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Object: Vertebrobasilar dissecting aneurysms (VBDAs) are known to have a poor natural history with high rates of re-bleeding and mortality. There is a strong relation between hyperhomocysteinemia (HHcy) and cerebrovascular disease; we perform a retrospective study within the male of Chinese Han population to explore the association between HHcy and VBDAs. Methods: Eighty-eight male patients with VBDA and Eighty-one male control subjects were evaluated for their serum total homocysteine levels. With multiple logistic regression analysis, the association between HHcy and the risk of VBDAs was estimated. Interaction and stratified analyses were conducted according to age, BMI, smoking status, drinking status, and chronic disease histories. The two-piecewise linear regression model examined the threshold effect. Results: The multivariate logistic regression analyses revealed a significant association between HHcy and VBDAs (odds ratio (OR) = 2.62; 95% confidence interval (CI), 1.02–6.71) after adjusting for classical vascular risk factors. The relationship was stable in all subgroup analysis. The interactive role was not found in the association between HHcy and VBDAs for the potential risk factor. Conclusions: In summary, our study provides evidence that HHcy can increases the risk of VBDAs in the male Han Chinese population. Further researches with appropriate study designs including sex differences and aneurysm types are needed to verify this association. [ABSTRACT FROM AUTHOR]

Hyperhomocysteinemia or high levels (> 15 µmol/L) of homocysteine (Hcy)in the blood has been suggested to affect the brain through vascular and neurodegenerative pathways and potentially impact cognition. The current study aims to explore the association of high homocysteine with cognition and brain volume changes in a cohort of middle and old agedr adults. The study recruited 1296 participants aged ≥ 45 years from Tata Longitudinal Study of Ageing (TLSA), an ongoing cohort study. The participants underwent detailed cognitive assessments using Addenbrooke's Cognitive Examination-III (ACE-III) and Computerized Assessment of Adult Information Processing (COGNITO) neuropsychological battery and MR imaging using a 3T scanner. The participants were classified based on the median homocysteine level (16.89 µmol/L) into low Hcy (≤ median) and high Hcy (> median) groups. When adjusted for age, gender, years of education, vitamin B12, folate and dyslipidaemia, Generalised Linear Model (GLM) found a significant association of high Hcy with vocabulary task [β (95% CI) − 1.354 (− 2.655, − 0.052); p = 0.041]. Significant associations was also obtained between cerebral white matter volume and high Hcy [β (95% CI) − 5617.182 (− 11062.762, − 173.602); p = 0.043]. The results suggest that people with high Hcy levels performed poorer in cognitive tasks related to language domain and had lesser cerebral white matter volume. This indicates that homocysteine might have a profound impact on brain structure as well as function. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives Cigarette smoking is an established risk factor for autoimmune diseases. However, whether smoking plays a clear role in thrombotic APS (TAPS) has not been determined. We aimed to investigate the effects of smoking on the clinical characteristics and prognosis of TAPS. Methods This was a prospective cohort study from 2013 to 2022. During the study period, 297 patients were diagnosed with TAPS, including 82 smokers and 215 non-smokers. After propensity score matching, 57 smokers and 57 non-smokers matched by age and sex were analysed. Results Overall, smokers with TAPS had more cardiovascular risk factors than non-smokers, including hypertension (36.59% vs 14.42%, P < 0.001), obesity (15.85% vs 7.44%, P = 0.029), dyslipidaemia (64.63% vs 48.37%, P = 0.012) and hyperhomocysteinaemia (62.20% vs 36.28%, P < 0.001). Arterial thrombotic events were more common in smokers at diagnosis (62.20% vs 46.05%, P  = 0.013), especially myocardial infarction, visceral thrombosis and peripheral vascular thrombosis. After matching, smokers showed balanced cardiovascular risk factors with non-smokers at baseline, but retained a higher prevalence of arterial thrombosis (59.65% vs 33.33%, P = 0.005), mainly distributed in cerebral vascular, cardiovascula and retinal vascular territories. During follow-up, smokers presented a tendency for more recurrent arterial thrombosis and less recurrent venous thrombosis. Smokers had significantly poorer outcomes for organ damage with higher Damage Index for APS score (median 2.00 vs 1.00, P = 0.008), especially in the cardiovascular (26.32% vs 3.51%, P = 0.001), gastrointestinal (15.79% vs 1.75%, P = 0.016) and ophthalmologic (10.53% vs 00.00%, P = 0.027) systems. Conclusion Smoking is related to increased arterial events and poor prognosis in TAPS patients. Patients with TAPS should be fully encouraged to avoid smoking. [ABSTRACT FROM AUTHOR]

