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.

Folate and retinal vascular diseases.

Folate, a pteroylglutamic acid derivative, participates in fundamental cellular metabolism. Homocysteine, an amino acid, serves as an intermediate of the methionine cycle and can be converted back to methionine. Hyperhomocysteinemia is a recognized risk factor for atherosclerotic and cardiovascular diseases. In recent decades, elevated plasma homocysteine levels and low folate status have been observed in many patients with retinal vascular diseases, such as retinal vascular occlusions, diabetic retinopathy, and age-related degeneration. Homocysteine-induced toxicity toward vascular endothelial cells might participate in the formation of retinal vascular diseases. Folate is an important dietary determinant of homocysteine. Folate deficiency is the most common cause of hyperhomocysteinemia. Folate supplementation can eliminate excess homocysteine in plasma. In in vitro experiments, folic acid had a protective effect on vascular endothelial cells against high glucose. Many studies have explored the relationship between folate and various retinal vascular diseases. This review summarizes the most important findings that lead to the conclusion that folic acid supplementation might be a protective treatment in patients with retinal vascular diseases with high homocysteine or glucose status. More research is still needed to validate the effect of folate and its supplementation in retinal vascular diseases.

Role of Vitamin B12 Deficiency and Hyperhomocysteinemia in Diabetic Retinopathy.

Diabetic retinopathy (DR) is one of the most important causes of preventable visual impairment among patients of working age and leading cause of blindness. Deficiency of vitamin B12 and folate has been associated with increased serum homocysteine (Hcy) levels. This study was done to find out the role of vitamin B12 and Hyperhomocysteine (HHcy) in Diabetic retinopathy. The present study is a hospital-based case-control study conducted during over a period of 12 months from January 2019 to December 2019 study conducted in the Department of Ophthalmology at BIRDEM General Hospital, Dhaka, Bangladesh consisting of 100 Type 2 DM patients either with or without retinopathy (DR, n=50 and DNR, n=50, respectively). Subjects with Type 2 DM with and without retinopathy were recruited from patients attending in the department of Ophthalmology at BIRDEM General Hospital, Dhaka and were matched for duration of diabetes. Diabetes subjects on nutritional supplements for the last 6 months and those with a history of nephropathy (based standard renal function tests) and complications other than DR were excluded. Homocysteine (Hcy) levels were inversely related (p<0.05) with Diabetes patients with retinopathy. Vitamin B12 also significant correlated with Diabetes patients with retinopathy. A statistically significant negative linear relationship was found between serum homocysteine and vitamin B12 levels (Pearson r = -0.918, p=0.001) Diabetes patients with retinopathy. Vitamin B12 significantly correlated with diabetes retinopathy and homocysteine levels were inversely related with diabetes patients with retinopathy.

Cerebral venous thrombosis with hyperhomocysteinemia due to loss of heterozygosity at methylenetetrahydrofolate reductase (MTHFR) locus: a case report.

BACKGROUND: Loss of heterozygosity (LOH) at methylenetetrahydrofolate reductase (MTHFR) locus has been reported in tumor tissue. But the mutation was never reported in cerebral venous thrombosis (CVT) with hyperhomocysteinemia (HHcy) before. CASE PRESENTATION: A 14-year-old girl was admitted with an intermittent headache and nausea for 2 months. The plasma homocysteine level was 77.2 µmol/L. Lumbar puncture revealed an intracranial pressure > 330 mmH2O. Cerebral MRI and MRV revealed superior sagittal sinus thrombosis. Whole-exome sequencing revealed LOH at Chr1:11836597-11,867,232 affects exons 10-21 of C1orf167, the entire MTHFR, and exons 1-2 of the CLCN6 gene. The normal allele was the c.665 C > T/677 C > T variant in MTHFR. The patient was treated with nadroparin for 2 weeks, followed by oral rivaroxaban. Supplemental folate and vitamins B12 and B6 were prescribed. One month later, she had no headache and the intracranial pressure had decreased to 215 mmH2O. MRI showed shrinkage of the thrombosis in the superior sagittal sinus, the degree of stenosis had significantly decreased. CONCLUSIONS: Rare LOH at the MTHFR locus should be analyzed in CVT with HHcy. With anticoagulation treatment, the prognosis was good.

Ischaemic stroke with multi-focal venous and arterial thrombosis due to hyperhomocysteinemia: anabolic androgenic steroid use and MTHFR c.667 C > T variant - a case report.

