Hyperhomocysteinemia in a Patient With Subdural Hematoma and Subarachnoid Hemorrhage Secondary to a Traumatic Brain Injury.

Traumatic brain injury (TBI) is a significant global health issue, contributing substantially to mortality and disability. Serum biomarkers, such as homocysteine (Hcy), play a critical role in the prognosis of brain injuries, with hyperhomocysteinemia (HHcy) potentially leading to neurological disorders. We present the case of a 64-year-old patient admitted to the emergency department following a road traffic accident (RTA). Magnetic resonance imaging (MRI) revealed parietal subdural hematoma (SDH), right frontal contusion, and left subarachnoid hemorrhage (SAH). The patient underwent a craniotomy to address SAH and SDH. Initial Hcy levels were markedly elevated compared to post-operative levels. Hcy represents a rapid, non-invasive, and cost-effective diagnostic tool for assessing brain injury severity and guiding medical intervention. Early detection of HHcy could potentially mitigate vascular and neurological complications, thereby improving patient outcomes.

A small molecule p38α MAPK inhibitor, MW150, attenuates behavioral deficits and neuronal dysfunction in a mouse model of mixed amyloid and vascular pathologies.

Background: Inhibition of p38 alpha mitogen activated protein kinase (p38α) has shown great promise as a treatment for Alzheimer's disease (AD) in preclinical tests. However, previous preclinical studies were performed in "pure" models of AD pathology. A vast majority of AD patients have comorbid dementia-contributing pathologies, particularly some form of vascular damage. The present study therefore aimed to test the potential of p38α inhibition to address dysfunction in the context of comorbid amyloid and vascular pathologies. Methods: An amyloid overexpressing mouse strain (5xFAD) was placed on an 8-week long diet to induce the hyperhomocysteinemia (HHcy) model of small vessel disease. Mice were treated with the brain-penetrant small molecule p38α inhibitor MW150 for the duration of the HHcy diet, and subsequently underwent behavioral, neuroimaging, electrophysiological, or biochemical/immunohistochemical analyses. Results: MW150 successfully reduced behavioral impairment in the Morris Water Maze, corresponding with attenuation of synaptic loss, reduction in tau phosphorylation, and a partial normalization of electrophysiological parameters. No effect of MW150 was observed on the amyloid, vascular, or neuroinflammatory endpoints measured. Conclusions: This study provides proof-of-principle that the inhibition of p38α is able to provide benefit even in the context of mixed pathological contributions to cognitive impairment. Interestingly, the benefit was mediated primarily via rescue of neuronal function without any direct effects on the primary pathologies. These data suggest a potential use for p38 inhibitors in the preservation of cognition across contexts, and in particular AD, either alone or as an adjunct to other AD therapies (i.e. anti-amyloid approaches). Future studies to delineate the precise neuronal pathways implicated in the benefit may help define other specific comorbid conditions amenable to this type of approach or suggest future refinement in pharmacological targeting.

Catalpol inhibits HHcy-induced EndMT in endothelial cells by modulating ROS/NF-κB signaling.

BACKGROUND: Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis (AS). Endothelial mesenchymal transition (EndMT) refers to the process in which endothelial cells lose endothelial cell morphology and characteristic gene expression, and acquire phenotypic characteristics and gene expression related to mesenchymal cells. Numerous studies have confirmed that EndMT is involved in the formation of atherosclerosis. Catalpol is one of the active components of Rehmannia, which has antioxidant, anti-inflammatory, anti-tumor, neuroprotective and other biological activities. Studies have shown that catalpol can reduce atherosclerotic plaque induced by high sugar or fat. However, the effect of catalpol on HHCY-induced EndMT is unclear. METHODS AND RESULTS: In vitro HHcy-treated primary human umbilical vein endothelial cells (HUVECs) were used to construct a cell model, and the antioxidants N-acetylcysteine (NAC) and catalase alcohol were administered. In vivo C57BL/6N mice were given a diet fed with 4.4% high methionine chow to construct a HHcy mice model and were treated with catalpol. The results showed that hhcy could induce morphological transformation of endothelial cells into mesenchymal cells, increase intracellular ROS content, up-regulate α-SMA, N-cadherin, p-p65 protein expression, down-regulate VE-cadherin, CD31 protein expression, induce pathological changes of aortic root endothelium, and increase aortic endothelial ROS content. Catalpol reversed these hhcy induced outcomes. CONCLUSIONS: Catalpol inhibits HHcy-induced EndMT, and the underlying mechanism may be related to the ROS/NF-κB signaling pathway. Catalpol may be a potential drug for the treatment of HHcy-related AS.

