SAH is a major metabolic sensor mediating worsening metabolic crosstalk in metabolic syndrome.

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

Genetic Polymorphisms of Endothelial Nitric Oxide Synthase Associated with Hypertension and Blood Homocysteine Levels.

Purpose: Endothelial dysfunction is a key mechanism in the development of hypertension and is closely linked to impairment of endothelial nitric oxide synthase (eNOS) and hyperhomocysteinemia. Genetic polymorphisms of eNOS (rs1799983 and rs2070744) are strongly associated with the risk of hypertension in individuals of Asian ethnicities. This study aimed to investigate the relationship between these polymorphisms and the risk of hypertension associated with homocysteine levels. Participants and Methods: For this cross-sectional study, we enrolled 370 Thai men aged 40-60 years from the Electricity Generating Authority of Thailand cohort study for both variants genotyping by TaqMan allelic discrimination analysis. Clinical, anthropometric, and biochemical parameters were also analyzed. Results: In the high blood pressure group (n = 267), systolic and diastolic blood pressure and triglyceride levels were higher in those with homocysteine levels ≥ 15 µmol/L than in those with homocysteine levels < 15 µmol/L (p < 0.05). Significant risk of hypertension was found in GG and GT of rs1799983 (G894T), and in TT and TC of rs2070744 (T-786C), with higher ORs in heterozygous genotypes (all p values < 0.05). Further evaluation of the interactions between SNPs and HCY revealed that individuals with the GT or TC genotype, together with hyperhomocysteinemia, had an increased risk of hypertension (all p<0.05). Conclusion: eNOS variants rs1799983 and rs2070744 may be risk factors for hypertension linked to hyperhomocysteinemia. These findings provide potentially useful healthcare strategies for the management of hypertension.

Preventing hyperhomocysteinemia using vitamin B6 supplementation in Givosiran-treated acute intermittent porphyria: Highlights from a case report and brief literature review.

Acute hepatic porphyrias are inherited metabolic disorders of heme biosynthesis characterized by the accumulation of toxic intermediate metabolites responsible for disabling acute neurovisceral attacks. Givosiran is a newly approved siRNA-based treatment of acute hepatic porphyria targeting the first and rate-limiting δ-aminolevulinic acid synthase 1 (ALAS1) enzyme of heme biosynthetic pathway. We described a 72-year old patient who presented with severe inaugural neurological form of acute intermittent porphyria evolving for several years which made her eligible for givosiran administration. On initiation of treatment, the patient developed a major hyperhomocysteinemia (>400 µmol/L) which necessitated to discontinue the siRNA-based therapy. A thorough metabolic analysis in the patient suggests that hyperhomocysteinemia could be attributed to a functional deficiency of cystathionine ß-synthase (CBS) enzyme induced by givosiran. Long-term treatment with vitamin B6, a cofactor of CBS, allowed to normalize homocysteinemia while givosiran treatment was maintained. We review the recently published cases of hyperhomocysteinemia in acute hepatic porphyria and its exacerbation under givosiran therapy. We also discuss the benefits of vitamin B6 supplementation in the light of hypothetic pathophysiological mechanisms responsible for hyperhomocysteinemia in these patients. Our results confirmed the importance of monitoring homocysteine metabolism and vitamin status in patients with acute intermittent porphyria in order to improve management by appropriate vitamin supplementation during givosiran treatment.

Podocyte-Specific Silencing of Acid Sphingomyelinase Gene to Abrogate Hyperhomocysteinemia-Induced NLRP3 Inflammasome Activation and Glomerular Inflammation.