BACKGROUND: Severely elevated serum homocysteine is a rare cause of ischaemic stroke and extra-cranial arterial and venous thrombosis. Several factors can lead to mild elevation of homocysteine including dietary folate and B12 deficiency, and genetic variants of the methylenetetrahydrofolate reductase (MTHFR) enzyme. The use of Anabolic androgenic steroid (AAS) is under-reported, but increasingly linked to ischaemic stroke and can raise homocysteine levels. CASE REPORT: We present a case of a man in his 40s with a large left middle cerebral artery (MCA) territory ischaemic stroke and combined multifocal, extracranial venous, and arterial thrombosis. His past medical history was significant for Crohn's disease and covert use of AAS. A young stroke screen was negative except for a severely elevated total homocysteine concentration, folate and B12 deficiencies. Further tests revealed he was homozygous for the methylenetetrahydrofolate reductase enzyme thermolabile variant (MTHFR c.667 C > T). The etiology of this stroke was a hypercoagulable state induced by raised plasma homocysteine. Raised homocysteine in this case was likely multifactorial and related to chronic AAS use in combination with the homozygous MTHFR c.677 C > T thermolabile variant, folate deficiency and, vitamin B12 deficiency. CONCLUSION: In summary, hyperhomocysteinemia is an important potential cause of ischaemic stroke and may result from genetic, dietary, and social factors. Anabolic androgenic steroid use is an important risk factor for clinicians to consider, particularly in cases of young stroke with elevated serum homocysteine. Testing for MFTHR variants in stroke patients with raised homocysteine may be useful to guide secondary stroke prevention through adequate vitamin supplementation. Further studies looking into primary and secondary stroke prevention in the high-risk MTHFR variant cohort are necessary.

Hyperhomocysteinemia in Adult Patients: A Treatable Metabolic Condition.

Hyperhomocysteinemia (HHcy) is recognized as an independent risk factor for various significant medical conditions, yet controversy persists around its assessment and management. The diagnosis of disorders afffecting homocysteine (Hcy) metabolism faces delays due to insufficient awareness of its clinical presentation and unique biochemical characteristics. In cases of arterial or venous thrombotic vascular events, particularly with other comorbidities, it is crucial to consider moderate to severe HHcy. A nutritional approach to HHcy management involves implementing dietary strategies and targeted supplementation, emphasizing key nutrients like vitamin B6, B12, and folate that are crucial for Hcy conversion. Adequate intake of these vitamins, along with betaine supplementation, supports Hcy remethylation. Lifestyle modifications, such as smoking cessation and regular physical activity, complement the nutritional approach to enhance Hcy metabolism. For individuals with HHcy, maintaining a plasma Hcy concentration below 50 µmol/L consistently is vital to lowering the risk of vascular events. Collaboration with healthcare professionals and dietitians is essential for developing personalized dietary plans addressing the specific needs and underlying health conditions. This integrated approach aims to optimize metabolic processes and reduce the associated health risks.

Epigallocatechin-3-gallate Enhances Cognitive and Memory Performance and Protects Against Brain Injury in Methionine-induced Hyperhomocysteinemia Through Interdependent Molecular Pathways.

Brain injury and cognitive impairment are major health issues associated with neurodegenerative diseases in young and aged persons worldwide. Epigallocatechin-3-gallate (EGCG) was studied for its ability to protect against methionine (Met)-induced brain damage and cognitive dysfunction. Male mice were given Met-supplemented in drinking water to produce hyperhomocysteinemia (HHcy)-induced animals. EGCG was administered daily concurrently with Met by gavage. EGCG attenuated the rise in homocysteine levels in the plasma and the formation of amyloid-ß and tau protein in the brain. Cognitive and memory impairment in HHcy-induced mice were significantly improved by EGCG administration. These results were associated with improvement in glutamate and gamma-aminobutyric acid levels in the brain. EGCG maintained the levels of glutathione and the activity of antioxidant enzymes in the brain. As a result of the reduction of oxidative stress, EGCG protected against DNA damage in Met-treated mice. Moreover, maintaining the redox balance significantly ameliorated neuroinflammation evidenced by the normalization of IL-1ß, IL-6, tumor necrosis factor α, C-reactive protein, and IL-13 in the same animals. The decreases in both oxidative stress and inflammatory cytokines were significantly associated with upregulation of the antiapoptotic Bcl-2 protein and downregulation of the proapoptotic protein Bax, caspases 3 and 9, and p53 compared with Met-treated animals, indicating a diminution of neuronal apoptosis. These effects reflect and explain the improvement in histopathological alterations in the hippocampus of Met-treated mice. In conclusion, the beneficial effects of EGCG may be due to interconnecting pathways, including modulation of redox balance, amelioration of inflammation, and regulation of antiapoptotic proteins.