The low-pressure and low-oxygen environment at high altitude causes a series of changes in the metabolic level in the human body. The high altitude environment increases the level of oxidative stress and homocysteine in the body, which damages vascular endothelial cells. Hyperhomocysteinemia exacerbates oxidative stress, further aggravates the damage to the vascular endothelium, and accelerates the occurrence and development of hypertension. The combination of antioxidant drugs on the basis of traditional antihypertensive drug treatment provides a new direction for the treatment of H-type hypertension in high-altitude areas. This article reviews the relationship between vascular endothelial function and oxidative stress in patients with H-type hypertension in high-altitude areas, and explores its pathogenesis and possible treatments.

Abstract Hyperhomocysteinemia or high levels (> 15 µmol/L) of homocysteine (Hcy)in the blood has been suggested to affect the brain through vascular and neurodegenerative pathways and potentially impact cognition. The current study aims to explore the association of high homocysteine with cognition and brain volume changes in a cohort of middle and old agedr adults. The study recruited 1296 participants aged ≥ 45 years from Tata Longitudinal Study of Ageing (TLSA), an ongoing cohort study. The participants underwent detailed cognitive assessments using Addenbrooke’s Cognitive Examination-III (ACE-III) and Computerized Assessment of Adult Information Processing (COGNITO) neuropsychological battery and MR imaging using a 3T scanner. The participants were classified based on the median homocysteine level (16.89 µmol/L) into low Hcy (≤ median) and high Hcy (> median) groups. When adjusted for age, gender, years of education, vitamin B12, folate and dyslipidaemia, Generalised Linear Model (GLM) found a significant association of high Hcy with vocabulary task [β (95% CI) − 1.354 (− 2.655, − 0.052); p = 0.041]. Significant associations was also obtained between cerebral white matter volume and high Hcy [β (95% CI) − 5617.182 (− 11062.762, − 173.602); p = 0.043]. The results suggest that people with high Hcy levels performed poorer in cognitive tasks related to language domain and had lesser cerebral white matter volume. This indicates that homocysteine might have a profound impact on brain structure as well as function.

Abstract 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.

Plasma homocysteine (Hcy) is an amino acid causing vascular injury. It is closely associated with endothelial cell injury, vascular smooth muscle proliferation, inflammatory responses, thrombosis and vascular calcification. An elevated level of Hcy may affect normal function of renal vasculature and glomeruli, thereby accelerating the progression of chronic kidney disease to end-stage renal disease. In maintenance hemodialysis (MHD) patients, the incidence of hyperhomocysteinemia (HHcy) is 33 folds that of normal individuals so that it becomes a common yet complex health issue. For accurately identifying HHcy and improving patient prognosis, this review summarized the common causes of HHcy in MHD patients and introduced various preventive and therapeutic measures.

Abstract 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.

Abstract 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 β‐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.

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

The role of hyperhomocysteinemia (Hhcy) as a prothrombotic risk factor has been researched and debated over many decades. Several prospective and retrospective studies have established the association of Hhcy as a modifiable risk factor in both arterial and venous thrombosis. This case series of nine patients with either recurrent or unprovoked thrombosis and thrombosis occurring at unusual sites aims to elucidate the association between Hhcy and thrombotic events as an independent risk factor. This study underscores the importance of screening for homocysteine (Hcy) levels for early management of high-risk patients and contributes to the existing evidence of the thrombogenic effects of Hcy, thereby highlighting future research to improve management guidelines and preventive protocols.

