with elevated hs-cTnT, hs-cTnI, and NT-proBNP in adults without CVD. Subclinical myocardial injury may substantially mediate Hcy-related cardiovascular mortality risk.

The role of nonesterified fatty acids in cancer biology: Focus on tryptophan and related metabolism

Plasma nonesterified fatty acids (NEFA) are elevated in cancer, because of decreased albumin levels and of fatty acid oxidation, and increased fatty acid synthesis and lipolysis. Albumin depletion and NEFA elevation maximally release albumin-bound tryptophan (Trp) and increase its flux down the kynurenine pathway, leading to increased production of proinflammatory kynurenine metabolites, which tumors use to undermine T-cell function and achieve immune escape. Activation of the aryl hydrocarbon receptor by kynurenic acid promotes extrahepatic Trp degradation by indoleamine 2,3-dioxygenase and leads to upregulation of poly (ADP-ribose) polymerase, activation of which and also of SIRT1 (silent mating type information regulation 2 homolog 1) could lead to depletion of NAD+ and ATP, resulting in cell death. NEFA also modulate heme synthesis and degradation, changes in which impact homocysteine metabolism and production of reduced glutathione and hydrogen sulphide. The significance of the interactions between heme and homocysteine metabolism in cancer biology has received little attention. Targeting Trp disposition in cancer to prevent the NEFA effects is suggested.

The different roles of homocysteine metabolism in hypertension among normal-weight and obese patients with obstructive sleep apnea

BackgroundObstructive sleep apnea (OSA) is associated with hypertension. However, the differential mechanisms underlying OSA-related hypertension between normal-weight vs. obese patients is limited. MethodsWe studied 92 patients with OSA and 24 patients with continuous positive airway pressure (CPAP) treatment. Blood pressure (BP) was measured twice during awake and continuously monitored during sleep. Obesity was defined as body mass index ≥28 kg/m2. Serum metabolite levels were assessed by metabolomics. ResultsAmong 59 normal-weight and 33 obese patients, 651 and 167 metabolites showed differences between hypertension and normotension or were associated with systolic and diastolic BP (SBP, DBP) after controlling confounders. These metabolites involved 16 and 12 Kyoto Encyclopedia of Genes and Genomes enrichment pathways in normal-weight and obese patients respectively, whereas 6 pathways overlapped. Among these 6 overlapping pathways, 4 were related to homocysteine metabolism and 2 were non-specific pathways. In homocysteine metabolism pathway, 13 metabolites were identified. Interestingly, the change trends of 7 metabolites associated with SBP (all interaction-p≤0.083) and 8 metabolites associated with DBP (all interaction-p≤0.033) were opposite between normal-weight and obese patients. Specifically, increased BP was associated with down-regulated folate-dependent remethylation and accelerated transsulfuration in normal-weight patients, whereas associated with enhanced betaine-dependent remethylation and reduced transsulfuration in obese patients. Similar findings were observed in ambulatory BP during sleep. After CPAP treatment, baseline low homocysteine levels predicted greater decrease in DBP among normal-weight but not obese patients. ConclusionsMechanisms in OSA-related hypertension differ between normal-weight and obese patients, which are explained by different changes in homocysteine metabolism.

Regulation of Betaine Homocysteine Methyltransferase by Liver Receptor Homolog-1 in the Methionine Cycle.

Betaine-homocysteine S-methyltransferase (BHMT) is one of the most abundant proteins in the liver and regulates homocysteine metabolism. However, the molecular mechanisms underlying Bhmt transcription have not yet been elucidated. This study aimed to assess the molecular mechanisms underlying Bhmt transcription and the effect of BHMT deficiency on metabolic functions in the liver mediated by liver receptor homolog-1 (LRH-1). During fasting, both Bhmt and Lrh-1 expression increased in the liver of Lrh-1f/f mice; however, Bhmt expression was decreased in LRH-1 liver specific knockout mice. Promoter activity analysis confirmed that LRH-1 binds to a specific site in the Bhmt promoter region. LRH-1 deficiency was associated with elevated production of reactive oxygen species (ROS), lipid peroxidation, and mitochondrial stress in hepatocytes, contributing to hepatic triglyceride (TG) accumulation. In conclusion, this study suggests that the absence of an LRH-1-mediated decrease in Bhmt expression promotes TG accumulation by increasing ROS levels and inducing mitochondrial stress. Therefore, LRH-1 deficiency not only leads to excess ROS production and mitochondrial stress in hepatocytes, but also disrupts the methionine cycle. Understanding these regulatory pathways may pave the way for novel therapeutic interventions against metabolic disorders associated with hepatic lipid accumulation.