Homocysteine, blood pressure and gene-diet interactions in relation to vascular function measures of black South Africans.

BACKGROUND AND AIMS: We investigated circulating homocysteine (Hcy), a cardiovascular disease (CVD) risk factor, examining its dietary associations to provide personalized nutrition advice. This study addressed the inadequacy of current dietary interventions to ultimately address the disproportionately high incidence of CVD in Black populations. METHODS AND RESULTS: Cross-sectional analyses of 1,867 Black individuals of the PURE-SA study allowed the identification of dietary intake and cardiovascular measure interactions on three sub-categories: (1) normal blood pressure (BP), hypertension or Hcy-related hypertension (H-type), (2) low, normal or high Hcy concentrations, and (3) Hcy-related genetic combinations. Favorable body composition, but adverse dietary intake and cardiovascular determinants, were observed in higher Hcy categories. H-types, compared to regular hypertensives, had higher alcohol and lower macronutrient and micronutrient consumption. Inverse associations with carotid-radial pulse wave velocity were evident between monounsaturated fatty acid (FA) consumption and H-type hypertension as well as polyunsaturated FA and CBS883/ins68 TT carriers. Energy intake was positively associated with vascular cell adhesion molecule-1 (VCAM-1) in variant CBST883C/ins68 and CBS9276 GG carriers. VCAM-1 was also positively associated with plant protein intake in CBS9276 GG and MTR2756 AA carriers and negatively with total protein intake and CBS9276 GG carriers. Alcohol intake was positively associated with intercellular adhesion molecule-1 in MTR2756 minor allele carriers. CONCLUSION: Because Hcy gene-diet interactions are evident, personalized nutrition, by adjusting diets based on genetic profiles (e.g., CBS and MTR variations) and dietary interactions (e.g., FAs and proteins), can enhance cardiovascular outcomes by managing Hcy and related hypertension in genetically susceptible individuals.

Case report: Rare variants in the MTRR gene, 66GG and 524TT cause hyperhomocysteinemia and folic acid deficiency linked to schizophrenia.

We present an adult patient with schizophrenia who was later found to have hyperhomocysteinemia, a condition that increases the risk of several diseases, due to a deficiency in folic acid. Although folic acid supplementation quickly normalized the hyperhomocysteinemia and folic acid levels, it did not significantly improve the overall mental and cognitive health. Genotype analysis was performed and the patient was found to have two pathogenic variants in the MTRR gene, 66GG and 524TT, which encodes for methionine synthase reductase (MSR), an enzyme crucial for homocysteine metabolism. The results can shed light on the reasons behind the patient's hyperhomocysteinemia and folic acid deficiency. Hyperhomocysteinemia confers an increased risk of several diseases. Indeed, the patient has neurodevelopment and cardiovascular health problems for decades. Given the rarity of the condition and the nonspecific nature of the symptoms, the detection of hyperhomocysteinemia or MSR deficiency can often be delayed or overlooked. Considering the potential irreversible and detrimental consequences of prolonged hyperhomocysteinemia and folic acid deficiency that our patient is likely experiencing, we suggest that clinicians be vigilant for associated signs when they encounter adolescents exhibiting psychotic symptoms, especially those with additional physical symptoms and a history of resistance to treatment.