Acid Sphingomyelinase has been reported to increase tissue ceramide and thereby mediate hHcy-induced glomerular NLRP3 inflammasome activation, inflammation, and sclerosis. In the present study, we tested whether somatic podocyte-specific silencing of Smpd1 gene attenuates hHcy-induced NLRP3 inflammasome activation and associated exosome release in podocytes and thereby suppresses glomerular inflammatory response and injury. In vivo, somatic podocyte-specific Smpd1 gene silencing almost blocked hHcy-induced glomerular NLRP3 inflammasome activation in Podocre mice compared to control littermates. By nanoparticle tracking analysis, floxed Smpd1 shRNA transfection was found to abrogate hHcy-induced elevation of urinary exosome excretion in Podocre mice. In addition, Smpd1 gene silencing in podocytes prevented hHcy-induced immune cell infiltration into glomeruli, proteinuria, and glomerular sclerosis in Podocre mice. In cell studies, we also confirmed that Smpd1 gene knockout or silencing prevented Hcy-induced elevation of exosome release in the primary cultures of podocyte isolated from Smpd1-/- mice or podocytes of Podocre mice transfected with floxed Smpd1 shRNA compared to WT/WT podocytes. Smpd1 gene overexpression amplified Hcy-induced exosome secretion from podocytes of Smpd1trg/Podocre mice, which was remarkably attenuated by transfection of floxed Smpd1 shRNA. Mechanistically, Hcy-induced elevation of exosome release from podocytes was blocked by ASM inhibitor, but not by NLRP3 inflammasome inhibitors. Super-resolution microscopy also showed that ASM inhibitor, but not NLRP3 inflammasome inhibitors, prevented the inhibition of lysosome-multivesicular body interaction by Hcy in podocytes. In conclusion, our findings suggest that ASM in podocytes plays a crucial role in the control of NLRP3 inflammasome activation and exosome release.

Diet-induced hyperhomocysteinemia causes sex-dependent deficiencies in offspring musculature and brain function.

Hyperhomocysteinemia (HHcy), characterized by elevated homocysteine (Hcy) levels, is a known risk factor for cardiovascular, renal, and neurological diseases, as well as pregnancy complications. Our study aimed to investigate whether HHcy induced by a high-methionine (high-Met) diet exacerbates cognitive and behavioral deficits in offspring and leads to other breeding problems. Dietary HHcy was induced four weeks before mating and continued throughout gestation and post-delivery. A battery of behavioral tests was conducted on offspring between postnatal days (PNDs) 5 and 30 to assess motor function/activity and cognition. The results were correlated with brain morphometric measurements and quantitative analysis of mammalian target of rapamycin (mTOR)/autophagy markers. The high-Met diet significantly increased parental and offspring urinary tHcy levels and influenced offspring behavior in a sex-dependent manner. Female offspring exhibited impaired cognition, potentially related to morphometric changes observed exclusively in HHcy females. Male HHcy pups demonstrated muscle weakness, evidenced by slower surface righting, reduced hind limb suspension (HLS) hanging time, weaker grip strength, and decreased activity in the beaker test. Western blot analyses indicated the downregulation of autophagy and the upregulation of mTOR activity in HHcy cortexes. HHcy also led to breeding impairments, including reduced breeding rate, in-utero fetal death, lower pups' body weight, and increased mortality, likely attributed to placental dysfunction associated with HHcy. In conclusion, a high-Met diet impairs memory and cognition in female juveniles and weakens muscle strength in male pups. These effects may stem from abnormal placental function affecting early neurogenesis, the dysregulation of autophagy-related pathways in the cortex, or epigenetic mechanisms of gene regulation triggered by HHcy during embryonic development.

Association between polymorphism in the MTHFR gene and encephaloduroarteriosynangiosis-induced collateral circulation formation.

OBJECTIVE: This study aimed to investigate whether high homocysteine (Hcy) levels associated with the MTHFR gene influence the formation of the collateral vascular network in patients with moyamoya disease (MMD) after encephaloduroarteriosynangiosis (EDAS) by influencing the number of endothelial progenitor cells (EPCs) in peripheral blood. METHODS: A total of 118 Chinese patients with bilateral primary MMD were prospectively included. Blood samples were collected from the anterior cubital vein before surgery, and MTHFR rs9651118 was genotyped using high-throughput mass spectrometry to determine the genotype of the test specimen. Serum Hcy and EPC levels were measured, the latter with flow cytometry. Digital subtraction angiography was performed 6 months after EDAS, and the formation of collateral circulation was evaluated using the Matsushima grade system. The correlations between MTHFR rs9651118 genotype, Hcy and EPC levels, and Matsushima grade were compared. RESULTS: Among the 118 patients, 53 had the TT genotype (wild type) of MTHFR rs9651118, 33 TC genotype (heterozygous mutation), and 32 CC genotype (homozygous mutation). The mean ± SD Hcy level was 13.4 ± 9.5 µmol/L in TT patients, 9.8 ± 3.2 µmol/L in TC patients, and 8.9 ± 2.9 µmol/L in CC patients (p < 0.001). The level of EPCs in the venous blood of TT patients was 0.039% ± 0.016%, that of TC patients 0.088% ± 0.061%, and that of CC patients 0.103% ± 0.062% (p < 0.001). When the rs9651118 gene locus was mutated, Matsushima grade was better (p < 0.001) but there was no difference between heterozygous and homozygous mutations. CONCLUSIONS: The results suggest that the MTHFR rs9651118 polymorphism is a good biomarker for collateral vascular network formation after EDAS in MMD patients.

