HYPERHOMOCYSTEINEMIA AS A CAUSE OF ERECTILE DYSFUNCTION.

Hyperhomocysteinaemia (elevated blood levels of the amino acid homocysteine) attracted the interest of researchers in the middle of the 20th century. At first. Butz and du Vigneaud in 1932 described a disorder of methionine metabolism in children, which was manifested by homocysteinuria (homocysteine is not normally detected in the urine). In 1962 Cavon and Neil found that homocysteinuria in children is associated with a defect in cystathione-B-synthase and manifests early development of atherosclerosis. It is quite possible that these facts would have remained unnoticed by the medical community had it not been for further research by Kilmer McQuilley, a professor in the Department of Pathology at Harvard Medical School. The scientist suggested that while high concentrations of homocysteine could damage blood vessels in young people, it was likely that lower concentrations of homocysteine, acting over a longer period of time, could cause cardiovascular disease in adults. Subsequent studies enabled him to formulate the "homocysteine" theory of atherosclerosis and to publish its main points in 1969. Hyperhomocysteinaemia in young men has been shown to cause damage to the endothelium of blood vessels, and consequently males face the consequent equally global problem of developing erectile dysfunction. Erection is a state regulated by a neurovascular process, characterized by blood filling of the cavernous bodies, provided by neural and humoral mechanisms occurring at different levels of the nervous system. Erectile dysfunction (ED) refers to the inability to achieve and maintain an erection at a level necessary to ensure satisfactory sexual intercourse, Although ED is not life-threatening. it is a serious psychological and physiological problem, and it has now been shown to correlate the quality of intimate life with general health and even with life expectancy, In the USA alone, ED is reported in 20-30 million men, and the prevalence of these disorders increases with age. A study of the homocysteine level of multidisciplinary hospital patients was used as the main marker. The work used laboratory and statistical research methods, as well as analysis and synthesis methods. Using patient analyses, laboratory and statistical data, it has been shown that hyperhomosysteinaemia is one of the molecular mechanisms in the development of erectile dysfunction.

Cerebral Venous Sinus Thrombosis Secondary to Vitamin B12 Deficiency - A Case Series with Emphasis on Food Fortification.

The etiology of cerebral venous sinus thrombosis (CVST) is multifactorial. Although many acquired and genetic factors have been recognized as risk factors, hyperhomocysteinemia (hHcy) is independently associated with CVST. We describe three cases of CVST in this case series. All of them presented with headache. Two patients had papilledema and visual disturbances. On evaluation, there was CVST, and prothrombotic workup showed hHcy. In addition, two of them reported very low Vitamin B12 levels. All of them were treated with low-molecular-weight heparin followed by oral anticoagulation and Vitamin B6, B9, and B12 supplements. All of them responded to treatment, and follow-up imaging studies in two of them showed resolution of thrombosis. hHcy should be considered in the evaluation of CVST, especially in the setting of a pure vegetarian diet. Fortification of the diet with Vitamin B12 may be considered the majority of Indians consume predominantly vegetarian food.

RésuméL'étiologie de la thrombose veineuse cérébrale (CVST) est multifactorielle. Bien que de nombreux facteurs acquis et génétiques aient été reconnus comme facteurs de risque, l'hyperhomocystéinémie (hHcy) est indépendamment associée à la CVST. Nous décrivons trois cas de CVST dans cette série de cas. Tous présentaient des maux de tête. Deux patients avaient un oedème papillaire et des troubles visuels. Lors de l'évaluation, il y avait une CVST et le bilan prothrombotique montrait une hHcy. De plus, deux d'entre eux ont rapporté des niveaux très bas de vitamine B12. Tous ont été traités avec de l'héparine de bas poids moléculaire suivie d'une anticoagulation orale et de suppléments de vitamines B6, B9 et B12. Tous ont répondu au traitement, et des études d'imagerie de suivi chez deux d'entre eux ont montré une résolution de la thrombose. L'hHcy doit être envisagée dans l'évaluation de la (CVST), en particulier dans le contexte d'un régime purement végétarien. La fortification de l'alimentation avec de la vitamine B12 peut être envisagée car la majorité des Indiens consomment principalement des aliments végétariens.

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.

Implications of high homocysteine levels in migraine pain: An experimental study of the excitability of peripheral meningeal afferents in rats with hyperhomocysteinemia.