Charinya Chaichanabut,1 Piyamitr Sritara,2 Jintana Sirivarasai3 1Master of Science Program in Nutrition, Faculty of Medicine Ramathibodi Hospital and Institute of Nutrition, Mahidol University, Bangkok, Thailand; 2Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 3Nutrition Unit, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, ThailandCorrespondence: Jintana Sirivarasai, Nutrition Unit, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand, Tel +662-201-1483, Fax +662-201-2625, Email jintana.sir@mahidol.ac.thPurpose: 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.Keywords: endothelial nitric oxide synthase, polymorphisms, hypertension, hyperhomocysteinemia

Context Although some research suggests that vitamin B12 (hereafter, B12) supplements can lower homocysteine (Hcy) levels and treat hyperhomocysteinemia, these results are still ambiguous when B12 is taken as an isolated supplement. Objective This study sought to determine how existing randomized controlled trials (RCTs) could be used to examine the effects of B12 supplementation on Hcy. Data Sources To find pertinent RCTs up to June 2022, databases, including PubMed/Medline, Web of Science, Scopus, Cochrane Library, and Embase, were searched. Data Extraction All selected RCTs investigated the impact of B12 supplements on Hcy. A meta-analysis of the eligible studies was performed using the random-effects model. Data Analysis This review included a total of 21 RCTs (N = 1625 participants). Hcy levels were significantly lower after B12 supplementation compared with the control group (pooled weighted mean difference, –4.15 μmol/L; 95% confidence interval, –4.86, –3.45; P  < 0.001), and this reduction was even greater with intervention durations ≥12 weeks and doses >500 µg/d. Furthermore, the effect of B12 supplementation in the form of hydroxocobalamin on the reduction of Hcy level was greater compared with other forms. Conclusion In conclusion, this meta-analysis shows that B12 supplementation has a positive impact on lowering blood Hcy levels, particularly when administered for a longer period and at a larger dose. Systematic Review Registration PROSPERO registration no. CRD42022364066 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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

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 pinteraction 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 highrisk population to reduce the incidence of thromboembolic events during hospitalization for psychiatric patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (β = 584.83, P = 0.044; β = 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 (β = -12.75, P = 0.019; β = -0.06, P <0.001). Plasma methylmalonic acid was negatively associated with total BMD and femur BMD in the full population (β = -0.01, P = 0.018; β = -0.01, P = 0.004). In older adults, methylmalonic acid significantly affected total BMD, femur BMD and knee extensor strength (β = -0.01, P = 0.048; β = -0.01, P = 0.025; β = -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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background. Polycystic ovary syndrome (PCOS) is an endocrine disease attributed to multiple genetic variants and environmental factors. We aimed to find the causal association of homocysteine (Hcy) with PCOS. Methods. A two-sample Mendelian randomization (MR) analysis was performed. We selected 14 single-nucleotide polymorphisms (SNPs) as instrumental variables to predict the risk of PCOS from genome-wide association studies (GWAS). The summary statistics of PCOS were obtained from 3 large genome-wide association studies in the European population, involving 4,138 cases and 20,129 controls, 3,609 cases and 229,788 controls, 994 cases and 165,817 controls, separately. Results. The IVM analyses revealed that plasma Hcy levels were not causally associated with the risk of PCOS in the meta-analysis (combined effect = 1.032, 95% confidence interval (CI): 0.885–1.203, p = 0.688). Conclusions. There was no sufficient evidence to support the causal association of the Hcy with the risk of PCOS. [ABSTRACT FROM AUTHOR]