A Case Report of Simultaneous Intracranial Hemorrhage and Cerebral Venous Sinus Thrombosis in a Young Indian Male: Diagnostic and Therapeutic Challenges.

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.

Central Retinal Artery Occlusion in Young Adults at High Altitude: Thin Air, High Stakes.

Rana, Vipin, Pradeep Kumar, Sandeepan Bandopadhyay, Vijay K. Sharma, Meenu Dangi, Dattakiran Joshi, Sanjay Kumar Mishra, Satyabrat Srikumar, and V.A. Arun. Central retinal artery occlusion in young adults at high altitude: thin air, high stakes. High Alt Med Biol. 00:000-000, 2024.-We present five cases of young security personnel who were posted at high altitude (HA) for a duration of at least 6 months and presented with a sudden decrease of vision in one eye. The diagnosis of central retinal artery occlusion (CRAO) was made in all patients. Fundus fluorescein angiography and optical coherence tomography of the macula supported the diagnosis. None of these cases had any preexisting comorbidities. Erythrocytosis was noticed in all patients, and two of them had hyperhomocysteinemia. Four out of five patients showed either middle cerebral artery or internal carotid artery (ICA) thrombosis on computed tomography angiography. The patients were managed by a team of ophthalmologist, hematologist, vascular surgeon, and neurologist. In cases of incomplete ICA occlusion, patients were managed surgically. However, in the case of complete ICA occlusion, management was conservative with antiplatelet drugs. This case series highlights HA-associated erythrocytosis and hyperhomocysteinemia as important risk factors for CRAO in young individuals stationed at HA.

Prevalence and clinical correlates of hyperhomocysteinemia in Chinese urban population with hypertension.

Context: The coexistence of hypertension and elevated homocysteine (Hcy) levels has a mutually reinforcing impact on the susceptibility to cardio-cerebrovascular disease. Objective: The aim was to assess the prevalence, clinical correlation, and demographic characteristics of hyperhomocysteinemia (HHcy) within the Chinese urban population with hypertension. Methods: A cohort of 473 individuals with hypertension were selected from four communities in Shenzhen, China. Demographic attributes, clinical profiles, and lifestyle behaviors were gathered and compared between individuals with and without HHcy. A logistic regression model was employed to examine potential factors associated with the prevalence of HHcy. Correlation between Hcy levels and clinical characteristics was assessed through multiple linear regression analysis. Results: The prevalence of HHcy in the population with hypertension was 31.3%. In comparison to individuals without HHcy, those with HHcy exhibited a higher proportion of males, a higher prevalence of smoking and alcohol consumption, and a higher proportion of cases with the homozygous (TT) genotype at the MTHFR C677T polymorphism. Moreover, individuals with HHcy had lower levels of folic acid (FA), and lower fruit and vitamin B12 intake. Furthermore, the risk factors for HHcy were male (B = 1.430, OR = 4.179) and MTHFR (TT) (B = 1.086, OR = 2.961). In addition, the multiple linear regression analysis revealed a significant association between Hcy levels and gender (B = -2.784, P = 0.004), MTHFR genotypes (B = 1.410, P = 0.005), and FA levels (B = -0.136, P = 0.030). Conclusion: The high prevalence of HHcy among hypertensive patients in this Chinese urban population underscores the necessity for interventions targeting modifiable risk factors such as dietary choices and lifestyle practices.

Association between MTHFR C677T polymorphism and cognitive impairment in patients with cerebral small vessel disease: a cross-sectional study.