Pirfenidone alleviates vascular intima injury caused by hyperhomocysteinemia.

OBJECTIVES: Hyperhomocysteinemia (HHcy) can induce vascular inflammatory and oxidative damage and accelerate intimal hyperplasia. This study investigated the protective effect of pirfenidone (PFD) on the recovery process of injured endothelial arteries during HHcy. MATERIALS AND METHODS: Thirty rabbits were randomly separated into three groups: A control group (n=10, standard rabbit chow), a model group (n=10, control diet plus 30 g methionine/kg food), and a PFD group (n=10, model diet plus oral administration of 90 mg/day of PFD). After 14 weeks of arterial injury, histopathological changes were determined. Plasma homocysteine (Hcy) concentrations, lipid profiles and oxidant and antioxidant status were evaluated. Macrophage infiltration was assessed using immunohistochemical staining. RESULTS: PFD supplementation decreased macrophage infiltration of iliac artery significantly without changes in blood lipids and Hcy concentrations. Compared with the model group, PFD restored superoxide dismutase and glutathione peroxidase activities and reduced malondialdehyde and reactive oxygen species levels. A high-methionine diet significantly increased neointimal area and the ratio between neointimal and media area. Systemic administration of PFD inhibited neointimal formation. CONCLUSIONS: PFD can partly alleviate intimal hyperplasia by inhibiting inflammatory and oxidative stress response induced by HHcy during endothelial injury. It may be a potential therapeutic agent for the prevention and treatment of endothelial injury-associated diseases such as atherosclerosis.

Vitamin B12 deficiency may play an etiological role in atrophic glossitis and its grading: A clinical case-control study.

BACKGROUND: Existing studies have reported the significant association between atrophic glossitis (AG) and hematinic deficiencies, including iron, folate and vitamin B12 deficiency. However, these findings were inconsistent. AG can be graded as partial or complete atrophy. It is still unclear whether hematinic deficiencies are associated with the grading of AG. METHODS: 236 AG patients and 208 sex- and age-matched healthy controls were enrolled in this study. Hematological tests including complete blood count, and serum levels of folate, ferritin and vitamin B12 were performed. The AG group was divided into those with partial AG and those with complete AG according to the extent of papillary atrophy. Statistical analysis was performed to assess whether hematinic deficiencies are risk factors for AG and its grading. RESULTS: Compared with the healthy controls, AG patients had significantly higher frequencies of vitamin B12 deficiency (68.22%), ferritin deficiency (13.98%) and anemia (21.61%). The differences in hematinic deficiencies and anemia between AG patients and healthy controls changed according to gender and age. The frequencies of serum vitamin B12 deficiency and anemia in the complete AG subgroup were significantly higher than those in the partial AG subgroup. Logistic regression analysis revealed that vitamin B12 deficiency and anemia were significantly correlated with AG and its grading. The AG patients with vitamin B12 deficiency responded well to supplement therapy. CONCLUSION: AG could be an important clinical indicator for potential vitamin B12 deficiency, especially when the degree of tongue atrophy more than 50% and complete atrophy. Vitamin B12 deficiency might play an etiological role in the development of AG.

Hyperhomocysteinemia Promotes Cardiac Hypertrophy in Hypertension.