OBJECTIVES: Investigation of chronic homocysteine action on the excitability and N-methyl-D-aspartate (NMDA) sensitivity of the peripheral trigeminovascular system of rats. BACKGROUND: Migraine is a neurological disease that affects 15%-20% of the general population. Epidemiological observations show that an increase of the sulfur-containing amino acid homocysteine in plasma-called hyperhomocysteinemia-is associated with a high risk of migraine, especially migraine with aura. In animal studies, rats with hyperhomocysteinemia demonstrated mechanical allodynia, photophobia, and anxiety, and higher sensitivity to cortical spreading depression. In addition, rats with hyperhomocysteinemia were more sensitive in a model of chronic migraine induced by nitroglycerin which indicated the involvement of peripheral nociceptive mechanisms. The present work aimed to analyze the excitability of meningeal afferents and neurons isolated from the trigeminal ganglion of rats with prenatal hyperhomocysteinemia. METHODS: Experiments were performed on male rats born from females fed with a methionine-rich diet before and during pregnancy. The activity of meningeal afferents was recorded extracellularly in hemiskull preparations ex vivo and action potentials were characterized using cluster analysis. The excitability of trigeminal ganglion neurons was assessed using whole-cell patch clamp recording techniques and calcium imaging studies. Meningeal mast cells were stained using toluidine blue. RESULTS: The baseline extracellular recorded electrical activity of the trigeminal nerve was higher in the hyperhomocysteinemia group with larger amplitude action potentials. Lower concentrations of KCl caused an increase in the frequency of action potentials of trigeminal afferents recorded in rat hemiskull ex vivo preparations. In trigeminal ganglion neurons of rats with hyperhomocysteinemia, the current required to elicit at least one action potential (rheobase) was lower, and more action potentials were induced in response to stimulus of 2 × rheobase. In controls, short-term application of homocysteine and its derivatives increased the frequency of action potentials of the trigeminal nerve and induced Ca2+ transients in neurons, which are associated with the activation of NMDA receptors. At the same time, in rats with hyperhomocysteinemia, we did not observe an increased response of the trigeminal nerve to NMDA. Similarly, the parameters of Ca2+ transients induced by NMDA, homocysteine, and its derivatives were not changed in rats with hyperhomocysteinemia. Acute incubation of the meninges in homocysteine and homocysteinic acid did not change the state of the mast cells, whereas in the model of hyperhomocysteinemia, an increased degranulation of mast cells in the meninges was observed. CONCLUSIONS: Our results demonstrated higher excitability of the trigeminal system of rats with hyperhomocysteinemia. Together with our previous finding about the lower threshold of generation of cortical spreading depression in rats with hyperhomocysteinemia, the present data provide evidence of homocysteine as a factor that increases the sensitivity of the peripheral migraine mechanisms, and the control of homocysteine level may be an important strategy for reducing the risk and/or severity of migraine headache attacks.

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.

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.

Exercise attenuates the perioperative neurocognitive disorder induced by hyperhomocysteinemia in mice.

The perioperative neurocognitive disorder (PND) is a severe complication that affects millions of surgical patients each year. Homocysteine (Hcy) is known to increase the risk of developing PND in both young and elderly mice. However, whether Hcy alone can induce cognitive deficits in middle-aged mice (12-month-old), whether exercise can attenuate Hcy-induced hippocampus-related cognitive deficits after surgery through suppressing neuroinflammation, synaptic elimination, and the level of Hcy remains unknown. The present study aimed to answer these questions through testing the possibility of establishing a PND model using 12-month-old mice which received homocysteine injections before exploratory laparotomy and the therapeutic mechanism of exercise. In the present study, it was found that levels of serum homocysteine were age-dependently increased in mice with a significant difference between that of 18-month-old mice and 6-week, 6-month, and 12-month-old mice. PND occurred in 18-month but not in 12-month-old mice after exploratory laparotomy under isoflurane anesthesia. Intraperitoneal injection of Hcy for 3 consecutive days before surgery rendered 12-month-old mice to develop PND after abdominal laparotomy under isoflurane anesthesia at a minimal dosage of 20 mg/kg. Neuroinflammation and synaptic elimination was present in 12-month-old preoperative Hcy-injected mice. Preoperative voluntary wheel exercise could prevent PND in 12-month-old mice that have received Hcy injection before surgery, which might be related to the decreased level of serum Hcy. Activation of glial cells, proinflammatory phenotype markers and synaptic elimination were attenuated in the hippocampus of 12-month-old preoperative Hcy-injected mice by this exercise. These results provide direct evidence that hyperhomocysteinemia can induce postoperative cognitive deficits in middle-aged mice. Pre-surgery exercise can effectively prevent Hcy-precipitated postoperative cognitive dysfunction.

The effect of metabolic factors on the association between hyperuricemia and chronic kidney disease: a retrospective cohort mediation analysis.

