Higher Homocysteine Levels Research Articles

High prevalence of chronic endometritis is associated with metabolic abnormality and reduced live birth rate among IVF women with non-uniform endometrial echogenicity.

To assess the prevalence of chronic endometritis (CE) among women with non-uniform endometrial echogenicity, and to evaluate the association between CE and metabolic characteristics as well as pregnancy outcomes in the subsequent frozen-thawed embryo transfer (FET) cycles. Retrospective cohort study. University-based hospitals and an academic medical center. A total of 315 patients included in this research underwent hysteroscopy and endometrial biopsy before the first FET cycle after whole embryos freezing. Patients were divided into CE (histopathologic CE or hysteroscopic CE) and non-CE groups. Freeze-all strategy, hysteroscopy and endometrial biopsy. Baseline and cycle characteristics, hysteroscopic, and histopathological profile, as well as pregnancy outcomes. The prevalence of histopathologic CE and hysteroscopic CE were 78.1% and 34.9%, respectively. CE was associated with higher homocysteine level and BMI, independent of insulin response and dyslipidemia. High homocysteine level and BMI were risk factors for histopathologic CE (OR: 1.182; 95% CI: 1.01-1.384; p=.037) and hysteroscopic CE (OR: 1.117; 95% CI: 1.041-1.199; p=.002), respectively. Histopathologic CE was a risk factor for live birth (OR:2.167; 95% CI: 1.037-4.525; p=.04), and hysteroscopic CE was an independent risk factor for both live birth (OR: 4.239; 95% CI: 1.929-9.313; p=.001) and cumulative live birth (OR: 3.963; 95% CI: 1.875-8.376; p=.001). Infertile women with non-uniform endometrial echogenicity have a high prevalence of CE which significantly reduces the live birth rate. Diagnosing CE by hysteroscopy is important to assess the cumulative probability of pregnancy in IVF patients.

Impact of Homocysteine as a Preconceptional Screening Factor for In Vitro Fertilization and Prevention of Miscarriage with Folic Acid Supplementation Following Frozen-Thawed Embryo Transfer: A Hospital-Based Retrospective Cohort Study.

Homocysteine is an amino acid naturally produced in the body and metabolized via the methionine cycle. High homocysteine levels can increase the risk of infertility and pregnancy complications, such as preeclampsia, preterm delivery, miscarriage, and low birth weight. Preconceptional homocysteine levels may be reduced by taking folic acid supplements to reduce the risk of such complications. This cross-sectional, hospital-based study was conducted to examine the role of homocysteine in 1060 infertile women with a history of IVF/intracytoplasmic sperm injection (ICSI) failure. We analyzed whether folic acid intervention altered homocysteine levels and influenced reproductive outcome. We found that a higher homocysteine level was statistically associated with a lower fertilization rate in patients with a history of IVF/ICSI failure. There was an inverse relationship between homocysteine levels and serum 25(OH)VD, and a trend towards lower anti mullerian hormone in the group with higher homocysteine levels. This is the first interventional study to identify that folic acid supplementation improved pregnancy outcomes following freeze embryo transfer (FET) in women with a history of FET failure by monitoring the reduction in homocysteine levels. Therefore, folic acid supplementation and homocysteine level monitoring may constitute a novel intervention for improving IVF/ICSI pregnancy outcomes.

Association of MTHFR polymorphism, folic acid and vitamin B12 with serum homocysteine levels in pregnant women.

Homocysteine is known to be associated with adverse vascular and metabolic effects, as well as pregnancy complications. Its serum levels are influenced by the function of the enzyme methylenetetrahydrofolate reductase (MTHFR) and the dietary intake of folic acid, vitamin B12, and methionine. In this cross-sectional study, we investigated the association of genetic polymorphisms of the MTHFR gene with vitamin status in pregnant women during mandatory folic acid supplementation. The study included 102 pregnant women between 24 and 28 weeks of gestation who were attending regular outpatient examinations at the maternity clinic. Homocysteine, folic acid, vitamin B12 levels, and MTHFR gene polymorphisms (C677T and A1298C) were analyzed. Significant associations were found between vitamin B12 and folic acid levels with homocysteine (P < 0.001), with lower serum levels of these vitamins being associated with higher homocysteine levels. Surprisingly, there was no significant association between MTHFR genetic polymorphisms and serum homocysteine levels, likely attributed to the supplementation of folic acid and vitamin B12 in vitamin supplements for pregnant women, which counteracts the effect of the mutation. Remarkably, a high prevalence of MTHFR gene mutations was found, with the C677T polymorphism present in 56.9% and the A1298C polymorphism in 87.2% of pregnant women. These findings emphasize the importance of adequate folic acid and vitamin B12 intake during pregnancy to regulate homocysteine levels. Although the MTHFR gene mutations were highly prevalent, their influence on homocysteine levels in this population appears to be mitigated by vitamin supplementation. Further research is warranted to explore the impact of these mutations on other aspects of pregnancy outcomes. The trial is registrated at Clinicaltrail.gov (NCT04952324).

