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Background and Objective: Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism and one-carbon metabolism. MTHFR gene polymorphism affects enzyme activity. MTHFR gene polymorphism is closely related to many human diseases, such as cardiocerebrovascular diseases, diabetes, neural tube defects (NTDs), tumors, and so on. In the field of Andrology, MTHFR gene polymorphism may be associated with male infertility and erectile dysfunction (ED), and there is a possibility of treating male infertility and ED by supplementing with folic acid. However, its exact pathophysiologic mechanism is not fully understood. We sought to obtain a robust understanding of the interactions between MTHFR gene polymorphism, oxidative stress, DNA methylation, hyperhomocysteinemia (HHcy), male infertility, and ED. Methods: We performed a non-systematic literature review using the PubMed database to identify articles specifically related to MTHFR, male infertility and ED. Key Content and Findings: Our literature review on MTHFR gene polymorphism in male infertility patients indicates a significant association between C677T gene polymorphism and male infertility. There is limited literature on the correlation between ED and MTHFR gene polymorphism, and there are two different conclusions, related and unrelated. More clinical data are needed to clarify the conclusion. There is a possibility of using folic acid supplementation to treat male infertility and ED, especially for patients with thymine-thymine (TT) genotype. Future research is necessary to further understand the relationship between MTHFR gene polymorphism and male infertility and ED. Conclusions: Our literature review on MTHFR gene polymorphism in male infertility patients indicates a significant association between C677T gene polymorphism and male infertility. Folic acid supplementation can improve sperm quality. The correlation between MTHFR gene polymorphisms and ED is questionable and needs to be confirmed by more clinical data. MTHFR gene polymorphisms are associated with homocysteine (Hcy) levels, which affects vascular endothelial function and may be related to the development of vascular ED (VED). Folic acid supplementation improves International Index for Erectile Function (IIEF) questionnaire scores in ED patients in whom phosphodiesterase 5 inhibitor (PDE5i) alone is ineffective.
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DNA damage is associated with hyperhomocysteinemia (HHcy) and neural tube defects (NTDs). Additionally, HHcy is a risk factor for NTDs. Therefore, this study examined whether DNA damage is involved in HHcy-induced NTDs and investigated the underlying pathological mechanisms involved. Embryonic day 9 (E9) mouse neuroectoderm cells (NE4C) and homocysteine-thiolactone (HTL, active metabolite of Hcy)-induced NTD chicken embryos were studied by Western blotting, immunofluorescence. RNA interference or gene overexpression techniques were employed to investigate the impact of Menin expression changes on the DNA damage. Chromatin immunoprecipitation-quantitative polymerase chain reaction was used to investigate the epigenetic regulation of histone modifications. An increase in γH2AX (a DNA damage indicator) was detected in HTL-induced NTD chicken embryos and HTL-treated NE4C, accompanied by dysregulation of phospho-Atr-Chk1-nucleotide excision repair (NER) pathway. Further investigation, based on previous research, revealed that disruption of NER was subject to the epigenetic regulation of low-expressed Menin-H3K4me3. Overexpression of Menin or supplementation with folic acid in HTL-treated NE4C reversed the adverse effects caused by high HTL. Additionally, by overexpressing the Mars gene, we tentatively propose a mechanism whereby HTL regulates Menin expression through H3K79hcy, which subsequently influences H3K4me3 modifications, reflecting an interaction between histone modifications. Finally, in 10 human fetal NTDs with HHcy, we detected a decrease in the expression of Menin-H3K4me3 and disorder in the NER pathway, which to some extent validated our proposed mechanism. The present study demonstrated that the decreased expression of Menin in high HTL downregulated H3K4me3 modifications, further weakening the Atr-Chk1-NER pathway, resulting in the occurrence of NTDs.
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Daño del ADN , Histonas , Homocisteína , Defectos del Tubo Neural , Proteínas Proto-Oncogénicas , Animales , Defectos del Tubo Neural/genética , Defectos del Tubo Neural/metabolismo , Embrión de Pollo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Homocisteína/análogos & derivados , Ratones , Histonas/metabolismo , Epigénesis Genética/efectos de los fármacos , Reparación del ADN/efectos de los fármacosRESUMEN
This case report details the sudden onset of an ischemic stroke in a man in his late 20s, attributed to elevated homocysteine levels. Despite his young age, the patient exhibited increased homocysteine levels, a recognized stroke risk factor. This report underscores the critical importance of recognizing hyperhomocysteinemia as a potential underlying cause of strokes, even in younger age groups. Following ischemic stroke-directed treatment along with the addition of folic acid, vitamin B6, vitamin B12, and methylcobalamin, the patient's condition improved, leading to discharge with normalized homocysteine levels. Highlighting the significance of identifying this risk factor is particularly essential in regions like Pakistan, where a notably high prevalence of hyperhomocysteinemia has been reported. This case serves as a poignant reminder of the need for comprehensive stroke evaluations, urging medical practitioners to consider homocysteine as a potential contributing factor, even when dealing with young and healthy patients.