Hyperhomocysteinemia (HHcy) is positively linked with several cardiovascular diseases; however, its role and underlying mechanisms in pathological cardiac hypertrophy are still unclear. Here, we focused on the effects and underlying mechanisms of HHcy in hypertensive cardiac hypertrophy, one of the most common and typical types of pathological cardiac hypertrophy. By a retrospective analysis of the association between HHcy and cardiac hypertrophy in a hypertensive cohort, we found that the prevalence of HHcy was higher in patients with hypertrophy and significantly associated with the presence of cardiac hypertrophy after adjusting for other conventional risk factors. In mice, HHcy induced by a methionine (2% wt/wt) diet feeding significantly promoted cardiac hypertrophy as well as cardiac inflammation and fibrosis induced by 3-week angiotensin ІІ (AngІІ) infusion (1000 ng/kg/min), while folic acid (0.006% wt/wt) supplement corrected HHcy and attenuated AngII-stimulated cardiac phenotypes. Mechanistic studies further showed that homocysteine (Hcy) exacerbated AngII-stimulated expression of Calcineurin and nuclear factor of activated T cells (NFAT), which could be attenuated by folic acid both in mice and in neonatal rat cardiomyocytes. Moreover, treatment with cyclosporin A, an inhibitor of Calcineurin, blocked Hcy-stimulated Calcineurin-NFAT signaling and hypertrophy in neonatal rat cardiomyocytes. In conclusion, our study indicates that HHcy promotes cardiac hypertrophy in hypertension, and Calcineurin-NFAT pathway might be involved in the pro-hypertrophic effect of Hcy.

Effect of hyperhomocysteinemia on a murine model of smoke-induced pulmonary emphysema.

Hyperhomocysteinemia was reported to enhance endoplasmic reticulum (ER) stress and subsequent apoptosis in several cells. However, the precise mechanisms of smoking susceptibility associated with hyperhomocysteinemia has not been fully elucidated. This study included 7- to 9-week-old C57BL6 male mice induced with hyperhomocysteinemia and were exposed to cigarette smoke (CS). A549 cells (human alveolar epithelial cell line) were cultured with homocysteine and were exposed to cigarette smoke extract (CSE) to observe cell viability and expression of proteins related to the ER stress. After 6 months of CS exposure, pulmonary emphysema was more severely induced in the group under the condition of hyperhomocysteinemia compared to that in the control group. The apoptotic A549 cells increased as homocysteine concentration increased and that was enhanced by CSE. Protein expression levels of ER stress markers were significantly increased after simultaneous stimulation. Notably, vitamin B12 and folate supplementation improved ER stress after simultaneous stimulation of A549 cells. In this study, we showed that hyperhomocysteinemia exacerbates CS exposure-induced emphysema in mice, suggesting that hyperhomocysteinemia and CS stimulation enhance ER stress and subsequent induced apoptosis in alveolar epithelial cells. It was suggested that there is a synergistic effect between homocysteine and CS.

Vitamin B12 and chronic kidney disease.

Chronic Kidney Disease (CKD) is an emerging public health issue with a fast-growing global prevalence. Impairment in vitamin B12 metabolism is considered a nontraditional risk factor of poor outcomes associated with CKD, and there is greater interest from the scientific community than ever before to explore the role and influence of vitamin B12 in CKD. Homocysteine metabolism forms an important component of the vitamin B12 metabolic pathway. Hyperhomocysteinemia is frequently observed in CKD and End-Stage Kidney Disease (ESKD), but its representation as a prognostic marker for CKD outcomes is still not fully clear. This chapter reviews the vitamin B12 and homocysteine metabolic pathways and their dysfunction in CKD states. Biochemical factors and the MTHFR genetic polymorphisms which disrupt vitamin B12 and homocysteine metabolism are explored. The mechanisms of homocysteine-mediated and vitamin B12-mediated tissue damage in CKD are discussed. This chapter reviews current perspective on definition and measurement of plasma vitamin B12 levels in the CKD population. Updated evidence investigating the prognostic role of vitamin B12 for CKD outcomes is presented. Findings from major clinical trials conducted relating to outcomes from multivitamin (including folic acid and vitamin B12) supplementation in nondialysis and dialysis-dependent CKD are highlighted. The prognostic value of vitamin B12 and effects of vitamin B12 supplementation in the context of kidney transplantation and acute kidney injury is also reviewed. Future research considerations are summarized based on evidence gaps in our knowledge base of this topic. Greater abundance of high-level evidence to guide an approach toward vitamin B12 measurement, monitoring and supplementation in CKD may contribute to improved clinical outcomes.

Paracentral acute middle maculopathy (PAMM) associated with ulcerative colitis and coexisting hyperhomocysteinemia: A case report.