A set of urinary peptides can predict early renal damage in primary hypertension.

Renal diseases caused by primary hypertension (HTN) are often asymptomatic without sensitive markers for early diagnosis and prediction, easily progressing to severe and irreversible renal damage in patients with clinical manifestations. This study explored whether a set of urinary peptides could serve as a potential biomarker for early prediction of renal damage in HTN. Urinary peptides level of healthy individuals, HTN + normoalbuminuric and HTN + albuminuria patients were compared, and 22 baseline data including sex, age, renal function, hypertensive fundus lesions were collected. Patients diagnosed with HTN, albuminuria, and normal renal function were followed up. According to the follow-up results, the cut-off value of a set of urinary peptides in predicting hypertensive renal injury was calculated and analyzed in the high-risk and low-risk groups of HTN patients for its performance in detecting early hypertensive renal injury. Among a sum of 319 participants, average urinary peptides level was significantly higher in patients with HTN than in normal individuals. A total of 147 HTN patients with normal albuminuria were followed up for a mean of 3.8 years. Thirty-five patients showed urinary albumin-to-creatinine ratio (uACR) at least 30 mg/g for three consecutive times. The receiver-operating characteristic (ROC) curve showed that the urinary peptides cut-off value for evaluating new-onset proteinuria in patients with HTN was 0.097. Based on this cut-off value, 39 and 108 patients were included in the high-risk and low-risk groups, respectively. Specifically, compared with patients in the low-risk group, those in the high-risk group showed significantly longer duration of HTN, higher proportions of hypertensive fundus lesions and at least 30 mg/g uACR, and higher levels of homocysteine (Hcy), cystatin C (CysC), beta-2 microglobulin (β2-MG), and uACR. 76.9% of high-risk patients had significantly higher new-onset proteinuria than the low-risk group. Correlation analysis demonstrated a positive correlation between urinary peptides and UACR ( r = 0.494, P < 0.001). The incidence of new-onset albuminuria was significantly higher in the high-risk group than in the low-risk group, as shown by Cox regression analysis. The areas under the curve of urinary peptides, Hcy, β2-MG and CysC were 0.925, 0.753, 0.796 and 0.769, respectively. A set of urinary peptides is a predictor of new-onset proteinuria in patients with HTN, therefore, it can be used for diagnosing patients with early renal injury in patients with HTN, contributing to early prevention and treatment of hypertensive nephropathy.

Susceptibility to preoperative seizures in glioma patients with elevated homocysteine levels.

Seizures are a common clinical presentation in patients with glioma and substantially impact patients' quality of life. Hyperhomocysteinemia is defined as abnormally high serum levels of homocysteine (Hcy) and is reportedly linked to susceptibility to various nervous system diseases. However, it remains unclear whether and how hyperhomocysteinemia and its associated genetic polymorphisms promote seizures in glioma patients. We retrospectively reviewed all medical data from 127 patients with malignant gliomas, who underwent initial tumor resection by our team between July 2019 and June 2021 and had preoperative measurements of serum Hcy levels. According to whether they had at least one seizure before surgery, they were divided into the seizure and nonseizure groups. We also detected polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and measured intratumoral Hcy levels in these patients. Hyperhomocysteinemia was a susceptibility factor for preoperative seizures in glioma patients according to both univariate analyses (P < 0.001) and multivariate logistic regression analyses (OR 1.239, 95% CI 1.062-1.445, P = 0.007). Patients with the MTHFR C677T variant exhibited elevated serum Hcy levels (P = 0.027) and an increased prevalence of preoperative seizures (P = 0.019). Intratumoral Hcy levels were positively correlated with serum Hcy levels (R = 0.231, P = 0.046) and were elevated in patients with hyperhomocysteinemia (P = 0.031), the MTHFR C677T variant (P = 0.002) and preoperative seizures (P = 0.003). High intratumoral Hcy levels, rather than hyperhomocysteinemia or the MTHFR C677T variant, emerged as an independent risk factor for preoperative seizures (OR 1.303, 95% CI 1.015-1.673, P = 0.038). Furthermore, the effects of hyperhomocysteinemia on epileptic susceptibility were reduced to nonsignificance when intratumoral Hcy was controlled to the same level between groups. Glioma patients with hyperhomocysteinemia and the MTHFR C677T variant were susceptible to preoperative seizures, suggesting their potential as biomarkers for the management of seizures in glioma patients. The elevation of intratumoral Hcy is a possible mechanism underlying this susceptibility.