Is serum homocysteine level a biomarker of suicide attempts: A preliminary study

Suicide is a global public health concern, and understanding its multifaceted determinants is crucial for effective prevention. This study was designed to find an answer to the question of whether serum homocysteine level can be a biomarker of suicide attempts. This preliminary study involving 90 participants (45 suicide attempt cases and 45 controls) was conducted at Elazig Fethi Sekin City Hospital. Biochemical analyses were performed to assess serum homocysteine, vitamin B12, and folic acid levels. Statistical analyses, including t-tests, Mann-Whitney U tests, and ROC analysis, were employed to explore differences between groups and assess the diagnostic potential of homocysteine. Elevated homocysteine levels were found in individuals who attempted suicide compared to the control group (p= <0.001). Additionally, lower levels of vitamin B12 (p=<0.001) and folic acid (p=<0.001) were observed in the suicide attempt group. ROC analysis indicated a significant diagnostic potential for homocysteine in predicting suicide attempts (AUC = 0.845, sensitivity = 91%, specificity = 71%). This study establishes a significant association between high homocysteine levels and suicide attempts, accompanied by lower vitamin B12 and folic acid levels. The findings suggest a potential link between disturbances in homocysteine metabolism and suicidal tendencies, urging further research to establish causation and explore therapeutic implications. Consideration of the study's limitations and directions for future research are warranted.

Exploring the metabolic implications of blue light exposure during daytime in rats

Excessive exposure to light is a global issue. Artificial light pollution has been shown to disrupt the body's natural circadian rhythm. To investigate the impacts of light on metabolism, we studied Sprague-Dawley rats chronically exposed to red or blue light during daytime or nighttime. Rats in the experimental group were exposed to extended light for 4 hours during daytime or nighttime to simulate the effects of excessive light usage. Strikingly, we found systemic metabolic alterations only induced by blue light during daytime. Furthermore, we conducted metabolomic analyses of the cerebrospinal fluid, serum, heart, liver, spleen, adrenal, cerebellum, pituitary, prostate, spermatophore, hypothalamus and kidney from rats in the control and blue light exposure during daytime. Significant changes in metabolites have been observed in cerebrospinal fluid, serum, hypothalamus and kidney of rats exposed to blue light during daytime. Metabolic alterations observed in rats encompassing pyruvate metabolism, glutathione metabolism homocysteine degradation, phosphatidylethanolamine biosynthesis, and phospholipid biosynthesis, exhibit analogous patterns to those inherent in specific physiological processes, notably neurodevelopment, cellular injury, oxidative stress, and autophagic pathways. Our study provides insights into tissue-specific metabolic changes in rats exposed to blue light during the daytime and may help explain potential mechanisms of photopathogenesis.

Abstract PO3-24-05: Cysteine metabolism related ferroptosis sensitivity in trastuzumab resistant HER2 positive breast cancer

Abstract Background Trastuzumab has shown great effectiveness in HER2 positive breast cancer treatment, but about 50% patients would undergo resistance during or after treatment. Although previous research has suggested several potential reasons for trastuzumab resistance, the metabolic reprogramming during resistance formation remains largely unclear. Here we identified aberrant ferroptosis associated cysteine metabolism in trastuzumab resistant HER2 positive breast cancer, which might become a novel target for overcoming resistance. Methods Trastuzumab sensitive HER2 positive breast cancer cell SKBR3 and resistant JITM1 were obtained for transcriptomics, proteomics, metabolomics and epigenomics analysis. Gene silencing was mediated by siRNAs. CUT&amp;Tag was applied to compare H3K4me3 and H3K27me3 binding regions. DNA methylation levels and different methylated regions were evaluated by WGBS-seq. CRISPRi with dCas9-DNMT3A was applied to regulate specific DNA methylation in CpG islands. Lipid ROS was measured by flow cytometry with BODIPY-C11. Results Joint analyses of transcriptomics and proteomics according to ferroptosis pathways revealed downregulated glutathione metabolism, glutamate transmembrane and homocysteine metabolism processes, as well as upregulated fatty acid metabolism and iron metabolism pathways in JIMT1. Metabolomics verified that JIMT1 increased cysteine metabolism and decreased glutathione metabolism. SLC7A11 expression and GSH/GSSG ratio were increased in JIMT1, while no difference was observed in free cysteine. JIMT1 featured significant higher UGC codon usage bias and increased cysteinyl-tRNA synthetase. The abundance of H3K4me3 other than H3K27me3 in SLC7A11 promoter region was found increased in JIMT1, and the 5-mC level of CpG islands in SLC7A11 promoter region was shown decreased. Using dCas9-DNMT3A, the methylation of SLC7A11 promoter was enhanced and SLC7A11 expression was reduced in JIMT1. Inhibition of SLC7A11 by siRNAs, CRISPRi or Erastin all indicated a higher ferroptosis sensitivity in JIMT1. Conclusion Trastuzumab resistant HER2 positive breast cancer features aberrant cysteine metabolism resulting from altered H3K4me3 modification and DNA methylation in SLC7A11 promoter region. This might provide novel targets for further anti-HER2 treatment. Citation Format: Yongmei Yin, Yijia Hua, Ningjun Duan, Chunxiao Sun, Fan Yang. Cysteine metabolism related ferroptosis sensitivity in trastuzumab resistant HER2 positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-24-05.