BACKGROUND: Hyperuricemia, hyperglycemia, hypertension, hyperlipidemia, and hyperhomocysteinemia are all established risk factors for chronic kidney disease (CKD), and their interplay could exacerbate CKD progression. This study aims to evaluate the potential mediation effects of hyperglycemia, hypertension, hyperlipidemia, and hyperhomocysteinemia on the association between hyperuricemia (HUA) and chronic kidney disease (CKD). METHODS: We collected electronic medical record data from 2055 participants who underwent physical examinations at the Affiliated Hospital of Qingdao University. The data were utilized to investigate the mediating effect of various factors including systolic blood pressure (SBP), diastolic blood pressure (DBP), homocysteine (HCY), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), blood glucose (Glu), and hemoglobin A1c (HbA1c) on the relationship between HUA and CKD. RESULTS: Upon adjusting for confounding variables, mediation analysis indicated that only HCY acted as a mediator in the HUA-CKD relationship (p value < 0.05), exhibiting a statistically significant mediation effect of 7.04%. However, after adjustment for multiple testing, none of these variables were statistically significant. CONCLUSIONS: Considering the observed associations between hyperuricemia, hyperglycemia, hypertension, hyperlipidemia, and CKD, none of the factors of interest remained statistically significant after adjusting for multiple testing as potential mediators of hyperuricemia on CKD.

Homocysteine Facilitates the Formation of Carotid Atherosclerotic Plaque Through Inflammatory and Noninflammatory Mechanisms.

Background: Elevated homocysteine (Hcy) was considered a significant risk factor in the development and progression of carotid atherosclerosis (CAS), which involves a combination of inflammatory and noninflammatory mechanisms. However, epidemiological surveys have presented conflicting results. In this study, we aim to offer an epidemiological viewpoint on how elevated Hcy impacts CAS and its potential mechanisms. Methods: Levels of high-sensitivity C-reactive protein (hsCRP) were measured to assess the inflammatory status. The estimation of CAS events was performed by assessing carotid intima-media thickness using Doppler ultrasonography. Univariate analysis was conducted to investigate the variations in biochemical parameters among three groups: normal, carotid atherosclerotic thickening (CAT), and carotid atherosclerotic plaque (CAP) formation. Logistic regression analysis was conducted to identify the risk factors associated with the progression of CAT and CAP. In addition, multivariate linear regression analysis was conducted to identify the independent factors that correlated with hsCRP levels. Results: The study encompassed 3897 participants, with 2992 (76.8%) being males and 905 (23.2%) being females. The incidence of CAT and CAP rose with higher Hcy levels, with an overall odds ratio (OR) of 2.04 [95% confidence intervals (CI) 1.69-2.40] for CAT and 2.68 (95% CI 2.32-3.05) for CAP. After adjusting for gender, age, and blood markers, the OR for CAT and CAP decreased, with an overall OR of 1.05 (95% CI 0.81-1.28) and OR of 1.24 (95% CI 1.02-1.46), respectively. CAP risk independently increased when Hcy level exceeded 19.7 µmol/L (P = 0.030), but not CAT risk (P = 0.299). The impact of hsCRP on CAS events is similar to that of Hcy, and a multiple linear analysis found a significant independent correlation between hsCRP and Hcy (P = 0.001). Conclusions: Elevated Hcy levels can facilitate the formation of CAP through both inflammatory and noninflammatory processes, but it does not independently influence CAT.

Homocysteine potentiates amyloid ß -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-resolution MRI vessel wall enhancement in moyamoya disease: risk factors and clinical outcomes.