Targeting Homocysteine and Hydrogen Sulfide Balance as Future Therapeutics in Cancer Treatment.

A high level of homocysteine (Hcy) is associated with oxidative/ER stress, apoptosis, and impairment of angiogenesis, whereas hydrogen sulfide (H2S) has been found to reverse this condition. Recent studies have shown that cancer cells need to produce a high level of endogenous H2S to maintain cell proliferation, growth, viability, and migration. However, any novel mechanism that targets this balance of Hcy and H2S production has yet to be discovered or exploited. Cells require homocysteine metabolism via the methionine cycle for nucleotide synthesis, methylation, and reductive metabolism, and this pathway supports the high proliferative rate of cancer cells. Although the methionine cycle favors cancer cells for their survival and growth, this metabolism produces a massive amount of toxic Hcy that somehow cancer cells handle very well. Recently, research showed specific pathways important for balancing the antioxidative defense through H2S production in cancer cells. This review discusses the relationship between Hcy metabolism and the antiapoptotic, antioxidative, anti-inflammatory, and angiogenic effects of H2S in different cancer types. It also summarizes the historical understanding of targeting antioxidative defense systems, angiogenesis, and other protective mechanisms of cancer cells and the role of H2S production in the genesis, progression, and metastasis of cancer. This review defines a nexus of diet and precision medicine in targeting the delicate antioxidative system of cancer and explores possible future therapeutics that could exploit the Hcy and H2S balance.

Relationship of Serum Vitamin B12 and Serum Homocysteine Levels with Pseudo Exfoliation Syndrome

Objective: To evaluate the relationship of serum Vitamin B12 and serum Homocysteine levels with Pseudo Exfoliation Syndrome. Study Design: Cross-sectional study. Place and Duration of Study: Department of Ophthalmology, Armed Forces Institute of Ophthalmology, Rawalpindi Pakistan, from Jun to Nov 2022. Methodology: We included 55 individuals with unilateral Pseudo Exfoliation Syndrome without glaucoma and 50 healthy individuals as controls. All participants were subjected to the assessment of serum Homocysteine levels by high-performance liquid chromatography and Vitamin B12 levels by chemi-luminescent enzyme immunoassay. Results: Thirty-two (58.18%) individuals out of 55 with unilateral Pseudo Exfoliation Syndrome had increased serum Homocysteine levels (&gt;5umol/L). Of these 32, 25(78.12%) individuals had moderately high serum Homocysteine levels, while 7(21.87%) had severely high serum Homocysteine levels. Twenty-six (47.27%) out of 55 individuals with Pseudo Exfoliation Syndrome had decreased serum Vitamin B12 levels, while the rest 29(52.72%) had normal-range serum Vitamin B12 levels. In comparison, 7(14%) had reduced serum Vitamin B12 levels, while the rest, 43(86%), had normal serum Vitamin B12 levels. Conclusion: Our study showed that raised Hcy levels were present in individuals with PXS without glaucoma and reduced serum Vitamin B12 levels. Assessment of Hcy level in individuals presenting with PXS may be undertaken as it is a known risk factor for vasuclopathies.

Association of osteoporosis and high serum homocysteine levels with intraoperative periprosthetic fracture during total hip arthroplasty: a propensity-score matching analysis.

Intraoperative periprosthetic fracture, one of the most frequent complications of total hip arthroplasty, is a very important factor that affects rehabilitation, hospitalization time, and cost of treatment. Osteoporosis is common in total hip arthroplasty patients and likely contributes to the increasing incidence of periprosthetic fracture. Despite this awareness, preoperative and postoperative osteoporosis evaluations remain insufficient. The purpose of this study was to evaluate the relationships between the occurrence of intraoperative periprosthetic fractures and both bone mineral density (BMD) and osteoporosis-related biomarkers. This single-center retrospective study included a total of consecutive 487 hip joints of patients with a mean age of 65.5 ± 11.8years who underwent total hip arthroplasty between July 2017 and December 2020. Patients with low BMD defined as T-score < -1.0 versus those with normal BMD were matched by a 1:1 propensity score to balance for patient baseline characteristics, and outcome was analyzed by a modified Poisson regression model. Our primary outcome was the incidence of intraoperative periprosthetic fracture during surgery. We also investigated the effect modification of osteoporosis-related biomarkers, including tartrate-resistant acid phosphatase 5b (TRACP-5b), total procollagen type 1 amino-terminal propeptide (total P1-NP), intact parathyroid hormone (intact PTH), and homocysteine, on osteoporosis and outcomes. After matching, 250 patients were analyzed. The risk of fracture was significantly higher in patients with low BMD than in normal BMD patients (Incidence rate ratio 5.00 [95% CI 1.11-22.43], p = 0.036). We also observed significant effect of high serum homocysteine on the occurrence of intraoperative fractures (Incidence rate ratio 8.38 × 106 [95% C; 3.44 × 106-2.01 × 107], p < 0.01). Preoperative osteoporosis and high serum homocysteine levels were risk factors for intraoperative periprosthetic fractures. III, A single-center retrospective study.