Analysis of MTHFR C677T genotype and related factors in H-type hypertension in Tibet, China.

BACKGROUND AND AIMS: H-type hypertension is essential hypertension combined with high homocysteine, and both synergistically increase the risk of cardiovascular and cerebrovascular events. The aim of this study was to investigate the risk factors of H-type hypertension in Tibetan plateau population and correlation with MTHFR C677T gene. METHODS AND RESULTS: A multi-stage cluster random sampling method was used to select the research subjects in Tibet Autonomous Region from June 2020 to November 2021. Among Tibetans, the incidence of H-type hypertension accounted for 84.31% of hypertensive patients. The logistic regression analysis demonstrated that age, uric acid (UA), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) were risk factors for the prevalence of H-type hypertension, the OR (95% CI) was 1.083(1.073-1.094), 1.002(1.001-1.004), 1.240(1.050-1.464) and 2.274(1.432-3.611), respectively. MTHFR C677T TT genotype patients with H-type hypertension OR (95% CI) was 1.629(1.004-2.643). Based on this, a nomogram model was established, and the reliability of the model was proved by area under ROC curve, Brier score and average absolute error. The model's results indicate that for every five years of age, the score increases by 6 points; for a 2mmol/L increase in TG, the score increases by 5.5 points; for a 1mmol/L increase in LDL-C, the score increases by 10 points; and individuals with the TT genotype receive 8 points. The higher the score, the greater the risk of disease. CONCLUSION: The MTHFR C677T TT genotype is a risk locus for Tibetan patients with H-type hypertension, with age, TG, and LDL-C were identified as risk factors for the disease.

Elevated homocysteine is negatively correlated with plasma cystathionine ß-synthase activity in givosiran-treated patients.

Givosiran is a subcutaneously administered, liver-targeted RNA interference (RNAi) therapeutic that has been approved for treating acute hepatic porphyria (AHP). Elevation in plasma homocysteine (hyperhomocysteinemia) has been reported in AHP patients, and treatment with givosiran has been reported to further increase homocysteine levels in some patients. The mechanism of homocysteine elevation during givosiran treatment is unknown, but has been hypothesized to be mediated by a reduction in activity of cystathionine ß-synthase (CBS), which uses homocysteine as a substrate. A liquid chromatography-tandem mass spectrometry-based assay was adapted to measure circulating CBS activity. Using plasma collected from the Phase III ENVISION study, CBS activity was measured to directly evaluate whether it is associated with elevated homocysteine levels in givosiran-treated patients. CBS activity was reduced following givosiran treatment and both homocysteine and methionine levels were inversely correlated with CBS activity. Following administration of a supplement containing vitamin B6, a cofactor for CBS, in four patients during the trial, plasma CBS activity was found to increase, mirroring a corresponding decrease in homocysteine levels. These results support the hypothesis that elevated homocysteine levels following givosiran treatment result from a reduction of CBS activity and that vitamin B6 supplementation lowers homocysteine levels by increasing CBS activity.

Is There a Connection between Hyperhomocysteinemia and the Cardiometabolic Syndrome?

This study investigates the distribution of hyperhomocysteinemia and cardiovascular metabolic syndrome (SM) among participants, shedding light on their prevalence and co-occurrence within the study cohort. Through an analysis of demographic characteristics and health parameters, including age, gender, and body mass index (BMI), alongside nutritional data, correlations between these factors and health risks are explored. Results reveal a notable prevalence of hyperhomocysteinemia, with 45.3% of participants exhibiting this condition. Furthermore, 31.4% of the cohort does not present hyperhomocysteinemia or SM, while 23.3% shows SM without hyperhomocysteinemia. The study underscores gender-specific dietary recommendations due to significant variations in nutrient intake patterns. Additionally, inverse correlations between health risks like obesity, hypertension, and hypercholesterolemia and nutrient requirements highlight the need for tailored dietary interventions. Age-related changes in nutrient needs and the positive correlation between physical activity levels and certain nutrient demands further emphasize the importance of personalized dietary strategies. Variations in nutrient intake by gender, inverse correlations with health risks, and age-related changes underscore the need for tailored dietary strategies. These findings provide valuable insights for healthcare professionals in developing targeted nutritional interventions to mitigate disease risk and promote overall health and well-being.