OBJECTIVES: Intracranial vessel wall enhancement (VWE) on high-resolution magnetic resonance imaging (HRMRI) is associated with the progression and poor prognosis of moyamoya disease (MMD). This study assessed potential risk factors for VWE in MMD. METHODS: We evaluated MMD patients using HRMRI and traditional angiography examinations. The participants were divided into VWE and non-VWE groups based on HRMRI. Logistic regression was performed to compare the risk factors for VWE in MMD. The incidence of cerebrovascular events of the different subgroups according to risk factors was compared using Kaplan-Meier survival and Cox regression. RESULTS: We included 283 MMD patients, 84 of whom had VWE on HRMRI. The VWE group had higher modified Rankin Scale scores at admission (p = 0.014) and a higher incidence of ischaemia and haemorrhage (p = 0.002) than did the non-VWE group. Risk factors for VWE included the ring finger protein 213 (RNF213) p.R4810K variant (odds ratio [OR] 2.01, 95% confidence interval [CI] 1.08-3.76, p = 0.028), hyperhomocysteinaemia (HHcy) (OR 5.08, 95% CI 2.34-11.05, p < 0.001), and smoking history (OR 3.49, 95% CI 1.08-11.31, p = 0.037). During the follow-up of 63.9 ± 13.2 months (median 65 months), 18 recurrent stroke events occurred. Cox regression showed that VWE and the RNF213 p.R4810K variant were risk factors for stroke. CONCLUSION: The RNF213 p.R4810K variant is strongly associated with VWE and poor prognosis in MMD. HHcy and smoking are independent risk factors for VWE. CLINICAL RELEVANCE STATEMENT: Vessel wall enhancement in moyamoya disease is closely associated with poor prognosis, especially related to the ring finger protein 213 p.R4810K variant, hyperhomocysteinaemia, and smoking, providing crucial risk assessment information for the clinic. KEY POINTS: • The baseline presence of vessel wall enhancement is significantly associated with poor prognosis in moyamoya disease. • The ring finger protein 213 p.R4810K variant is strongly associated with vessel wall enhancement and poor prognosis in moyamoya disease. • Hyperhomocysteinaemia and smoking are independent risk factors for vessel wall enhancement in moyamoya disease.

Homocysteine, hyperhomocysteinemia, and H-type hypertension.

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

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 and Parkinson's disease.

Homocysteine (Hcy) is an important metabolite in methionine metabolism. When the metabolic pathway of homocysteine is abnormal, it will accumulate in the body and eventually lead to hyperhomocysteinemia. In recent years, many studies have found that hyperhomocysteinemia is related to the occurrence and development of Parkinson's disease. This study reviews the roles of homocysteine in the pathogenesis of Parkinson's disease and illustrates the harmful effects of hyperhomocysteinemia on Parkinson's disease.

Hyperhomocysteinemia may aggravate abdominal aortic aneurysm formation by up-regulating RASSF2.

Abdominal aortic aneurysm (AAA) is a fatal cardiovascular disorder with high mortality and morbidity rates. To date, no drug has shown to significantly alleviate the risk of AAA. Previous studies have indicated that hyperhomocysteinemia (HHcy) significantly increases the incidence of AAA by disrupting endothelial cell homeostasis; however, the potential molecular mechanisms require clarification. Herein, we aimed to integrate transcriptomics analysis and molecular biology experiments to explore the potential molecular targets by which HHcy may increase the incidence of AAA. We integrated two AAA data profiles (GSE57691 and GSE7084) based on previously published microarray ribonucleic acid sequencing (RNAseq) data from the GEO database. Additionally, 500 µM homocysteine-treated human aorta endothelium cells microarray dataset (GSE175748) was downloaded and processed. Subsequently, single-cell RNA-seq profiles of the aortic aneurysms (GSE155468) were downloaded, scaled, and processed for further analysis. The microarray profiles analysis demonstrated that the Ras association domain family member 2 (RASSF2) and interleukin (IL)-1ß are potentially the target genes involved in the HHcy-mediated aggravation of AAA formation. Single-cell RNAseq analysis revealed that RASSF2 might impair endothelial cell function by increasing inflammatory cell infiltration to participate in AAA formation. Finally, we conducted reverse transcription quantitative polymerase chain reaction and immunofluorescence analysis to validate the up-regulated mRNA expression of RASSF2 (p = 0.008) and IL-1ß (p = 0.002) in AAA tissue compared to control tissue. Immunofluorescence staining revealed overexpression of RASSF2 protein in AAA tissue sections compared to control tissue (p = 0.037). Co-localization of RASSF2 and the aortic endothelium cell marker, CD31, was observed in tissue sections, indicating the potential involvement of RASSF2 in aortic endothelial cells. To summarise, our preliminary study revealed that HHcy may worsen AAA formation by up-regulating the expression of RASSF2 and IL-1ß in aortic endothelium cells.

[Research progress on the role and mechanism of endothelial dysfunction in hyperhomocysteine-induced atherosclerosis].

Hyperhomocysteinemia (HHcy) is considered to be an independent risk factor for cardiovascular diseases, but the molecular mechanisms underlying its pathogenesis are not fully understood. Endothelial dysfunction is a key initiating factor in the pathogenesis of atherosclerosis, which is commonly observed in almost all HHcy-induced vascular diseases. HHcy promotes oxidative stress, inhibits nitric oxide production, suppresses hydrogen sulfide signaling pathway, promotes endothelial mesenchymal transition, activates coagulation pathways, and promotes protein N-homocysteination and cellular hypomethylation, all of which can cause endothelial dysfunction. This article reviews the specific links between HHcy and endothelial dysfunction, and highlights recent evidence that endothelial mesenchymal transition contributes to HHcy-induced vascular damage, with a hope to provide new ideas for the clinical treatment of HHcy-related vascular diseases.