Association of Long-term Exposure to Air Pollution and Dementia Risk: The Role of Homocysteine, Methionine, and Cardiovascular Burden.

Growing evidence links air pollution with dementia risk, but the biological mechanisms are largely unknown. We investigated the role played by homocysteine (tHcy) and methionine in this association and explored whether this could be explained by cardiovascular diseases (CVDs). Data were extracted from the ongoing Swedish National study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study. At baseline, 2,512 dementia-free participants were examined up to 2013 (mean follow-up: 5.18 ± 2.96 years). Two air pollutants (particulate matter ≤2.5 μm [PM2.5] and nitrogen oxides [NOx]) were assessed yearly from 1990 until 2013 using dispersion models at residential addresses. The hazard ratio of dementia over air pollution levels was estimated using Cox models adjusted for age, sex, education, smoking, socioeconomic status, physical activity, retirement age, creatinine, year of assessment, and the use of supplements. The total effect of air pollutants on dementia was decomposed into 4 pathways involving tHcy/methionine: (1) direct effect; (2) indirect effect (mediation); (3) effect due to interaction; and (4) effect due to both mediation and interaction. To test whether the association was independent from CVDs (ischemic heart disease, atrial fibrillation, heart failure, and stroke), we repeated the analyses excluding those individuals who developed CVDs. The mean age of the study participants was 73.4 years (SD: 10.4), and 62.1% were female individuals. During an average period of 5 years (mean: 5.18; SD: 2.96 years), 376 cases with incident dementia were identified. There was a 70% increased hazard of dementia per unit increase of PM2.5 during the 5 years before baseline (hazard ratio [HR]: 1.71; 95% CI 1.33-2.09). Overall, 50% (51.6%; 95% CI 9.0-94.1) of the total effect of PM2.5 on dementia was due to mediation of tHcy (6.6%; 95% CI 1.6-11.6) and/or interaction (47.8%; 95% CI 4.9-91.7) with tHcy and 48.4% (p = 0.03) to the direct effect of PM2.5 on dementia. High levels of methionine reduced the dementia hazard linked to PM2.5 by 31% (HR: 0.69; 95% CI 0.56-0.85) with 24.8% attributable to the interaction with methionine and 25.9% (p = 0.001) to the direct effect of PM2.5. No mediation effect was found through methionine. Attenuated results were obtained for NOx. Findings for tHcy were attenuated after excluding those who developed CVDs, while remained similar for methionine. High levels of homocysteine enhanced the dementia risk attributed to air pollution, while high methionine concentrations reduced this risk. The impact of homocysteine on cardiovascular conditions partly explains this association. Alternative pathways other than cardiovascular mechanisms may be at play between methionine and dementia.

Double whammy: the genetic variants in CECR2 and high Hcy on the development of neural tube defects.

Introduction: Neural tube defects (NTDs) are serious congenital malformations. The etiology of NTDs involves both genetic and environmental factors. Loss of CECR2 in mice has been shown to result in NTDs. Our previous study indicated that high homocysteine (HHcy) levels could further reduced the expression level of CECR2. This investigation aims to explore the genetic influence of the chromatin remodeling gene, CECR2, in humans and determine if HHcy can have a synergistic effect on protein expression. Methods: We conducted Next-Generation Sequencing (NGS) of the CECR2 gene in 373 NTD cases and 222 healthy controls, followed by functional assay application to select and evaluate CECR2 missense variants and subsequent Western blotting to identify protein expression levels. Results: From the analysis, we identified nine rare, NTD-specific mutations within the CECR2 gene. Significantly, four missense variants (p.E327V, p.T521S, p.G701R, and p.G868R) were selected via functional screening. The E9.5 mouse ectodermal stem cell line NE-4C, transfected with plasmids expressing p.E327V, p.T521S, p.G868R variants or a recombinant harboring all four (named as 4Mut), exhibited notable reductions in CECR2 protein expression. Furthermore, exposure to homocysteine thiolactone (HTL), an extremely reactive homocysteine metabolite, amplified the reduction in CECR2 expression, accompanied by a significant increase in the apoptotic molecule Caspase3 activity, a potential NTD inducer. Importantly, folic acid (FA) supplementation effectively counteracted the CECR2 expression decline induced by CECR2 mutation and HTL treatment, leading to reduced apoptosis. Discussion: Our observations underscore a synergistic relationship between HHcy and genetic variations in CECR2 concerning NTDs, thereby reinforcing the concept of gene-environment interaction phenomena in NTD etiology.