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Hyperhomocysteinemia (HHcy) is an independent risk factor of atherosclerosis (AS). Some reports have shown that homocysteine (Hcy) could accelerate the development of AS by promoting endothelial cell senescence. miRNAs were widely involved in the pathophysiology of HHcy. However, few studies have focused on the changes of miRNA-mRNA networks in the artery of HHcy patients. For this reason, RNA-sequencing was adopted to investigate the expression of miRNA and mRNA in HHcy model mouse arteries. We found that the expression of 216 mRNAs and 48 miRNAs were significantly changed. Using TargetScan and miRDB web tools, 29 miRNA-mRNA pairs were predicted. Notably, miR-20b-5p and FJX1 shared the highest predicted score in TargetScan, and further study indicated that the miR-20b-5p inhibitor significantly upregulated the FJX1 expression in HHcy human umbilical vein endothelial cells (HUVECs) model. PPI analysis revealed an important sub-network which was centered on CDK1. Gene ontology (GO) enrichment analysis showed that HHcy had a significant effect on cell cycle. Further experiments found that Hcy management increased reactive oxygen species (ROS) generation, the activity of senescence associated ß-galactosidase (SA-ß-gal) and the protein expression of p16 and p21 in HUVECs, which were rescued by miR-20b-5p inhibitor. In general, our research indicated the important role of miR-20b-5p in HHcy-related endothelial cell senescence.
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Aterosclerosis , Hiperhomocisteinemia , MicroARNs , Animales , Ratones , Aterosclerosis/genética , Senescencia Celular/genética , Células Endoteliales de la Vena Umbilical Humana , Hiperhomocisteinemia/genética , MicroARNs/genética , MicroARNs/metabolismo , ARN Mensajero/metabolismoRESUMEN
In recent decades, the increased incidence of cardiovascular disease (CVD) mortality among young adults has raised concerns. Although clinical manifestations of CVD typically occur later in life, the underlying pathological processes emerge early on. This review article summarizes the association between vitamin B deficiency-induced hyperhomocysteinemia and subclinical atherosclerosis in adolescents. Numerous studies have demonstrated that elevated homocysteine levels are an independent risk factor for endothelial dysfunction (ED) and arterial stiffness, which are key contributors to CVD. Notably, vitamin B deficiency, particularly in vitamin B9 and vitamin B12, emerges as a significant factor in childhood hyperhomocysteinemia, initiating the development of subclinical atherosclerosis in early life. A comprehensive review of relevant literature from prominent bibliographic databases, including PubMed/MEDLINE, PubMed Central, Google Scholar, and Cochrane, was performed. Four cross-sectional studies focusing on homocysteine levels as an exposure variable and markers of atherosclerosis as outcome measures were included and reviewed as part of our analysis. The reviewed studies demonstrate a positive correlation between homocysteine levels and markers of atherosclerosis, including increased carotid intima-media thickness (CIMT) and ED. Mainly, adolescents with vitamin B12 deficiency exhibit a significant positive correlation between homocysteine levels and CIMT. These findings underscore the potential of hyperhomocysteinemia as an early marker for detecting subclinical atherosclerosis in adolescents with vitamin B deficiency. Despite limited research in this area, recognizing the importance of early detection and management of subclinical atherosclerosis in adolescents can help mitigate the risk of severe cardiovascular events such as myocardial infarction and stroke in young adulthood.