Objective: Cerebral small vessel disease (CSVD) is the most common vascular cause of cognitive impairment. This study aimed to explore the association between MTHFR C677T polymorphism and cognitive impairment in CSVD patients. Methods: Demographic, medical, laboratory, cognitive evaluation, and MTHFR C677T polymorphism data were collected from CSVD patients admitted to our hospital between January 2019 and July 2023. Inclusion criteria for CSVD were based on the Standards for Reporting Vascular changes on Neuroimaging (STRIVE) criteria, with age ≥ 45 years. Binary logistic regression models were used to analyze risk factors associated with WMH and cognitive impairment. Results: A total of 330 CSVD participants were recruited in this study, including 179 male and 151 female, with a median age of 64 years (interquartile range: 58-73 years). There were 185 patients (56.1%) with cognitive impairment, 236 patients (71.5%) with WMH, 89 patients (27.0%) with CMB, 87 patients (26.4%) with lacunes. All participants completed MTHFR polymorphism analysis, 149 cases (45.2%) of the CC genotype, 112 cases (33.9%) of the CT genotype and 69 cases (20.9%) of the TT genotype. Patients with TT genotype exhibited higher plasma homocysteine levels and more severe WMH and cognitive impairment (p < 0.001). Multivariable binary logistic regression model showed that WMH was significantly associated with age (p = 0.019), history of hypertension (p = 0.011), HHcy (p = 0.019) and MTHFR genotype (p = 0.041); while cognitive impairment was significantly associated with age (p = 0.033), history of hypertension (p = 0.019), HHcy (p = 0.040), MTHFR genotype (p = 0.039), WMH (p = 0.041), and lacunes (p = 0.001). Conclusion: In this cross-sectional study, we investigated the association between MTHFR C677T polymorphism and cognitive function in CSVD patients. We found that MTHFR 677 TT genotype was an independent risk factor for the progression of WMH and cognitive impairment in CSVD patients.

Cardiogenic Shock in a Patient With 4G/4G PAI Polymorphism and MTHFR A1298C Mutation.

Myocardial infarction (MI) remains a common cause of morbidity and mortality. Although many well-known risk factors exist, the association between inherited thrombophilia disorders and acute MI is not well described. Here, we present a case of a 75-year-old male with known 4G/4G PAI-1 polymorphism, methylenetetrahydrofolate reductase (MTHFR) mutation, and peripheral artery disease (PAD) post stent placement who presented with cardiogenic shock in the setting of acute MI with no prior significant cardiac history.

Cerebral venous sinus thrombosis due to desogestrel intake in a young lady: A case report.

Cerebral Venous Sinus Thrombosis (CVST) is a subtype of venous thromboembolism, which occurs in the dural venous sinuses. Blockage of the venous drainage of the brain leads to the development of hemorrhages. Strokes can hence develop in any individual, irrespective of age or sex. CVST is a very serious condition requiring immediate thrombolysis to prevent residual neurological deficits. We report the case of a lady aged 25 years, who presented to the emergency department with a severe diffuse headache for 4 days, associated with vomiting. This was followed by multiple episodes of seizures and altered sensorium the previous day. She had been taking desogestrel for the past 2 months. On examination, the patient was unconscious and febrile (102.8 F). On admission, Glasgow Coma Scale score of E2V2M3 and bilateral extensor plantar response were noted. Signs of meningeal irritation were absent. Her pupils were mid-dilated, sluggishly reactive to light, and papilledema was present bilaterally. Based on imaging studies, she was diagnosed with a case of CVST. Her homocysteine levels were elevated. She recovered on appropriate treatment and was discharged on Ryle's feeding tube after 26 days of hospital stay with a Glasgow Coma Scale score of E4V5M6 and a flexor plantar response. The case emphasizes the need to rule out CVST in young adult females on oral contraceptive pills (OCP) presenting with severe neurological dysfunction. Vigilant screening, clinical suspicion and timely management can help cut down the associated mortality and morbidity in such cases.

A cross-sectional study of factors influencing left ventricular myocardial work in peritoneal dialysis patients.

Objectives: To evaluate myocardial work in peritoneal dialysis patients by pressure-strain loop. To analyze the factors influencing myocardial work in peritoneal dialysis patients with preserved ejection fraction. Methods: We collected clinical data on possible effects on myocardial work in 105 maintenance peritoneal dialysis patients with preserved ejection fraction and applied ultrasonic pressure-strain loops to obtain the left ventricular global constructive work (GCW), Global work index (GWI), global work waste (GWW), and global work efficiency (GWE) of the patients. Then, the clinical data and myocardial work indices were statistically described and correlated. Results: Left ventricular hypertrophy was observed in 78 % of peritoneal dialysis patients with left ventricular ejection fraction preservation. There is a correlation between the left ventricular mass index and myocardial work indices (P < 0.05). On multiple linear regression analysis, systolic blood pressure (SBP), IL-6, and hemoglobin correlated with GCW(P < 0.05); SBP and IL-6 correlated with GWI(P < 0.05); homocysteine, SBP, TNF-α, and hemoglobin correlated with GWW(P < 0.05); homocysteine, TNF-α and hemoglobin correlated with GWE (P < 0.05). Conclusions: Using noninvasive pressure-strain loops to assess left ventricular myocardial work can provide information on cardiac function more consistent with pathophysiological changes than conventional ejection fraction. Hypertension, anemia, hyperhomocysteinemia, and inflammation influence left ventricular myocardial work in peritoneal dialysis patients, and they selectively affect one or more myocardial work indices.