The association between hyperhomocysteinemia and the prevalence of bilateral carotid atherosclerotic plaques in a middle-aged population.

OBJECTIVE: We conducted a cross-sectional study to investigate the impact of hyperhomocysteinemia (HHcy) on the prevalence of CASP among middle-aged individuals, aiming to provide insights for CASP prevention. METHODS: 1105 subjects were categorized into HHcy group or normal tHcy group based on their plasma total homocysteine (tHcy). All participants underwent carotid artery ultrasonography to assess the presence of unilateral and bilateral CASP. Comparative analyses of demographic and clinical data were conducted between the two groups. Logistic regression and prespecified subgroup analyses were performed to determine whether HHcy independently contributed to bilateral CASP. RESULTS: 132 individuals exhibited bilateral CASP. The prevalence of bilateral CASP was significantly higher in the HHcy group compared to the normal tHcy group (21.55 % vs. 10.82 %, p = 0.003). Univariate logistic analysis showed a significant association between HHcy and the prevalence of bilateral CASP (OR = 2.056, 95 %CI 1.089-3.881, p = 0.026). In all four models of multivariate logistic analysis, HHcy consistently emerged as an independent risk factor for bilateral CASP, with odd ratios of 1.958, 2.047, 2.023, and 2.186. This association remained significant across all five subgroups stratified by age, sex, hypertension, diabetes, and BMI. CONCLUSION: Our studies demonstrated HHcy was an independent risk factor for the prevalence of bilateral CASP in the middle-aged population. Theses results emphasized the importance of addressing HHcy in preventive strategies aimed at mitigating the burden of CASP among middle-aged individuals.

H2S prevents the disruption of the blood-brain barrier in rats with prenatal hyperhomocysteinemia.

Elevation of the homocysteine concentration in the plasma called hyperhomocysteinemia (hHCY) during pregnancy causes a number of pre- and postnatal developmental disorders. The aim of our study was to analyze the effects of H2S donors -NaHS and N-acetylcysteine (NAC) on blood-brain barrier (BBB) permeability in rats with prenatal hHCY. In rats with mild hHCY BBB permeability assessed by Evans Blue extravasation in brain increased markedly throughout life. Administration of NaHS or NAC during pregnancy attenuated hHCY-associated damage and increased endogenous concentrations of sulfides in brain tissues. Acute application of dl-homocysteine thiolactone induced BBB leakage, which was prevented by the NMDA receptor antagonist MK-801 or H2S donors. Rats with hHCY demonstrated high levels of NO metabolite - nitrites and proinflammatory cytokines (IL-1ß, TNF-α, IL-6) in brain. Lactate dehydrogenase (LDH) activity in the serum was higher in rats with hHCY. Mitochondrial complex-I activity was lower in brain of hHCY rats. NaHS treatment during pregnancy restored levels of proinflammatory cytokines, nitrites and activity of the respiratory chain complex in brain as well as the LDH activity in serum. Our data suggest that H2S has neuroprotective effects against prenatal hHCY-associated BBB disturbance providing a potential strategy for the prevention of developmental impairments in newborns.

Hyperhomocysteinemia is associated with the risk of venous thromboembolism in patients with mental illness: a case-control study.