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Background: Previous studies have shown that estrogen, kidney function, and homocysteine (Hcy) or hyperhomocysteinemia (HHcy) are related to each other. However, the underlying biological mechanisms still remain unclear. We aimed to explore the association between estradiol (E2) and HHcy in the female population, and to further evaluate the mediating role of renal function indicators. Methods: This unmatched case-control study consisted of 1,044 female participants who were 60.60 ± 12.46 years old. Data on general demographic characteristics, such as age, smoking and drinking status, menopause and so on were collected in a personal interview, and laboratory examinations were performed by well-trained personnel. The mediating effect model was applied to analyze the direct and indirect effects of E2 on Hcy. Results: The average levels of Hcy and E2 of the participants were 12.6 µmol/L and 14.95 pg/ml. There were statistical differences in renal indexes blood urea nitrogen (BUN), serum creatinine (Scr), uric acid (UA), glomerular filtration rate (GFR) and E2 between HHcy group and non-HHcy group. The logistic regression models showed that UA was risk factor for HHcy (P <0.001), GFR and E2 were protective factors for HHcy after adjusting for confounding factors (P <0.001). The indirect effects of E2 on Hcy through UA and GFR accounted for 14.63 and 18.29% of the total impacts of E2 on Hcy. Conclusions: These data indicated that E2 was a protective factor of HHcy, and the effects of E2 on HHcy may be mediated by renal function indicators UA and GFR.
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Hiperhomocisteinemia , Anciano , Estudios de Casos y Controles , Estradiol , Femenino , Humanos , Hiperhomocisteinemia/complicaciones , Hiperhomocisteinemia/epidemiología , Riñón/fisiología , Persona de Mediana Edad , Ácido ÚricoRESUMEN
Objective: To investigate the alleviating effect of hydrogen (H2) on homocysteine (Hcy) levels and non alcoholic fatty liver in rats with hyperhomocysteinemia (HHcy). Methods: After one week of adaptive feeding, Wistar rats were randomly divided into three groups: the general diet group (CHOW), the high methionine group (HMD), and the high methionine plus hydrogen rich water group (HMD+HRW), with 8 rats in each group. The CHOW group was fed with AIN-93G feed, while the HMD and HMD+HRW groups were fed with AIN-93G+2% methionine feed to construct an HHcy model. The HMD+HRW group was also gavaged with hydrogen rich water (3 ml/animal, twice a day, with a hydrogen concentration of 0.8 mmol/L), and body weight data were recorded. After 6 weeks of feeding, the plasma and liver samples were processed and collected. The plasma homocysteine (Hcy) and lipid contents of each group were measured, and the histological morphology of the liver was observed. The activities of key enzymes in the Hcy metabolism pathway and mRNA expression were detected in the liver. Results: Compared with the CHOW group rats, the Hcy level in the blood of HMD rats was significantly increased significantly (Pï¼0.05). Pathological tissue sections showed liver enlargement, injury, and fatty liver in the rats; Compared with the HMD group rats, the HMD+HRW group rats showed a significant decrease in Hcy in the blood, reduced liver damage, and increased Hcy metabolism key enzyme activity and mRNA expression in the liver, with statistical differences (Pï¼0.05). Conclusion: Hydrogen has a significant improvement effect on liver injury induced by HMD diet in HHcy rats, possibly by enhancing the three metabolic pathways of Hcy to reduce excessive Hcy in the body, thereby improving liver metabolic function and symptoms of non-alcoholic fatty liver disease.
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Hiperhomocisteinemia , Enfermedad del Hígado Graso no Alcohólico , Ratas , Animales , Metionina , Ratas Wistar , Racemetionina , Dieta , Homocisteína , Hidrógeno , Agua , ARN MensajeroRESUMEN
Homocysteine (Hcy) metabolism is crucial for regulating methionine availability, protein homeostasis, and DNA-methylation presenting, therefore, key pathways in post-genomic and epigenetic regulation mechanisms. Consequently, impaired Hcy metabolism leading to elevated concentrations of Hcy in the blood plasma (hyperhomocysteinemia) is linked to the overproduction of free radicals, induced oxidative stress, mitochondrial impairments, systemic inflammation and increased risks of eye disorders, coronary artery diseases, atherosclerosis, myocardial infarction, ischemic stroke, thrombotic events, cancer development and progression, osteoporosis, neurodegenerative disorders, pregnancy complications, delayed healing processes, and poor COVID-19 outcomes, among others. This review focuses on the homocysteine metabolism impairments relevant for various pathological conditions. Innovative strategies in the framework of 3P medicine consider Hcy metabolic pathways as the specific target for in vitro diagnostics, predictive medical approaches, cost-effective preventive measures, and optimized treatments tailored to the individualized patient profiles in primary, secondary, and tertiary care.