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 (Aβ40) species, and particularly Aβ40‐E22Q (AβQ22; 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 Aβ and homocysteine function through common molecular mechanisms. We tested the hypotheses that Hhcy exacerbates Aβ‐induced cEC DR4/5‐mediated apoptosis, barrier dysfunction, and angiogenesis defects. This study was the first to demonstrate that Hhcy specifically potentiates AβQ22‐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 Aβ, precipitating BBB permeability. Furthermore, Hhcy and AβQ22, 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 Aβ‐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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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The study presents a case of a 70-year-old obese male with hyperhomocysteinemia, hypertension, abnormal glucose tolerance, and a history of stroke. Despite medication, his condition persisted due to dietary factors, including excessive salt, protein, and fat intake, and inadequate intake of vitamins B6 and folic acid. The intervention aimed to reduce homocysteine levels, achieve weight loss, improve metabolic health, and optimize nutrient intake. A reduction diet based on DASH and Mediterranean principles was implemented, emphasizing glycemic index/load education and nutrient-balanced meals. After 3 months, significant improvements were observed: weight loss (3.3 kg), reduced body fat percentage, improved body composition, and biochemical enhancements, including decreased homocysteine levels (3.1 μmol/L), increased plasma levels of vitamins B6, B12, and folic acid, and improved lipid profile and glucose levels. These positive outcomes were achieved solely through dietary changes, highlighting the efficacy of tailored dietary interventions in managing complex health conditions without additional pharmacological treatment. The study underscores the importance of personalized dietary strategies in holistic health management, emphasizing the potential for significant health improvements through targeted dietary modifications. [ABSTRACT FROM AUTHOR]

Background: Squamous cell carcinoma (SCC) is the second most common amongst skin cancers, following the basal cell carcinoma. SCC of the lip carries relatively better prognosis if detected early and treated adequately. Public awareness about the significance of early presentation would help to improve the outcome of management. Objective: The current study was conducted to determine the clinical presentation of lip SCC and management outcome with surgery as the primary treatment modality. Methods: This descriptive study was carried out at the National Institute of Rehabilitation Medicine, Islamabad over a period of seven years. All patients who presented with lip SCCs during the study period were prospectively included in the study. Non-consenting patients were excluded. The lesions were excised with 1-2-cm palpable macroscopic safety margins. Results: Out of 37 patients, there were 28 (75.67%) males and 9 (24.32%) females. The ages ranged between 47-79 years with a mean of 59.91±9.17 years. Lower lip was the most commonly affected site (n=30; 81.08%). The duration of the lesions at first presentation varied from 6-13 months with a mean of 7.32±1.79 months. Majority (n=31; 83.78%), of the patients had early stage (stage I and II disease) whereas 6(16.21%) patients had stage III disease. The margin clearance rate after initial excision of the lesions was 91.89%. Karapandzic flap was employed as reconstructive tool among 15(40.54%) patients. The 5-year overall survival rate was 62.16%. Conclusion: Lip SCCs were found more frequently among males aged over 50 years. Lower lip was the commonest seat of lip SCCs. Surgical excision with recommended safety margins was associated with tumor free margins in 91.89% cases. Karapandzic flap was the most useful reconstructive tool. The 5-year overall survival rate was 62.16%. [ABSTRACT FROM AUTHOR]

Copyright of Acta Neurológica Colombiana is the property of Colombian Association of Neurology / Asociacion Colombiana de Neurologia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The work is devoted to the study of neurodegenerative changes in the ultrastructural organization of hippocampal CA1 in adult rats that have suffered prenatal hyperhomocysteinemia (pHHC). Electron microscopy in the neural networks of the CA1 region of the dorsal hippocampus in adult rats with pHHC, in contrast to control animals, revealed signs of pathological changes: degeneration of pyramidal neurons and destruction of the myelin sheath of axons, as well as destruction of the axial cylinders of basal and apical dendrites directed from a pyramidal layer of neurons in the direction of tractus temporammonic or Schaffer collaterals, respectively. In control animals, on the distal branches of dendrites in the layers of the stratum oriens and stratum radiatum, using the Golgi method, a dense network of varicose dendritic extensions was identified, providing an increase in the area of synaptic contacts. In rats that have undergone pHHC, significant destructive changes are found in these dendritic varicosities: destruction of mitochondrial cristae and the appearance of dilated cisterns. In adult rats with pHHC, it completely eliminates the preference for the smell of valerian, which is normally a physiologically significant stimulus, which indicates a negative effect of pHHC on the functioning of the olfactory analyzer, the activity of which is closely connected with the hippocampus. The obtained facts indicate the detrimental effect of homocysteine on the structure and interneuronal connections in the nervous tissue of the CA1 region of the dorsal hippocampus, as a morphological substrate for the integration of stimuli entering it. [ABSTRACT FROM AUTHOR]