Reference Gene Validation in the Embryonic and Postnatal Brain in the Rat Hyperhomocysteinemia Model.

Maternal hyperhomocysteinemia (HCY) induced by genetic defects in methionine cycle enzymes or vitamin imbalance is known to be a pathologic factor that can impair embryonal brain development and cause long-term consequences in the postnatal brain development as well as changes in the expression of neuronal genes. Studies of the gene expression on this model requires the selection of optimal housekeeping genes. This work aimed to analyze the expression stability of housekeeping genes in offspring brain. Pregnant female Wistar rats were treated daily with a 0.15% L-methionine solution in the period starting on the 4th day of pregnancy until delivery, to cause the increase in the homocysteine level in fetus blood and brain. Housekeeping gene expression was assessed by RT-qPCR on whole embryonic brain and selected rat brain areas at P20 and P90. The amplification curves were analyzed, and raw means Cq data were imported to the RefFinder online tool to assess the reference genes stability. Most of the analyzed genes showed high stability of mRNA expression in the fetal brain at both periods of analysis (E14 and E20). However, the most stably expressed genes at different age points differed. Actb, Ppia, Rpl13a are the most stably expressed on E14, Ywhaz, Pgk1, Hprt1 - on E20 and P20, Hprt1, Actb, and Pgk1 - on P90. Gapdh gene used as a reference in various studies demonstrates high stability only in the hippocampus and cannot be recommended as the optimal reference gene on HCY model. Hprt1 and Pgk1 genes were found to be the most stably expressed in the brain of rat subjected to HCY. These two genes showed high stability in the brain on E20 and in various areas of the brain on the P20 and P90. On E14, the preferred genes for normalization are Actb, Ppia, Rpl13a.

Homocysteine potentiates amyloid ß $$ \upbeta $$ -induced death receptor 4- and 5-mediated cerebral endothelial cell apoptosis, blood brain barrier dysfunction and angiogenic impairment.

Cerebrovascular dysfunction has been implicated as a major contributor to Alzheimer's Disease (AD) pathology, with cerebral endothelial cell (cEC) stress promoting ischemia, cerebral-blood flow impairments and blood-brain barrier (BBB) permeability. Recent evidence suggests that cardiovascular (CV)/cerebrovascular risk factors, including hyperhomocysteinemia (Hhcy), exacerbate AD pathology and risk. Yet, the underlying molecular mechanisms for this interaction remain unclear. Our lab has demonstrated that amyloid beta 40 (Aß40) species, and particularly Aß40-E22Q (AßQ22; vasculotropic Dutch mutant), promote death receptor 4 and 5 (DR4/DR5)-mediated apoptosis in human cECs, barrier permeability, and angiogenic impairment. Previous studies show that Hhcy also induces EC dysfunction, but it remains unknown whether Aß and homocysteine function through common molecular mechanisms. We tested the hypotheses that Hhcy exacerbates Aß-induced cEC DR4/5-mediated apoptosis, barrier dysfunction, and angiogenesis defects. This study was the first to demonstrate that Hhcy specifically potentiates AßQ22-mediated activation of the DR4/5-mediated extrinsic apoptotic pathway in cECs, including DR4/5 expression, caspase 8/9/3 activation, cytochrome-c release and DNA fragmentation. Additionally, we revealed that Hhcy intensifies the deregulation of the same cEC junction proteins mediated by Aß, precipitating BBB permeability. Furthermore, Hhcy and AßQ22, impairing VEGF-A/VEGFR2 signaling and VEGFR2 endosomal trafficking, additively decrease cEC angiogenic capabilities. Overall, these results show that the presence of the CV risk factor Hhcy exacerbates Aß-induced cEC apoptosis, barrier dysfunction, and angiogenic impairment. This study reveals specific mechanisms through which amyloidosis and Hhcy jointly operate to produce brain EC dysfunction and death, highlighting new potential molecular targets against vascular pathology in comorbid AD/CAA and Hhcy conditions.

High Homocysteine-Thiolactone Leads to Reduced MENIN Protein Expression and an Impaired DNA Damage Response: Implications for Neural Tube Defects.