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Aims: The aims of this study were to explore the left ventricular (LV) structural remodeling and its risk factors in type 2 diabetes mellitus (T2DM) patients with or without hyperhomocysteinemia (hHcy) and to detect the accompanied LV dysfunction using three-dimensional speckle tracking echocardiography (3DSTE). Methods: There were totally 80 T2DM patients with undamaged LV ejection fraction (≥55%) in this study, 40 of whom were also diagnosed with hHcy as co-morbidity. Forty age- and gender-matched controls were also recruited. The risk factors and corresponding diagnostic values for LV remodeling (LVR) were, respectively, determined using logistic regression and area under the receiver operating characteristic curves (AUC). The 3DSTE was used to measure global longitudinal strain (GLS), global circumferential strain (GCS), global area strain (GAS), and global radial strain (GRS). Results: The constituent ratio of LV geometry showed significant differences among the study populations (P = 0.01). Compared with the controls, three types of LVR accounted for larger proportion in the two T2DM groups, whereas LV hypertrophy was most prevalent in those with T2DM and hHcy. Glycosylated hemoglobin (HbA1c), total plasma homocysteine (tHcy), and HbA1c plus tHcy were all significant risk factors associated with LVR in T2DM patients (AUC values: 0.741, 0.746 and 0.851, respectively). The patients with T2DM alone had significantly lower GLS and GAS than the controls (both P < 0.05). The patients with T2DM and hHcy had significantly lower GLS, GCS, GAS, and GRS than the controls (all P < 0.001), and also had significantly lower GLS, GCS, and GRS than the patients with T2DM alone (all P < 0.05). Conclusions: The 3DSTE plus conventional echocardiography could be used as an effective supplement for detecting early and occult cardiac damages in T2DM patients with plasma homocysteine at normal or elevated levels.
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Diabetes Mellitus Tipo 2 , Ecocardiografía/métodos , Homocisteína/sangre , Hiperhomocisteinemia , Disfunción Ventricular Izquierda/diagnóstico por imagen , Anciano , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Hiperhomocisteinemia/sangre , Hiperhomocisteinemia/complicaciones , Imagenología Tridimensional , Masculino , Persona de Mediana Edad , Disfunción Ventricular Izquierda/sangre , Disfunción Ventricular Izquierda/etiología , Remodelación VentricularRESUMEN
Our meta-analysis focused on the relationship between homocysteine (Hcy) level and the incidence of aneurysms and looked at the relationship between smoking, hypertension and aneurysms. A systematic literature search of Pubmed, Web of Science, and Embase databases (up to March 31, 2020) resulted in the identification of 19 studies, including 2,629 aneurysm patients and 6,497 healthy participants. Combined analysis of the included studies showed that number of smoking, hypertension and hyperhomocysteinemia (HHcy) in aneurysm patients was higher than that in the control groups, and the total plasma Hcy level in aneurysm patients was also higher. These findings suggest that smoking, hypertension and HHcy may be risk factors for the development and progression of aneurysms. Although the heterogeneity of meta-analysis was significant, it was found that the heterogeneity might come from the difference between race and disease species through subgroup analysis. Large-scale randomized controlled studies of single species and single disease species are needed in the future to supplement the accuracy of the results.
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Aneurisma , Hiperhomocisteinemia , Hipertensión , Homocisteína , Humanos , Hiperhomocisteinemia/diagnóstico , Hiperhomocisteinemia/epidemiología , PlasmaRESUMEN
Hydrogen sulfide (H2S) is endogenously produced from sulfur containing amino acids, including homocysteine and exerts neuroprotective effects. An increase of homocysteine during pregnancy impairs fetal growth and development of the offspring due to severe oxidative stress. We analyzed the effects of the H2S donor-sodium hydrosulfide (NaHS) administered to female rats with hyperhomocysteinemia (hHcy) on behavioral impairments and levels of oxidative stress of their offspring. Rats born from females fed with control or high methionine diet, with or without H2S donor injections were investigated. Rats with maternal hHcy exhibit increased levels of total locomotor activity and anxiety, decreased muscle endurance and motor coordination, abnormalities of fine motor control, as well as reduced spatial memory and learning. Oxidative stress in brain tissues measured by activity of glutathione peroxidases and the level of malondialdehyde was higher in rats with maternal hHcy. Concentrations of H2S and the activity and expression of the H2S generating enzyme-cystathionine-beta synthase-were lower compared to the control group. Administration of the H2S donor to females with hHcy during pregnancy prevented behavioral alterations and oxidative stress of their offspring. The acquisition of behavioral together with biochemical studies will add to our knowledge about homocysteine neurotoxicity and proposes H2S as a potential agent for therapy of hHcy associated disorders.