High homocysteine is associated with idiopathic normal pressure hydrocephalus in deep perforating arteriopathy: a cross-sectional study

Background and objectiveThe pathogenesis and pathophysiology of idiopathic normal pressure hydrocephalus (iNPH) remain unclear. Homocysteine may reduce the compliance of intracranial arteries and damage the endothelial function of the blood-brain barrier (BBB), which may be the underlying mechanism of iNPH. The overlap cases between deep perforating arteriopathy (DPA) and iNPH were not rare for the shared risk factors. We aimed to investigate the relationship between serum homocysteine and iNPH in DPA.MethodsA total of 41 DPA patients with iNPH and 49 DPA patients without iNPH were included. Demographic characteristics, vascular risk factors, laboratory results, and neuroimaging data were collected. Multivariable logistic regression analysis was performed to investigate the relationship between serum homocysteine and iNPH in DPA patients.ResultsPatients with iNPH had significantly higher homocysteine levels than those without iNPH (median, 16.34 mmol/L versus 14.28 mmol/L; P = 0.002). There was no significant difference in CSVD burden scores between patients with iNPH and patients without iNPH. Univariate logistic regression analysis demonstrated that patients with homocysteine levels in the Tertile3 were more likely to have iNPH than those in the Tertile1 (OR, 4.929; 95% CI, 1.612–15.071; P = 0.005). The association remained significant after multivariable adjustment for potential confounders, including age, male, hypertension, diabetes mellitus, atherosclerotic cardiovascular disease (ASCVD) or hypercholesterolemia, and eGFR level.ConclusionOur study indicated that high serum homocysteine levels were independently associated with iNPH in DPA. However, further research is needed to determine the predictive value of homocysteine and to confirm the underlying mechanism between homocysteine and iNPH.

Raised Maternal Homocysteine Levels in Antenatal Women at 10 to 14 Weeks of Gestation and Placenta-Mediated Complications: A Cohort Study.

Background Placenta-mediated complications, such as preeclampsia, placental abruption, and fetal growth restriction, can indeed lead to significant maternal and perinatal morbidity and mortality. Early detection and management of these conditions are crucial to ensuring optimal outcomes for both the mother and baby.However, there have been inconsistent correlations found between maternal homocysteine levels and placenta-related problems in various studies. Therefore, prospective research based on data pointing to a role for hyperhomocysteinemia in placenta-mediated complications will open doors for early detection and management of these complications. Thus, this study aims to determine if a higher risk of placenta-mediated problems is connected with a higher maternal plasma homocysteine content between 10 and 14 weeks of gestation. Methodology An observational prospective cohort study was conducted in the Department of Obstetrics and Gynecology, consisting of all the antenatal women between 10 and 14 weeks of gestation attending outpatient departments or inpatients admitted in labor rooms or wards having singleton pregnancies. Along with socio-demographic information and detailed history, a clinical examination was performed, and blood samples were collected to determine plasma homocysteine levels. Results As per thereceiver operating characteristic curve (ROC curve), the cut-off value taken was <5 for the low level of serum homocysteine, 5 to 15 micromol/L for the normal value, and >15 micromol/L for a raised serum homocysteine level. The cutoff value for our study was 45 micromol/L with a sensitivity of 78.33%, a specificity of 91.67%, a positive predictive value of 90.38%, and a negative predictive value of 80.88% with a diagnostic accuracy of 85%. This means that, for most of the women included in the present study, those who developed placenta-mediated complications had serum blood homocysteine levels of 45 micromol/L or more at 10-14 weeks of gestation. Conclusion Women with high homocysteine levels in the late first trimester had more placenta-mediated complications, such as abruption, pre-eclampsia, restricted fetal growth, and recurrent pregnancy losses, compared to women with a normal level of homocysteine in the late first trimester. Therefore, measuring blood homocysteine levels in pregnancy may be helpful as a diagnostic test for the early detection of high-risk individuals for placenta-mediated complications.