Histone deacetylase 9 exacerbates podocyte injury in hyperhomocysteinemia through epigenetic repression of Klotho.

Although hyperhomocysteinemia (hHcys) has been recognized as an important independent risk factor in the progression of end-stage renal disease and the development of cardiovascular complications related to end-stage renal disease, the mechanisms triggering pathogenic actions of hHcys are not fully understood. The present study was mainly designed to investigate the role of HDACs in renal injury induced by hHcys. Firstly, we identified the expression patterns of HDACs and found that, among zinc-dependent HDACs, HDAC9 was preferentially upregulated in the kidney from mice with hHcys. Deficiency or pharmacological inhibition of HDAC9 ameliorated renal injury in mice with hHcys. Moreover, podocyte-specific deletion of HDAC9 significantly attenuated podocyte injury and proteinuria. In vitro, gene silencing of HDAC9 attenuated podocyte injury by inhibiting apoptosis, reducing oxidative stress and maintaining the expressions of podocyte slit diaphragm proteins. Mechanically, we proved for the first time that HDAC9 reduced the acetylation level of H3K9 in the promoter of Klotho, then inhibited gene transcription of Klotho, finally aggravating podocyte injury in hHcys. In conclusion, our results indicated that targeting of HDAC9 might be an attractive therapeutic strategy for the treatment of renal injury induced by hHcys.

The Role of Methionine-Rich Diet in Unhealthy Cerebrovascular and Brain Aging: Mechanisms and Implications for Cognitive Impairment.

As aging societies in the western world face a growing prevalence of vascular cognitive impairment and Alzheimer's disease (AD), understanding their underlying causes and associated risk factors becomes increasingly critical. A salient concern in the western dietary context is the high consumption of methionine-rich foods such as red meat. The present review delves into the impact of this methionine-heavy diet and the resultant hyperhomocysteinemia on accelerated cerebrovascular and brain aging, emphasizing their potential roles in cognitive impairment. Through a comprehensive exploration of existing evidence, a link between high methionine intake and hyperhomocysteinemia and oxidative stress, mitochondrial dysfunction, inflammation, and accelerated epigenetic aging is drawn. Moreover, the microvascular determinants of cognitive deterioration, including endothelial dysfunction, reduced cerebral blood flow, microvascular rarefaction, impaired neurovascular coupling, and blood-brain barrier (BBB) disruption, are explored. The mechanisms by which excessive methionine consumption and hyperhomocysteinemia might drive cerebromicrovascular and brain aging processes are elucidated. By presenting an intricate understanding of the relationships among methionine-rich diets, hyperhomocysteinemia, cerebrovascular and brain aging, and cognitive impairment, avenues for future research and potential therapeutic interventions are suggested.

Development and Validation of a Novel Model for Predicting Coronary Heart Disease in Snoring Hypertensive Patients with Hyperhomocysteinemia.

Hypertensive patients with snoring and elevated plasma homocysteine levels are common. When these factors are combined, the risk of coronary heart disease (CHD) is high. Herein, we developed and validated an easy-to-use nomogram to predict high-risk CHD in snoring hypertensive patients with elevated plasma homocysteine.Snoring patients (n = 1,962) with hyperhomocysteinemia and hypertension were divided into training (n = 1,373, 70%) and validation (n = 589, 30%) sets. We extracted CHD predictors using multivariate Cox regression analysis, then constructed a nomogram model. Internal validation using 1,000 bootstrap resampling was performed to assess the consistency and discrimination of the predictive model using the area under the receiver operating characteristic curve (AUC) and calibration plots.We constructed a nomogram model with the extracted predictors, including age, waist-height ratio, smoking, and low-density lipoprotein cholesterol levels. The AUCs of the training and validation cohorts at 80 months were 0.735 (95% CI: 0.678-0.792) and 0.646 (95% CI: 0.547-0.746), respectively. The consistency between the observed CHD survival and the probability of CHD survival in the training and validation sets was acceptable based on the calibration plots. A total of more than 151 points in the nomogram can be used in the identification of high-risk patients for CHD among snoring hypertensive patients with elevated plasma homocysteine.We developed a CHD risk prediction model for snoring hypertension patients with hyperhomocysteinemia. Our findings provide a useful clinical tool for the rapid identification of high-risk CHD at an early stage.