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Ansiedad/prevención & control , Disfunción Cognitiva/prevención & control , Sulfuro de Hidrógeno/administración & dosificación , Hiperhomocisteinemia/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Complicaciones del Embarazo/tratamiento farmacológico , Animales , Ansiedad/etiología , Ansiedad/metabolismo , Disfunción Cognitiva/etiología , Cistationina betasintasa/metabolismo , Femenino , Homocisteína/sangre , Sulfuro de Hidrógeno/farmacología , Hiperhomocisteinemia/psicología , Masculino , Embarazo , Complicaciones del Embarazo/psicología , Ratas , Especies Reactivas de Oxígeno/metabolismo , Resultado del TratamientoRESUMEN
Research purpose was to put together the available pieces of present scientific data and to close the gap in the knowledge of Hcy levels in pregnancy and its association with some pregnancy complications. Scientific data were taken from research papers published between January 1990 and December 2017, and found on the Internet (PubMed, ClinicalKey and Embase databases) by the following tags entered in English, Russian, French and German languages: pregnancy, homocysteine, pregnancy complications, pregnancy loss, preeclampsia, intrauterine growth restriction, and placental abruption. The review showed that Hcy levels range in uncomplicated pregnancy. Upon that, Hcy level tends to decrease during the second and third trimesters. Some studies have revealed a link between polymorphism and abortion. Sufficient data were obtained indicating the relationship between HHcy and PE. Placental abruption was also associated with high Hcy levels increasing the risk 5.3-fold, but still there are data not supporting the hypothesis that Hcy levels correlate with placental abruption.
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Aborto Espontáneo/patología , Desprendimiento Prematuro de la Placenta/patología , Retardo del Crecimiento Fetal/patología , Homocisteína/análisis , Preeclampsia/patología , Aborto Espontáneo/metabolismo , Desprendimiento Prematuro de la Placenta/metabolismo , Femenino , Retardo del Crecimiento Fetal/metabolismo , Humanos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo de Nucleótido Simple , Preeclampsia/metabolismo , EmbarazoRESUMEN
In the United States, Alzheimer's disease (AD) is the most common cause of dementia, accompanied by substantial economic and emotional costs. During 2015, more than 15 million family members who provided care to AD patients had an estimated total cost of 221 billion dollars. Recent studies have shown that elevated total plasma levels of homocysteine (tHcy), a condition known as hyperhomocysteinemia (HHcy), is a risk factor for AD. HHcy is associated with cognitive decline, brain atrophy, and dementia; enhances the vulnerability of neurons to oxidative injury; and damages the blood-brain barrier. Many therapeutic supplements containing vitamin B12 and folate have been studied to help decrease tHcy to a certain degree. However, a therapeutic cocktail approach with 5-methyltetrahydrofolate, methyl B12, betaine, and N-acetylcysteine (NAC) have not been studied. This novel approach may help target multiple pathways simultaneously to decrease tHcy and its toxicity substantially.
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BACKGROUND: Ginkgo biloba extract EGb761 has shown the neuroprotective effects on Alzheimer's disease (AD) through the protection against the Aß-induced neurotoxicity. However, it is not completedly clear whether EGb761 attenuates tau hyperphosphorylation, another of the most prominent mechanisms underlying the pathology of AD. METHODS: we employed hyperhomocysteinemia (HHcy) to mimic AD like pathological alterations and memory deficits in rats as model, and injected EGb761 with or after HHcy injection as prevention and treatment, injected saline as control. We measured the status of oxidative damage and spatial and learning memory in rats. Then we detected the level of memory-related proteins, tau phosphorylation and the level and activity of tau kinase (GSK-3ß) and phosphatase (PP2A) by Western blotting and Immunohistochemistry. RESULTS: We found that EGb761 could significantly antagonize HHcy-induced oxidative damage, recover PP2Ac and GSK3ß activities deregulated by HHcy. Furthermore, tau was hyperphosphorylated at Thr231, Ser262, Ser396, and Ser404, most common PP2Ac and GSK3ß targeted sites in the hippocampus and prefrontal cortex of HHcy rats, whereas EGb761 recovered the tau phosphorylation at those sites. Behavioral tests revealed that EGb761 rescued HHcy-induced spatial reference memory deficit and upregulated the expression of synapse-associated protein PSD95 and synapsin-1. CONCLUSION: EGb761 might be a promising drug to treat AD through its anti-oxidative activity and decreasing tau hyperphosphorylation besides the protection against the Aß-induced neurotoxicity.