ROLE OF THE T (-344) C POLYMORPHISM OF ALDOSTERONE SYNTHASE GENE CYP11B2 IN THE DEVELOPMENT OF CARDIORENAL SYNDROME IN PATIENTS WITH DIABETES MELLITUS

Objective: To evaluate the role of the T (-344)C polymorphism of CYP11B2 gene in the development of cardiorenal syndrome (CRS) in diabetes mellitus (DM). Design and method: We examined 270 patients with type 1 and type 2 diabetes aged over 25 years. Control group included 60 healthy patients the same age. Renal function was assessed based on the levels of serum creatinine, cystatin C, eGFR, which was calculated according to the CKD-EPI formula, and albuminuria, which was assessed as albumin/creatinine ratio. All patients underwent molecular genetic analysis using deoxyribonucleic acid isolated from whole venous blood. Results: The frequency of carriage of the TT polymorphism of the CYP11B2 gene was significantly higher (47%) in the group of patients with DM than in the control group (26%). Carriers of the TT genotype had significantly high levels of homocysteine (10.5 [8.3;15.1] μmol/L) and FGF-23 (3.22 [0.77;7.60] pmol/L) as in DM group and in the control group (8.3 [7.54;10.9] μmol/l and 2.4 [2.19;2.6] pmol/l, respectively) than carriers of the CC genotype. The TT genotype was associated with the risk of developing CRS manifestations such as left ventricular hypertrophy (odds ratio (OR) 2.64; 95% CI (0.93–4.19), chronic heart failure (OR 4.26; 95% CI (2.26 - 8.06), subclinical atherosclerosis (OR 4.04; 95% CI (1.89 - 8.58), chronic kidney disease (CKD) (OR 10.77; 95% CI (3.56 - 32.61), and the CT genotype (OR 3.28; 95% CI (1.02 – 10.59) with CKD risk. Conclusions: There are pathogenetic association between the renin-angiotensin-aldosterone system, cardiovascular complications and a decrease renal function. Further research is needed for a deep understanding of the complex pathogenetic mechanisms of the development and progression of cardiovascular and renal pathology.

Association of Elevated Serum Homocysteine Level in Women with Gestational Diabetes Mellitus

Background: In gestational diabetes mellitus (GDM), risk prediction is mostly based on maternal history and clinical risk factors and may not optimally identify high risk pregnancies. Therefore, universal screening is widely recommended. Homocysteine levels during pregnancy in women with GDM have been studied; however, it remains unclear whether hyperhomocysteinemia is a useful predictor of GDM. Objective: To determine the association of serum homocysteine level in women with gestational diabetes mellitus. Methods: Case control study was conducted in the Department of Obstetrics and Gynaecology, Institute of Child and Mother Health (ICMH), Dhaka. Pregnant women in their 24 weeks to 40 weeks of gestation attended for antenatal care diagnosed as GDM was selected as cases. Non- diabetic pregnant women matching with cases by age and gestational age were selected as control in this study. GDM was diagnosed by oral glucose tolerance test (OGTT). The serum homocysteine level of these patients was measured. Descriptive and inferential analysis was carried out using SPSS version 22.0. P-value less than 0.05 will be considered as statistically significant. Results: Among the cases fasting blood sugar (6.13 ± 0.66) and controls (4.60 ± 0.57). Similarly, 2 hours after 75 gm. glucose blood sugar among cases (8.46 ± 0.88) and controls (6.32 ± 0.96). Both results were statistically significant p=0.001. Majority of patients were at third trimester of pregnancy (67.0%). 37.5% were primigravida and 2.5% were multigravida. Mean gestational age of cases (30.25 ± 2.74) and controls (30.02 ± 3.03). Among the cases 62.1% had history of GDM where 37.9% don’t have history of GDM. Among control group only 7.7% had history of GDM. This result statistically significant p=0.001. 6.9% cases had history of macrocosmic child which was not statistically significant p=0.49. There was no history of still birth or other congenital defect. Mean serum homocysteine level among cases (6.50 ± 1.72) and controls (5.20 ± 1.87) which was statistically significant p=0.001. Positive correlation observed between maternal serum homocysteine level and maternal blood sugar (r=0.209, p=0.005) in this study. Respondents with high homocysteine level have 3.94 times more chance to develop GDM (OR=3.94; 95% CI = 1.59-9.77). Conclusion: Finding from the present study suggests that maternal elevated serum homocysteine level in pregnancy is significantly associated with Gestational Diabetes Mellitus.