0451 Different Roles of Homocysteine Metabolism in Hypertension Among Normal-weight and Obese Patients with OSA

0451 Different Roles of Homocysteine Metabolism in Hypertension Among Normal-weight and Obese Patients with OSA

Homocysteine as a predictor of apnea-hypopnea index in obstructive sleep apnea: a longitudinal epidemiological study (EPISONO).

Obstructive sleep apnea (OSA) affects nearly 1 billion people globally, and has established links with cardiovascular and neurocognitive complications. Although it has some limitations, the apnea-hypopnea index (AHI) is commonly used to gauge OSA severity and therapeutic response. Homocysteine (Hcy) metabolism, when impaired, can elicit cellular senescence mechanisms that may be shared with OSA. Hence, our objective was to explore the role of Hcy concentrations both as a predictor of AHI values and as a potential risk factor for OSA. Involving 1042 volunteers aged 20 to 80years, the initial study (2007) included polysomnographic evaluations, questionnaires on sleep and general health, as well as biochemical analyses. After an 8-year interval, 715 participants from the initial study were invited for a follow-up assessment in 2015. Our findings showed that Hcy was a predictor for an increased AHI, and AHI increased over time. Individuals with plasma Hcy concentrations ≥ 15µmol/L experienced an average AHI increase of 7.43 events/hour ([beta coefficient] β = 7.43; 95%CI 2.73 to 12.13) over time, compared to those with plasma concentrations < 10µmol/L. A similar trend was apparent in those with plasma Hcy concentrations between 10 ≥ and < 15µmol/L, who had an AHI increase with an average beta coefficient of 3.20 events/hour (95%CI 1.01 to 5.39) compared to those with plasma Hcy concentrations < 10µmol/L. In summary, our study suggests that increased plasma Hcy concentrations could be considered a risk factor for the development of OSA. These findings highlight that elevated plasma Hcy concentrations can predict the severity of OSA, underscoring their correlation with the AHI.

Homocysteine metabolites inhibit autophagy by upregulating miR-21-5p, miR-155-5p, miR-216-5p, and miR-320c-3p in human vascular endothelial cells

Nutritional and genetic deficiencies in homocysteine (Hcy) metabolism lead to hyperhomocysteinemia (HHcy) and cause endothelial dysfunction, a hallmark of atherosclerosis, which is a major cause of cardiovascular disease (CVD). Impaired autophagy causes the accumulation of damaged proteins and organelles and is associated with CVD. Biochemically, HHcy is characterized by elevated levels of Hcy and its metabolites, Hcy-thiolactone and N-Hcy-protein. However, whether these metabolites can dysregulate mTOR signaling and autophagy in endothelial cells is not known. Here, we examined the influence of Hcy-thiolactone, N-Hcy-protein, and Hcy on autophagy human umbilical vein endothelial cells. We found that treatments with Hcy-thiolactone, N-Hcy-protein, or Hcy significantly downregulated beclin 1 (BECN1), autophagy-related 5 (ATG5), autophagy-related 7 (ATG7), and microtubule-associated protein 1 light chain 3 (LC3) mRNA and protein levels. We also found that these changes were mediated by upregulation by Hcy-thiolactone, N-Hcy-protein, and Hcy of autophagy-targeting microRNA (miR): miR-21, miR-155, miR-216, and miR-320c. The effects of these metabolites on levels of miR targeting autophagy as well as on the levels of BECN1, ATG5, ATG7, and LC3 mRNA and protein were abrogated by treatments with inhibitors of miR-21, miR-155, miR-216, and mir320c. Taken together, our findings show that Hcy metabolites can upregulate miR-21, miR-155, miR-216, and mir320c, which then downregulate autophagy in human endothelial cells, important for vascular homeostasis.