DNA damage is associated with hyperhomocysteinemia (HHcy) and neural tube defects (NTDs). Additionally, HHcy is a risk factor for NTDs. Therefore, this study examined whether DNA damage is involved in HHcy-induced NTDs and investigated the underlying pathological mechanisms involved. Embryonic day 9 (E9) mouse neuroectoderm cells (NE4C) and homocysteine-thiolactone (HTL, active metabolite of Hcy)-induced NTD chicken embryos were studied by Western blotting, immunofluorescence. RNA interference or gene overexpression techniques were employed to investigate the impact of Menin expression changes on the DNA damage. Chromatin immunoprecipitation-quantitative polymerase chain reaction was used to investigate the epigenetic regulation of histone modifications. An increase in γH2AX (a DNA damage indicator) was detected in HTL-induced NTD chicken embryos and HTL-treated NE4C, accompanied by dysregulation of phospho-Atr-Chk1-nucleotide excision repair (NER) pathway. Further investigation, based on previous research, revealed that disruption of NER was subject to the epigenetic regulation of low-expressed Menin-H3K4me3. Overexpression of Menin or supplementation with folic acid in HTL-treated NE4C reversed the adverse effects caused by high HTL. Additionally, by overexpressing the Mars gene, we tentatively propose a mechanism whereby HTL regulates Menin expression through H3K79hcy, which subsequently influences H3K4me3 modifications, reflecting an interaction between histone modifications. Finally, in 10 human fetal NTDs with HHcy, we detected a decrease in the expression of Menin-H3K4me3 and disorder in the NER pathway, which to some extent validated our proposed mechanism. The present study demonstrated that the decreased expression of Menin in high HTL downregulated H3K4me3 modifications, further weakening the Atr-Chk1-NER pathway, resulting in the occurrence of NTDs.

Hyperhomocysteinemia Presenting as Stroke in a Young Individual: A Case Report.

This case report details the sudden onset of an ischemic stroke in a man in his late 20s, attributed to elevated homocysteine levels. Despite his young age, the patient exhibited increased homocysteine levels, a recognized stroke risk factor. This report underscores the critical importance of recognizing hyperhomocysteinemia as a potential underlying cause of strokes, even in younger age groups. Following ischemic stroke-directed treatment along with the addition of folic acid, vitamin B6, vitamin B12, and methylcobalamin, the patient's condition improved, leading to discharge with normalized homocysteine levels. Highlighting the significance of identifying this risk factor is particularly essential in regions like Pakistan, where a notably high prevalence of hyperhomocysteinemia has been reported. This case serves as a poignant reminder of the need for comprehensive stroke evaluations, urging medical practitioners to consider homocysteine as a potential contributing factor, even when dealing with young and healthy patients.

Effects of Aerobic Treadmill Training on Oxidative Stress Parameters, Metabolic Enzymes, and Histomorphometric Changes in Colon of Rats with Experimentally Induced Hyperhomocysteinemia.

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.

Adult-onset combined methylmalonic acidemia and hyperhomocysteinemia, cblC type with aortic dissection and acute kidney injury: a case report.

BACKGROUND: Combined methylmalonic acidemia (MMA) and hyperhomocysteinemia, cobalamin C (cblC) type, also named cblC deficiency is a rare autosomal recessive genetic metabolic disease. It progressively causes neurological, hematologic, renal and other system dysfunction. The clinical manifestations are relatively different due to the onset time of disease. CASE PRESENTATION: This report describes a rare case of a 26 year old man with cblC deficiency who developed life-threatening aortic dissection and acute kidney injury (AKI) and showed neuropsychiatric symptoms with elevated serum homocysteine and methylmalonic aciduria. After emergent operation and intramuscular cobalamin supplementation therapy, the male recovered from aortic dissection, neurological disorder and AKI. Finally, two previously published compound heterozygous variants, c.482G > A (p.R161Q) and c.658_660del (p.K220del) in the MMACHC gene were detected in this patient and he was confirmed to have cblC deficiency. CONCLUSIONS: Poor cognizance of presenting symptoms and biochemical features of adult onset cblC disease may cause delayed diagnosis and management. This case is the first to depict a case of adult-onset cblC deficiency with aortic dissection. This clinical finding may contribute to the diagnosis of cblC deficiency.

Homocysteine, hyperhomocysteinemia and H-type hypertension.

Homocysteine (Hcy) is a sulfur-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 µmol/L 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.