Objective: The risk of venous thromboembolism in patients with mental illness has been insufficiently addressed. This study aimed to assess the correlation between hyperhomocysteinemia and venous thromboembolism prevalence among this population. Methods: Patients with a diagnosis of mental illness and concurrent venous thromboembolism, admitted to Sir Run Run Shaw Hospital at Zhejiang University School of Medicine between January 2014 and December 2021, were included in the venous thromboembolism group. The control group, approximately twice the size, comprised individuals with mental illness but without venous thromboembolism. Basic clinical data were gathered for both cohorts. Results: In psychiatric patients, elevated D-dimer levels(OR=5.60,95% CI 3.28-10.00), hyperhomocysteinemia (OR=2.37,95% CI 1.10-5.14), and hyperprolactinemia(OR= 2.68,95% CI 1.12-6.42)were significant risk factors for venous thromboembolism. According to further subgroup analyses, hyperhomocysteinemia is a significant risk factor associated with pulmonary embolism, with an OR of 5.08 (95% CI 1.20-21.48). An interaction effect between gender and homocysteine level was found, with a p-interaction of 0.022. A subsequent analysis confirmed the association between hyperhomocysteinemia and venous thromboembolism in female psychiatric patients, with an OR of 3.34 (95% CI 1.68-6.65), indicating that hyperhomocysteinemia is a significant risk factor for venous thromboembolism in women. Conclusion: Patients with psychiatric disorders were found to have an elevated risk of venous thromboembolism, which was associated with increased levels of D-dimer, hyperprolactinemia, and hyperhomocysteinemia. A strong correlation between hyperhomocysteinemia and pulmonary embolism was identified in patients with mental illnesses. Furthermore, the study revealed that female psychiatric patients with hyperhomocysteinemia constituted a high-risk group for venous thromboembolism. This finding holds significant clinical implications, suggesting that early preventative measures could be implemented for this high-risk population to reduce the incidence of thromboembolic events during hospitalization for psychiatric patients.

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.

The Etiology of the Thrombotic Phenomena Involved in the Process of Coronary Artery Disease-What Is the Role of Thrombophilic Genes in the Development of This Pathology?

Cardiovascular diseases, among which includes coronary artery disease, represent one of the most important causes of mortality and morbidity worldwide. Research aimed at determining the risk factors involved recognizes a group of "traditional" risk factors, but also more recent studies identified over 100 "novel" ones which may have a role in the disease. Among the latter is the thrombophilia profile of a patient, a pathology well-established for its involvement in venous thromboembolism, but with less studied implications in arterial thrombosis. This paper reviews the literature, explaining the pathophysiology of the thrombophilia causes associated most with coronary thrombosis events. Results of several studies on the subject, including a meta-analysis with over 60,000 subjects, determined the significant involvement of factor V Leiden, prothrombin G20210A mutation, plasminogen activator inhibitor-1 and antiphospholipid syndrome in the development of coronary artery disease. The mechanisms involved are currently at different stages of research, with some already established and used as therapeutic targets.

Associations of serum vitamin B12 and its biomarkers with musculoskeletal health in middle-aged and older adults.

Introduction: The effects of vitamin B12 metabolism on musculoskeletal health and the exact mechanism have not been fully determined. Our study aimed to assess the association of vitamin B12 and its biomarkers with musculoskeletal health in middle-aged and older adults. Methods: The data from the National Health and Nutrition Examination Survey 2001-2002 were used to investigate the effects of serum vitamin B12 and its biomarkers (homocysteine and methylmalonic acid) on skeletal muscle health. Bone mineral density (BMD), lean mass, gait speed and knee extensor strength were used as indicators for musculoskeletal health. Results: Serum vitamin B12 level was positively correlated with the total and appendicular lean mass (ß = 584.83, P = 0.044; ß = 291.65, P = 0.043) in older adults over 65 years of age. In the full population, plasma homocysteine was associated with total lean mass, appendicular lean mass, gait speed, and knee extensor strength (all P < 0.05). Among older adults over 65 years of age, homocysteine level was significantly negatively correlated with gait speed and knee extensor strength (ß = -12.75, P = 0.019; ß = -0.06, P <0.001). Plasma methylmalonic acid was negatively associated with total BMD and femur BMD in the full population (ß = -0.01, P = 0.018; ß = -0.01, P = 0.004). In older adults, methylmalonic acid significantly affected total BMD, femur BMD and knee extensor strength (ß = -0.01, P = 0.048; ß = -0.01, P = 0.025; ß = -7.53, P = 0.015). Conclusions: Vitamin B12 and its biomarkers are closely related to BMD, body composition, muscle strength and physical function in middle-aged and older adults. Vitamin B12 may be an important indicator of musculoskeletal health in the elderly.