Homocysteine levels, H-Hypertension, and the MTHFR C677T genotypes: A complex interaction

Background and objectivesHigh homocysteine levels are associated with increased risk of hypertension and stroke. Homocysteine is metabolized by the methylenetetrahydrofolate reductase (MTHFR). We aimed to investigate the levels of homocysteine and their association with hypertension, stroke, and antihypertensive medication usage in patients with different MTHFR C677T genotypes. Methods and resultsGenotype frequency of MTHFR polymorphism was performed, and plasma homocysteine levels were measured in 2,640 adult Lebanese patients. Hypertension, history of stroke, and list of medications were documented, among other clinical and demographic parameters. The TT mutant genotype and the T mutant allele of MTHFR were more prevalent in hyperhomocysteinemia (HHcy) and H-hypertensive (H-HTN, defined as hypertension with hyperhomocysteinemia) patients when compared to non-HHcy subjects and non H-HTN patients respectively. Homocysteine levels were significantly higher in hypertensive patients specifically among those on diuretics. A higher level of homocysteine was found in hypertensive patients with the MTHFR T allele compared to patients carrying the C allele. Among the T allele carriers, the average plasma homocysteine level was 13.3 ± 0.193 μmol/L for hypertensive subjects compared to 11.9 ± 0.173 μmol/L (non-hypertensives). Furthermore, homocysteine levels significantly correlated with stroke risk in patients with the T alleles. ConclusionsWe found an association of homocysteine with hypertension, hypertensive medication, and stroke risk among patients with the MTHFR T allele and the TT genotype. The association of diuretics therapy with higher homocysteine levels calls for routine measurements and therapeutic control of homocysteine in patients on diuretic, to improve health-related outcomes.

A classifier based on 273 urinary peptides predicts early renal damage in primary hypertension.

Renal diseases caused by primary hypertension (HTN) are often asymptomatic without sensitive markers for early diagnosis and prediction, easily progressing to severe and irreversible renal damage in patients with clinical manifestations. This study explored whether a classifier developed based on 273 urinary peptides (CKD273) could serve as a potential biomarker for early prediction of renal damage in HTN. Urinary CKD273 level of healthy individuals, HTN + normoalbuminuric and HTN + albuminuria patients were compared, and 22 baseline data including sex, age, renal function, and hypertensive fundus lesions were collected. Patients diagnosed with HTN, albuminuria, and normal renal function were followed up. According to the follow-up results, the cut-off value of CKD273 in predicting hypertensive renal injury was calculated and analyzed in the high-risk and low-risk groups of HTN patients for its performance in detecting early hypertensive renal injury. Among a sum of 319 participants, average urinary CKD273 level was significantly higher in patients with HTN than in normal individuals. A total of 147 HTN patients with normal albuminuria were followed up for a mean of 3.8 years. Thirty-five patients showed urinary albumin-to-creatinine ratio (uACR) at least 30 mg/g for three consecutive times. The receiver-operating characteristic (ROC) curve showed that the urinary CKD273 cut-off value for evaluating new-onset proteinuria in patients with HTN was 0.097. Based on this cut-off value, 39 and 108 patients were included in the high-risk and low-risk groups, respectively. Specifically, compared with patients in the low-risk group, those in the high-risk group showed significantly longer duration of HTN, higher proportions of hypertensive fundus lesions and at least 30 mg/g uACR, and higher levels of homocysteine (Hcy), cystatin C (CysC), beta-2 microglobulin (β2-MG), and uACR. 76.9% of high-risk patients had significantly higher new-onset proteinuria than the low-risk group. Correlation analysis demonstrated a positive correlation between urinary CKD273 and UACR ( r = 0.494, P = 0.000). The incidence of new-onset albuminuria was significantly higher in the high-risk group than in the low-risk group, as shown by Cox regression analysis. The areas under the curve of CKD273, Hcy, β2-MG, and CysC were 0.925, 0.753, 0.796, and 0.769, respectively. Urinary CKD273 is a predictor of new-onset proteinuria in patients with HTN, therefore, it can be used for diagnosing patients with early renal injury in patients with HTN, contributing to early prevention and treatment of hypertensive nephropathy.

ASSOCIATION OF HOMOCYSTEINE AND ISCHEMIC STROKE IN PAKISTANI POPULATION: A CASE CONTROL STUDY

Elevated homocysteine levels have been associated with an increased risk of ischemic stroke in various populations. This study aims to find the association between homocysteine and ischemic stroke in the Pakistani population. The study recruited 100 cases with ischemic stroke and 100 controls without any history of stroke from two tertiary care hospitals in Pakistan. Homocysteine levels were measured in both groups using a chemiluminescent microparticle immunoassay. The mean homocysteine level was significantly higher in cases compared to controls (24.64±7.41 µmol/L vs. 12.02±3.59 µmol/L, p&lt;0.001). Logistic regression analysis revealed that high homocysteine levels were independently associated with an increased risk of ischemic stroke (OR=3.62, 95% CI: 2.02-6.50, p&lt;0.001) after adjusting for potential confounders. This study provides evidence for the association between homocysteine levels and ischemic stroke in the Pakistani population. High homocysteine levels were found to be an independent risk factor for ischemic stroke.