Introduction: Chronic kidney disease (CKD) is a heterogeneous group of disorders that manifest differently with a multifactorial etiology. In addition to known factors such as diabetes, high blood pressure, genetic predisposition, age, gender, race, physical inactivity, obesity, and MIA, in recent years, high concentrations of homocysteine have also been considered as an independent risk factor in the acceleration of the progression of CKD, which, together with arterial hypertension, apparently affect the acceleration of the progress of chronic renal diseases. Materials and Methods: In a cohort-prospective study, 100 patients were treated (40 women with an average age of 55.40±8.20 years and 60 men with an average age of 56.00±9.50 years) with CKD in the third stage (stage III and b b) with a GFR of 30- 59 ml/min/ 1.73m2 determined according to the formula modification of diet in renal disease (MDRD- GFR in ml/min for 1.73 m2=175 x Serum creatinine (Cr) -1.154 x age-0.203x1.212 (if the patient is black) x 0.742 (if female) treated in the internal medicine clinic at the Clinical Hospital in Tetovo, in the period January-2023-December-2023 randomized according to gender, age, nationality, primary kidney disease… Results: The results obtained at the beginning of the study for all the examined parameters and those obtained after 12 months, both from the patients with Chronic disease and the control group of healthy individuals, are presented in the text below. A significant difference was observed between the patients and the control group with p

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 β-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.

Hyperhomocysteinemia is considered a risk factor for many diseases, including thrombosis. Patients with chronic kidney disease often have vascular complications in the form of arterial or venous thrombosis, and it is important to consider the blood homocysteine level as a predictor of thrombophilia. The causes of hyperhomocysteinemia can be both genetic mutations and deficiency of homocysteine metabolism enzymes, as well as deficiency of folic acid, vitamin B12 and, to a lesser extent, deficiency of vitamin B6, which affects methionine metabolism. Given the role of hyperhomocysteinemia as a predictor of cardiovascular events in patients with kidney diseases, in our opinion, the multifactorial nature of increased homocysteine requires further research into some links of its pathogenesis in chronic kidney disease and the development of targeted therapeutic interventions.