INTRODUCTION: Paracentral acute middle maculopathy (PAMM) is a tomographic finding of a retinal occlusive vascular disorders with different aetiologies. Despite the well documented triple association among hyper-homocysteine, retinal vein occlusion and PAMM, up to date no reports exist on the development of PAMM in young patients affected by ulcerative colitis (UC). CASE DESCRIPTION: A multimodal imaging study, including fundus photographs, optical coherence tomography (OCT) B-scans, OCT angiography (OCT-A) and fluorescein and indocyanine green angiography, was performed in a 32-years-old male complaining of acute-onset paracentral scotoma in the right eye. Fundus images demonstrated the typical dark gray area of retinal capillary ischemia, corresponding on OCT B-scans to the hyper-reflective plaques in the INL, and consistent with PAMM lesions.The deep capillary plexus (DCP) was normal on OCT-A. Fluorescein angiography revealed a concurrent branch retinal vein preocclusion and showed capillary drop out parafoveally. Patient's anamnesis was negative except for a 15-years history of UC and use of acetylsalicylic acid (ASS). At the time of presentation, UC was quiescent, but new blood tests revealed concomitant high values of homocysteinemia requiring oral vitamin B12 and folate supplementation. Two months later PAMM lesions had disappeared on OCT B-scans and a retinal thinning at the level of the inner nuclear layer (INL) was visible. The DCP on OCT-A remained unchanged without any sign of capillary ischemia. CONCLUSIONS: Although no definitive evidence directly links UC with PAMM, the latter should be suspected in young patients affected by IBD with coexisting hyper-homocysteinemia and unexplained visual symptoms.

Prevalence of hyperhomocysteinemia (HHcy) and its major determinants among hypertensive patients over 35 years of age.

OBJECTIVE: Hyperhomocysteinemia (HHcy) and hypertension are associated with cardiovascular events. However, effects of Hcy-lowing interventions on cardiovascular outcome were conflicting. Serum folate level was proposed to be a possible determinant of efficacy of extra folate supplementation on cardiovascular outcome. The aims of the present study were to describe representative information on the levels of serum homocysteine and folate in hypertensive patients, and to explore the major determinants of HHcy. METHODS: 11,007 participants with hypertension were analyzed in this cross-sectional study. Blood pressure and serum levels of biochemical indicators were measured. Multivariate logistic regression model was used to assess the associated factors of HHcy. RESULTS: Geometric mean of serum total homocysteine was 14.1 (95% CI: 13.9, 14.4) µmol/L and prevalence of HHcy was 36.1 (95% CI: 34.0, 38.1) % in hypertensive patients. HHcy was strongly associated with factors including male sex, older age, elevated serum creatinine (SCr), lower serum folate and vitamin B12, and uncontrolled blood pressure in hypertensive patients. Elevated SCr attributed to HHcy with the etiologic fraction of 0.29. The change of the odds ratio of HHcy associated with folate was significantly higher in patients with elevated SCr compared with that of patients with normal SCr. CONCLUSION: The results suggested the protection of female sex and higher levels of folate and vitamin B12 from HHcy and attribution of older age and elevated SCr to HHcy. Restoring renal function deserved attention for hypertensive patients to benefit from Hcy-lowing measures.

The protective mechanism of folic acid on hyperhomocysteinemia-related arterial injury in spontaneously hypertensive rats: Folic acid against arterial inflammation.

BACKGROUND: Hypertension associated with hyperhomocysteinemia (HHcy) is correlated with a high risk of vascular diseases. Studies found that folic acid (FA) supplementation can reduce the risk of cardiovascular and cerebrovascular events. The aim of the present study was to explore the potential mechanisms of FA attenuating HHcy-related arterial injury in spontaneously hypertensive rats (SHRs). METHODS: 24 SHRs were randomized into the control group, the HHcy group, and the HHcy + FA group (8 per group). The SHRs in the HHcy group and the HHcy + FA group were given DL-Hcy intraperitoneally to mimic hypertension associated with HHcy. The SHRs in the HHcy + FA group were given FA by gavage to mimic an FA-fortified diet. The histopathology and immunohistochemistry of rat aorta and carotid artery were analyzed, and the relative expression levels of immune/inflammation and oxidative stress molecules in arterial tissue were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. RESULTS: FA significantly reduced the expression levels of nuclear factor-κ-gene binding (NF-κB) p65/Rela and interleukin-6 (IL-6) in rat arterial tissues, as well as the levels of plasma HHcy and serum malondialdehyde (MDA) in hypertension associated with HHcy rats (p < 0.05). At the same time, FA significantly increased the serum superoxide dismutase (SOD) level in hypertension associated with HHcy rats, and even the SOD level of the HHcy + FA group was higher than that of the control group (p < 0.05). However, HHcy induced the opposite results of the above indicators in SHRs compared with the control group (p < 0.05). CONCLUSIONS: The arterial protection mechanisms of FA are related to reducing the concentration of HHcy to eliminate the tissue toxicity of HHcy, inhibiting NF-κBp65/Rela/IL-6 pathway molecules to regulate inflammatory response, and promoting the potential anti-oxidative stress pathway molecules to reduce oxidative stress level.