Hyperhomocysteinemia activates NLRP3 inflammasome to cause hepatic steatosis and insulin resistance via MDM2-mediated ubiquitination of HSF1.

Hyperhomocysteinemia (HHcy) is associated with nonalcoholic fatty liver disease (NAFLD) and insulin resistance (IR). However, the underlying mechanism is still unknown. Recent studies have demonstrated that NLRP3 inflammasome activation plays a vital role in NAFLD and IR. Our study aimed to explore whether NLRP3 inflammasome contributed to HHcy-induced NAFLD and IR as well as dissected the underlying mechanism. C57BL/6 mice were fed a high-methionine diet (HMD) for 8weeks to establish the HHcy mouse model. Compared with a chow diet, HMD induced hepatic steatosis (HS) and IR as well as activation of hepatic NLRP3 inflammasome. Moreover, HHcy-induced NAFLD and IR characterization disclosed that NLRP3 inflammasome activation occurred in liver tissue of HMD-fed mice, but was very marginal in either NLRP3-/- or Caspase-1-/- mice. Mechanistically, high levels of homocysteine (Hcy) up-regulated the expression of mouse double minute 2 homolog (MDM2), which directly ubiquitinates heat shock transcription factor 1 (HSF1) and consequently activated hepatic NLRP3 inflammasome in vivo and in vitro. In addition, in vitro experiments showed P300-mediated HSF1 acetylation at K298 hindered MDM2-mediated ubiquitination of HSF1 at K372, which plays important role in determining the HSF1 level. Importantly, either inhibition of MDM2 by JNJ-165 or activation of HSF1 by HSF1A reversed HMD-induced hepatic NLRP3 inflammasome, and consequently alleviated HS and IR in mice. This study demonstrates that NLRP3 inflammasome activation contributes to HHcy-induced NAFLD and IR, and further identified that HSF1 as a new substrate of MDM2 and its decrease on MDM2-mediated ubiquitination at K372 modulates NLRP3 inflammasome activation. These findings may provide novel therapeutic strategies aimed at halting HS or IR.

Association of Blood Lipid Profile Components with White Matter Hyperintensity Burden in Cerebral Small Vessel Disease.

Cerebral small vessel disease (CSVD) refers to a common cerebrovascular disease and white matter hyperintensities (WMHs) constitute a typical feature of CSVD. However, there has not been a large number of studies investigating the relationship between lipid profile components and WMHs. Altogether, 1019 patients with CSVD were enrolled at the First Affiliated Hospital of Zhengzhou University between April 2016 to December 2021. Baseline data were collected for all patients, including demographic characteristics and clinical data. WMH volumes were evaluated by two experienced neurologists using the MRIcro software. Multivariate regression analysis was used to investigate the relationship among the severity of WMHs, blood lipids and common risk factors. Altogether, 1019 patients with CSVD were enrolled, including 255 in the severe WMH group and 764 in the mild WMH group. After including age, sex and blood lipids to construct a multivariate logistic regression equation, we observed that the severity of WMHs was independently predicted by low-density lipoprotein (LDL), homocysteine level and history of cerebral infarction. We used WMH volume, a highly accurate measure, to assess its relationship with lipid profiles. The WMH volume increased with a decrease in LDL. This relationship was more significant, especially among the subgroups of patients aged <70 years and men. Patients with cerebral infarction and higher homocysteine levels were more likely to have higher WMH volumes. Our study has provided a reference for clinical diagnosis and therapy, especially for discussing the role of blood lipid profiles in the pathophysiology of CSVD.

Homocysteine accelerates hepatocyte autophagy by upregulating TFEB via DNMT3b-mediated DNA hypomethylation.

Autophagy plays a critical role in the physiology and pathophysiology of hepatocytes. High level of homocysteine (Hcy) promotes autophagy in hepatocytes, but the underlying mechanism is still unknown. Here, we investigate the relationship between Hcy-induced autophagy level and the expression of nuclear transcription factor EB (TFEB). The results show that Hcy-induced autophagy level is mediated by upregulation of TFEB. Silencing of TFEB decreases the level of autophagy-related protein LC3BII/I and increases p62 expression level in hepatocytes after exposure to Hcy. Moreover, the effect of Hcy on the expression of TFEB is regulated by hypomethylation of the TFEB promoter catalyzed by DNA methyltransferase 3b (DNMT3b). In summary, this study shows that Hcy can activate autophagy by inhibiting DNMT3b-mediated DNA methylation and upregulating TFEB expression. These findings provide another new mechanism for Hcy-induced autophagy in hepatocytes.