Background H-type hypertension seriously affects people's health and quality of life. Currently, the clinical treatment of hypertension mainly selects drugs based on the experience, and the antihypertensive effect is not ideal. It is urgent to explore the pharmacogenetic polymorphisms of antihypertensive drugs and provide individualized medication guidance for hypertensive patients. Objective To investigate pharmacogenetic polymorphisms and the intervention effects of folic acid combined with vitamin D in patients with H-type hypertension in Jinan community, and provide reference for the implementation of integrated precision medicine for hypertension. Methods From June 2020 to June 2022, 200 hypertensive patients with poorly controlled blood pressure in 20 community health service centers of Huaiyin District, Jinan City, Shandong Province were randomly selected as the research objects. Before treatment, the gene polymorphisms of five commonly used individualized antihypertensive drugs, including diuretics, β-blockers, angiotensin-converting enzyme inhibitors (ACEI) , calcium channel inhibitors (CCB) , angiotensin-Ⅱ receptor antagonists (ARB) , were detected. Patients were randomly divided into the gene-directed treatment group (genome group) and gene-directed synergistic folic acid and vitamin D treatment group (gene-directed group) , with 100 cases in each group. The genome group adjusted the drug according to the characteristics of the detected hypertension gene loci; the gene-directed group received folic acid and vitamin D in addition to the genomic therapy regimen. Sitting systolic and diastolic blood pressures in the morning without antihypertensive drugs were collected from patients at the initial intervention (M0) , 3 months of intervention (M3) , and 6 months of intervention (M6) . Case status, adverse reactions and stroke were recorded, gene sequencing was performed, and serum homocysteine (Hcy) concentration was detected. Pearson correlation analysis or Spearman's rank correlation analysis were used to explore the correlation between sex, age, systolic blood pressure, diastolic blood pressure and Hcy. Results Gender (rs=-0.463) , systolic blood pressure (r=0.181) and diastolic blood pressure (r=0.188) were correlated with Hcy level (PC) , CYP2D6 (c.100C>T) were associated with polymorphism loci of drug metabolism enzyme genes, respectively. ADRB1, ACEI (I/D) , AGTR1 and NPPA were associated with the polymorphic loci of drug target sensitivity genes. Genome A6986G:CYP3A5*1/*1 (AA) , ACEI (I/D) :D/D, C.100 C>T:CYP2D6*1/*1 (CC) patients at M3 and M6 had lower diastolic blood pressure than M0, A6986G:CYP3A5a1/a3 (AG) , ADRB1 C.1165 G>C:GG, c.1075A>C:CYP2C9*1/*3 (AC) , c.1075A>c:CYP2C9*3/*3 (CC) patients at M6 had lower systolic and diastolic blood pressure than M0, A6986G:CYP3A5*3/*3 (GG) , ADRB1 C.1165 G>C:CC, ACEI (I/D) :I/I, c.1075A>C:CYP2C9*1/*1 (AA) , AGTR1 C.1166A>c:AA, NPPA T2238C:TT, c.100 C>T:CYP2D6*10/*10 (TT) patients at M3 and M6 had lower systolic and diastolic blood pressure than M0, ADRB1 C.1165 G>C:GC, ACEI (I/D) :I/D, c.100 C>T:CYP2D6*1/*10 (CT) patients at M6 had lower systolic blood pressure than M0, and lower diastolic blood pressure than M0, the difference was statistically significant (P

Abstract 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.

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.

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

Background: Cerebral venous sinus thrombosis (CVST) is a rare, treatable cause of stroke. Even though CVST has an established medical treatment, 15% of patients remain refractory to treatment. These patients may be candidates for endovascular treatment (EVT), yet the selection of patients remains a challenge. The study aims to understand the profile and outcome of patients treated with EVT and the type of procedure associated with good outcomes. Methods: This is a single-center, retrospective analysis of CVST patients who underwent EVT from 2009 till 2022. Patients who received only medical management were excluded. Modified Rankin Scale (mRS) ≤2 at 3 months was taken as the primary outcome. Secondary outcomes assessed were hospital stay, death, recurrence, mRS ≤ 2 at discharge, and angiographic recanalization. Results: Fifty-two patients were included. Twenty-eight (53.8%) were males; the mean age was 33.3 ± 12.3 years. Headache (n = 44, 84.6%) predominated among the symptoms. The common risk factors were anemia (n = 13, 25.5%) and hyperhomocysteinemia (n = 13, 25.5%). Worsening of sensorium (n = 21, 40.3%) and non-improvement of symptoms (n = 15, 28.8%) were the common indications for the procedure. Twenty-five (48.1%) people underwent in situ thrombolysis (IST). Death occurred in eight (15.3%) patients. Thirty-six (73.5%; 36/49) patients had a good outcome at 3 months. IST had a significantly better outcome (mRS ≤ 2, n = 20, 80%) compared to other procedures (P = 0.04). Hospital stay was lesser in the IST subgroup, but without statistical significance. Midline shift >5 mm (odds ratio [OR] 6.8 [1.5--30.9], P = 0.01) and Glasgow Coma Scale <9 before the procedure (OR 27.2 [3.1--236.4], P = 0.002) predicted bad outcomes at 3 months. Female gender (OR 4.5 [1.07--8.8], P = 0.03), presence of altered sensorium (OR 10.2 [1.2--87.5], P = 0.01), encephalopathic syndrome (P = 0.02), presence of parenchymal bleed (OR 3.7 [0.9--4.5], P = 0.04), and midline shift (OR 4.8 [1.1--20.2], P = 0.03) were associated with poor outcome at discharge. Conclusion: EVT yielded good outcomes in carefully selected, medically refractory patients of CVST. IST performed well compared to other procedures. [ABSTRACT FROM AUTHOR]