The role of B vitamins in stroke prevention.

Elevated plasma levels of homocysteine (Hcy) are a recognized risk factor for stroke. This relationship represents one aspect of the debated `Hcy hypothesis'. Elevated Hcy may be an independent and treatable cause of atherosclerosis and thrombotic vascular diseases. Further observations indicate that proper dietary supplementation with B-vitamins decreases total plasma Hcy concentrations and may be an effective intervention for stroke prevention. Metabolic vitamin B12 deficiency is a nutritional determinant of total Hcy and stroke risk. Genetic factors may link B vitamins with stroke severity due to the impact on Hcy metabolism of polymorphism in the genes coding for methylenetetrahydrofolate reductase, methionine-synthase, methionine synthase reductase, and cystathionine ß-synthase. Several meta-analyses of large randomized controlled trials exist. However, they are not completely in agreement about B vitamins' role, particularly folic acid levels, vitamin B12, and B6, in lowering the homocysteine concentrations in people at high stroke risk. A very complex relationship exists between Hcy and B vitamins, and several factors appear to modify the preventive effects of B vitamins in stroke. This review highlights the regulating factors of the active role of B vitamins active in stroke prevention. Also, inputs for further large, well-designed studies, for specific, particularly sensitive subgroups are given.

Ameliorative Effect of Acetyl L-carnitine in Alzheimer's Disease via Downregulating of Homocysteine Levels in Hyperhomocysteinemia Induced Cognitive Deficit in Mouse Model.

AIMS: The study was aimed at exploring the role of Acetyl L-Carnitine supplementation attenuating dementia and degradation of cognitive abilities in Hyperhomocysteinemia induced AD manifestations in the mouse model. BACKGROUND: Alzheimer's disease (AD) is a neurological disorder that is marked by dementia, and degradation of cognitive abilities. There is great popularity gained by natural supplements as the treatment for AD, due to the higher toxicities of synthetic drugs. Hyperhomocysteinemia causes excitotoxicity to the cortical neurons, which brought us to the point that amino acids possibly have a role in causing cholinergic deformities, which are an important etiological parameter in AD. Acetyl L-Carnitine a methyl donor with the presence of three chemically reactive methyl groups linked to a nitrogen atom was found to possess neuroprotective activity against experimental models of AD. OBJECTIVE: The objective of the present investigation was to investigate and evaluate the pharmacological effect of Acetyl L-Carnitine against hyperhomocysteinemia induced Alzheimer's disease (AD) in the mouse model. MATERIALS AND METHODS: The animals were divided into normal control (vehicle-treated), HHcy (dl-Homocysteine thiolactone treated) negative control, test group i.e., low dose (50mg/kg, p.o) of acetyl L-carnitine (L-ALC), high dose (100mg/kg,p.o) of acetyl L-carnitine (H-ALC), L-ALC+ SOV (Sodium orthovanadate) and H-ALC+SOV. HHcy was induced by administration of dl-Homocysteine thiolactone (dl-HCT; 1 g/kg, p.o.) on day-1 to day-15 of experimental schedule to all animals except normal control. The changes in the behaviour pattern of the animals due to neuroinflammation, and cholinergic dysfunction were examined in rotarod, novel objective recognition, passive avoidance, elevated plus maze, and morris water maze analysis. Biochemical investigation includes the estimation of total homocysteine (tHcy), Creatinine Kinase (CK), Acetylcholinesterase (AChE), thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and IL-6 and TNF-α. RESULTS: Supplementation of ALC in mouse considerably lowered the HHcy-induced AD manifestations in the experimental animals. It was found that ALC and SOV successfully diminished the behaviour abnormalities and lessened the Hcy-induced alteration in systemic Hcy levels, CK activity, and cholinergic dysfunction with improved bioenergetics in the Prefrontal cortex of the mice. CONCLUSION: ALC was found to improve the HHcy-induced cognitive disabilities which was found to be associated with the decreased systemic levels of Hcy, CK, and cholinergic abnormalities. It also combats the oxidative stress-induced neuroinflammation with diminished pro-inflammatory markers in the pre frontal cortex. The outcomes collectively indicate ALC's potential to be used as a supplementation in the pharmacotherapy of AD.