Podocyte-specific silencing of acid sphingomyelinase gene to abrogate hyperhomocysteinemia-induced NLRP3 inflammasome activation and glomerular inflammation.

Acid sphingomyelinase (ASM) has been reported to increase tissue ceramide and thereby mediate hyperhomocysteinemia (hHcy)-induced glomerular nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation, inflammation, and sclerosis. In the present study, we tested whether somatic podocyte-specific silencing of Smpd1 gene (mouse ASM gene code) attenuates hHcy-induced NLRP3 inflammasome activation and associated extracellular vesicle (EV) 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 (podocyte-specific expression of cre recombinase) mice compared with control littermates. By nanoparticle tracking analysis (NTA), floxed Smpd1 shRNA transfection was found to abrogate hHcy-induced elevation of urinary EV 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. Such protective effects of podocyte-specific Smpd1 gene silencing were mimicked by global knockout of Smpd1 gene in Smpd1-/- mice. On the contrary, podocyte-specific Smpd1 gene overexpression exaggerated hHcy-induced glomerular pathological changes in Smpd1trg/Podocre (podocyte-specific Smpd1 gene overexpression) mice, which were significantly attenuated by transfection of floxed Smpd1 shRNA. In cell studies, we also confirmed that Smpd1 gene knockout or silencing prevented homocysteine (Hcy)-induced elevation of EV release in the primary cultures of podocyte isolated from Smpd1-/- mice or podocytes of Podocre mice transfected with floxed Smpd1 shRNA compared with WT/WT podocytes. Smpd1 gene overexpression amplified Hcy-induced EV secretion from podocytes of Smpd1trg/Podocre mice, which was remarkably attenuated by transfection of floxed Smpd1 shRNA. Mechanistically, Hcy-induced elevation of EV release from podocytes was blocked by ASM inhibitor (amitriptyline, AMI), but not by NLRP3 inflammasome inhibitors (MCC950 and glycyrrhizin, GLY). 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. Moreover, we found that podocyte-derived inflammatory EVs (released from podocytes treated with Hcy) induced podocyte injury, which was exaggerated by T cell coculture. Interstitial infusion of inflammatory EVs into renal cortex induced glomerular injury and immune cell infiltration. In conclusion, our findings suggest that ASM in podocytes plays a crucial role in the control of NLRP3 inflammasome activation and inflammatory EV release during hHcy and that the development of podocyte-specific ASM inhibition or Smpd1 gene silencing may be a novel therapeutic strategy for treatment of hHcy-induced glomerular disease with minimized side effect.NEW & NOTEWORTHY In the present study, we tested whether podocyte-specific silencing of Smpd1 gene attenuates hyperhomocysteinemia (hHcy)-induced nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation and associated inflammatory extracellular vesicle (EV) release in podocytes and thereby suppresses glomerular inflammatory response and injury. Our findings suggest that acid sphingomyelinase (ASM) in podocytes plays a crucial role in the control of NLRP3 inflammasome activation and inflammatory EV release during hHcy. Based on our findings, it is anticipated that the development of podocyte-specific ASM inhibition or Smpd1 gene silencing may be a novel therapeutic strategy for treatment of hHcy-induced glomerular disease with minimized side effects.

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.

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.