Objective To investigate the prevalence and influencing factors of hyperhomocysteinemia among Tibetan residents in the west of Xizang Ali. Methods By using the method of multi-stage cluster random sampling, Tibetan residents were randomly selected from the western area of Xizang Ali for physical examination and questionnaire survey, and blood routine and biochemical indexes were collected. The prevalence and influencing factors of hyperhomocysteinemia in this area were analyzed by chi-square test and multivariate logistic regression. Results A total of 1 362 Tibetan residents in the western region of Xizang Ali were investigated. The results showed that there were 1 044 patients with hyperhomocysteinemia, with a prevalence rate of 76.7%. The prevalence rate of males (84.8%) was higher than that of females (71.5%). Smoking (OR=1.988, 95%CI: 1.076-3.675), poor household (OR = 1.775, 95%CI: 1.204-2.540), hyperuricemia (OA =3.416, 95%CI: 2.494-4.679), hypercholesterolemia (OA =4.051, 95%CI: 2.811-5.838), and hypertriglyceridemia (OR=2.589, 95%CI: 1.765-3.798) were risk factors of hyperhomocysteinemia. Female (0R=0.538, 95%CI: 0.384-0.752) and agricultural and pastoral areas (OR = 0.312, 95%CI: 0.156-0.625) were protective factors. Conclusion The prevalence rate of hyperhomocysteinemia is high in the western region of Xizang Ali. Sex, residence, smoking, and poor households are the influencing factors of hyperhomocys- teinemia. Hyperhomocysteinemia is significantly associated with hyperuricemia, hypercholesterolemia, hypertriglyceridemia, and other diseases. [ABSTRACT FROM AUTHOR]

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

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. [ABSTRACT FROM AUTHOR]