The link between homocysteine, folic acid and vitamin B12 in chronic kidney disease.

Patients with chronic kidney disease or end-stage renal disease experience tremendous cardiovascular risk. Cardiovascular events are the leading causes of death in these patient populations, thus the interest in non-traditional risk factors such as hyperhomocysteinemia, folic acid and vitamin B12 metabolism is growing. Hyperhomocysteinemia is commonly found in CKD patients because of impaired renal metabolism and reduced renal excretion. Folic acid, the synthetic form of vitamin B9, is critical in the conversion of homocysteine to methionine like vitamin B12. Folic acid has also been shown to improve endothelial function without lowering homocysteine, suggesting an alternative explanation for the effect of folic acid on endothelial function. Whether hyperhomocysteinemia represents a reliable marker of cardiovascular risk and cardiovascular mortality or a therapeutic target in this population remains unclear. However, it is reasonable to consider folic acid with or without methylcobalamin supplementation as appropriate adjunctive therapy in patients with CKD. The purpose of this review is to summarize the characteristics of homocysteine, folic acid, and vitamin B12 metabolism, the mechanism of vascular damage, and the outcome of vitamin supplementation on hyperhomocysteinemia in patients with CKD, ESRD, dialysis treatment, and in kidney transplant recipients.

[n-3 Polyunsaturated fatty acid attenuates hyperhomocysteinemia-induced hepatic steatosis by increasing hepatic LXA5 content].

Nonalcoholic fatty liver disease (NAFLD) and hyperhomocysteinemia (HHcy) both are major health problems worldwide, whose incidence are closely related with each other. We previously reported the mechanism of HHcy-caused hepatic steatosis, but the role of n-3 polyunsaturated fatty acid (n-3 PUFA) in HHcy-induced hepatic steatosis remains unclear. In this study, 6-week-old C57BL/6 male mice were given a high methionine diet (HMD, 2% methionine diet), and plasma homocysteine levels were measured by ELISA to confirm the establishment of an HHcy model. Meantime, mice were fed HMD with or without n-3 PUFA supplement for 8 weeks to determine the role and mechanism of n-3 PUFA in hepatic steatosis induced by HHcy. Results showed that n-3 PUFA significantly improved hepatic lipid deposition induced by HHcy. qRT-PCR analysis demonstrated that n-3 PUFA inhibited the upregulation of Cd36, a key enzyme of fatty acid uptake, caused by HHcy. Further, the inhibition of hepatic Cd36 expression was associated with the inactivation of aryl hydrocarbon receptor (Ahr) induced by n-3 PUFA. Of note, mass spectrometry revealed that hepatic content of lipoxin A5 (LXA5) was significantly increased in HMD+n-3 PUFA-fed mice compared with that in HMD-fed mice. In primary cultured hepatocytes, LXA5 treatment markedly reversed homocysteine-evoked Cd36 upregulation and Ahr activation, which resulted in reduced lipid accumulation. In conclusion, we demonstrate that n-3 PUFA inactivates HHcy-induced Ahr-Cd36 pathway by increasing hepatic LXA5 content, which alleviates hepatic steatosis. Thus, our results may provide a potential strategy for treatment of NAFLD.

Ligustrazine Attenuates Hyperhomocysteinemia-induced Alzheimer-like Pathologies in Rats.

Ligustrazine, an alkaloid extracted from the traditional Chinese herbal medicine Ligusticum Chuanxiong Hort, has been clinically applied to treat the cerebrovascular diseases. Hyperhomocysteinemia (Hhcy) is an independent risk factor for Alzheimer's disease (AD). Memory deficits can be caused by Hhcy via pathologies of AD-like tau and amyloid-ß (Aß) in the hippocampus. Here, we investigated whether homocysteine (Hcy) can induce AD-like pathologies and the effects of ligustrazine on these pathologies. The Hcy rat model was constructed by 14-day Hcy injection via vena caudalis, and rats were treated with daily intragastric administration of ligustrazine at the same time. We found that the pathologies of tau and Aß were induced by Hcy in the hippocampus, while the Hcy-induced tau hyperphosphorylation and Aß accumulation could be markedly attenuated by simultaneous ligustrazine treatment. Our data demonstrate that ligustrazine may be used as a promising neuroprotective agent to treat the Hcy-induced AD-like pathologies.