Diabetic patients have elevated homocysteine levels, and hyperhomocysteinemia is shown to exacerbate mitochondrial damage, which plays a central role in diabetic retinopathy. Glutathione peroxidases (GPx) catalyze hydrogen peroxide (H2O2) reduction using glutathione (GSH) as a cofactor. GSH and GPx are mainly cytosolic but are also present in the mitochondria to neutralize H2O2 produced by superoxide dismutase, and in diabetes, they are downregulated. Hyperhomocysteinemia also disrupts the balance between S-adenosyl-L-homocysteine and S-adenosylmethionine (SAM); SAM is also a methyl donor for DNA methylation. The aim of this study was to investigate the role of homocysteine in mitochondrial GSH–GPx1 regulation in diabetic retinopathy. Human retinal endothelial cells in 20 mM D-glucose + high homocysteine were analyzed for ROS, GSH and GPx in the mitochondria, and SAM levels and GPx1 promoter DNA methylation were also studied (5-methylcytosine and MS-PCR). The results were confirmed in the retina from streptozotocin-induced hyperhomocysteinemic (cystathionine-β-synthase-deficient) diabetic mice. High homocysteine exacerbated the glucose-induced decrease in GSH levels and GPx activity in the mitochondria and the downregulation of GPx1 transcripts and further increased SAM levels and GPx1 promoter DNA methylation. Similar results were obtained in a hyperglycemic–hyperhomocysteinemic mouse model. Thus, elevated homocysteine in diabetes hypermethylates GPx1 promoter, thus decreasing the mitochondrial GPx/GSH pool and exacerbating mitochondrial damage. Modulating hyperhomocysteinemia could be a potential therapeutic avenue to target mitochondrial dysfunction in diabetic retinopathy. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effects of aerobic treadmill training regimen of four weeks duration on oxidative stress parameters, metabolic enzymes, and histomorphometric changes in the colon of hyperhomocysteinemic rats. Male Wistar albino rats were divided into four groups (n = 10, per group): C, 0.9% NaCl 0.2 mL/day subcutaneous injection (s.c.) 2x/day; H, homocysteine 0.45 µmol/g b.w./day s.c. 2x/day; CPA, saline (0.9% NaCl 0.2 mL/day s.c. 2x/day) and an aerobic treadmill training program; and HPA, homocysteine (0.45 µmol/g b.w./day s.c. 2x/day) and an aerobic treadmill training program. The HPA group had an increased level of malondialdehyde (5.568 ± 0.872 μmol/mg protein, p = 0.0128 vs. CPA (3.080 ± 0.887 μmol/mg protein)), catalase activity (3.195 ± 0.533 U/mg protein, p < 0.0001 vs. C (1.467 ± 0.501 U/mg protein), p = 0.0012 vs. H (1.955 ± 0.293 U/mg protein), and p = 0.0003 vs. CPA (1.789 ± 0.256 U/mg protein)), and total superoxide dismutase activity (9.857 ± 1.566 U/mg protein, p < 0.0001 vs. C (6.738 ± 0.339 U/mg protein), p < 0.0001 vs. H (6.015 ± 0.424 U/mg protein), and p < 0.0001 vs. CPA (5.172 ± 0.284 U/mg protein)) were detected in the rat colon. In the HPA group, higher activities of lactate dehydrogenase (2.675 ± 1.364 mU/mg protein) were detected in comparison to the CPA group (1.198 ± 0.217 mU/mg protein, p = 0.0234) and higher activities of malate dehydrogenase (9.962 (5.752–10.220) mU/mg protein) were detected in comparison to the CPA group (4.727 (4.562–5.299) mU/mg protein, p = 0.0385). Subchronic treadmill training in the rats with hyperhomocysteinemia triggers the colon tissue antioxidant response (by increasing the activities of superoxide dismutase and catalase) and elicits an increase in metabolic enzyme activities (lactate dehydrogenase and malate dehydrogenase). This study offers a comprehensive assessment of the effects of aerobic exercise on colonic tissues in a rat model of hyperhomocysteinemia, evaluating a range of biological indicators including antioxidant enzyme activity, metabolic enzyme activity, and morphometric parameters, which suggested that exercise may confer protective effects at both the physiological and morphological levels. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, are immune-mediated chronic inflammatory diseases of the intestinal tract. Under conditions of low vitamin B content, homocysteine accumulates and leads to hyperhomocysteinemia. The association between hyperhomocysteinemia and the risk of IBD has been widely studied. In the current study, Rosa canina L. fruit (RC) extract was analyzed by GC–MS, which revealed the presence of n-hexadecanoic acid, oleic acid, and stearic acid, which were identified as major compounds. The total phenolic and flavonoid contents of the RC extract were assessed. Additionally, the antioxidant activity of RC extract was checked using several radical scavenging activities, furthermore, a step-down method was used to confirm the nontoxicity of RC. The protective effect of RC on mice intestinal inflammation (induced by hyperhomocysteinemia) was evaluated according to an experimental in vivo procedure of 21 days. The level of plasma inflammatory markers (hs-CRP, homocysteine), and the reduced glutathione (GSH) content of liver tissue were measured. Additionally, the histological sections of the intestinal tissue were examined. Our results revealed a potent antioxidant capacity of RC extract. On the other hand, RC considerably reduced the histopathological changes, increased the level of GSH, and restored the integrity of the intestinal epithelium. Therefore, we recommend the use of RC as a natural anti hyperhomocysteinemia and antiinflammatory therapeutic agent. [ABSTRACT FROM AUTHOR]