Effect of long-term chronic hyperhomocysteinemia on retinal structure and function in the cystathionine-ß-synthase mutant mouse.

Elevated levels of the excitatory amino acid homocysteine (Hcy) have been implicated in retinal diseases in humans including glaucoma and macular degeneration. It is not clear whether elevated Hcy levels are pathogenic. Models of hyperhomocysteinemia (Hhcy) have proven useful in addressing this including mice with deficiency in the enzyme cystathionine ß-synthase (CBS). Cbs+/- mice have a ∼two-fold increase in plasma and retinal Hcy levels. Previous studies of visual function and structure in Cbs+/- mice during the first 10 months of life revealed mild ganglion cell loss, but minimal electrophysiological alterations. It is not clear whether extended, chronic exposure to moderate Hhcy elevation will lead to visual function loss and retinal pathology. The present study addressed this by performing comprehensive analyses of retinal function/structure in 20 month Cbs+/- and Cbs+/+ (WT) mice including IOP, SD-OCT, scotopic and photopic ERG, pattern ERG (pERG), and visual acuity. Eyes were harvested for histology and immunohistochemical analysis of Brn3a (ganglion cells), dihydroethidium (oxidative stress) and GFAP (gliosis). The analyses revealed no difference in IOP between groups for age/strain. Visual acuity measured ∼0.36c/d for mice at 20 months in Cbs+/- and WT mice; contrast sensitivity did not differ between groups at either age. Similarly SD-OCT, scotopic/photopic ERG and pERG revealed no differences between 20 month Cbs+/- and WT mice. There was minimal disruption in retinal structure when eyes were examined histologically. Morphometric analysis revealed no significant differences in retinal layers. Immunohistochemistry revealed ∼5 RGCs/100 µm retinal length in both Cbs+/- and WT mice at 20 months. While there was greater oxidative stress and gliosis in older (20 month) mice versus young (4 month) mice, there was no difference in these parameters between the 20 month Cbs+/- and WT mice. We conclude that chronic, moderate Hhcy (at least due to deficiency of Cbs) is not accompanied by retinal structural/functional changes that differ significantly from age-matched WT littermates. Despite considerable evidence that severe Hhcy is toxic to retina, moderate Hhcy appears tolerated by retina suggesting compensatory cellular survival mechanisms.

Mild hyperhomocysteinemia induces blood-brain barrier dysfunction but not neuroinflammation in the cerebral cortex and hippocampus of wild-type mice.

This study explored the potential effects of mild hyperhomocysteinemia (HHcy) on the blood-brain barrier (BBB) and neuroinflammation. Seven-week-old male wild-type C57BL/6 mice were fed normal mouse chow (the control group) or a methionine-enriched diet (the HHcy group) for 14 weeks. Mice in the HHcy group exhibited a slight increase in serum Hcy levels (13.56 ± 0.61 µmol/L). Activation of the ERK signaling pathway, up-regulation of matrix metalloproteinase-9 (MMP-9), and degradation of tight junction proteins (occludin and claudin-5) were observed in both the cerebral cortex and hippocampus of mice with mild HHcy. However, microglia were not activated and the levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were not changed in either the cerebral cortex or hippocampus of mice with mild HHcy. Moreover, the signaling activity of STAT3 also did not differ significantly between the two groups. These findings demonstrate that the BBB is highly vulnerable to homocysteine insult. Even a slight increase in serum homocysteine levels up-regulates MMP-9 expression and disrupts the BBB integrity. Meanwhile, microglia activation or the STAT3 pathway might not contribute to the effects of mild HHcy on the brain.

Late-onset methylmalonic acidemia and homocysteinemia.

INTRODUCTION: Introduction: cobalamin C (Cbl C) deficiency is the most common defect in intracellular cobalamin metabolism, associated with methylmalonic acidemia and homocystinuria. Its late clinical presentation is heterogeneous and may lead to a diagnostic delay. Case report: we report the case of a 45-year-old man with a 20-year history of chronic kidney disease and recently diagnosed spastic paraparesis, both of unknown origin. Metabolic studies revealed elevated levels of homocysteine and methylmalonic acid in the blood and urine. A genetic study confirmed cobalamin C deficiency. Treatment with hydroxocobalamin, betaine, carnitine, and folic acid was started. The patient eventually received a kidney transplant. Discussion: early diagnosis and appropriate treatment improve the clinical evolution of patients with Cbl C deficiency. Determination of homocysteine, organic acids, and other amino acids should be included in the differential diagnosis of patients with nephrological-neurological symptoms without a clear etiology.

INTRODUCCIÓN: Introducción: la deficiencia de cobalamina C (Cbl C) es el defecto más común en el metabolismo intracelular de la cobalamina, asociado a acidemia metilmalónica y homocistinuria. Su presentación clínica tardía es heterogénea y puede llevar a un retraso en el diagnóstico. Caso clínico: presentamos el caso de un varón de 45 años con 20 años de evolución de enfermedad renal crónica y paraparesia espástica de reciente diagnóstico, ambos de origen desconocido. Los estudios metabólicos revelaron niveles elevados de homocisteína y ácido metilmalónico en sangre y orina. El estudio genético confirmó el déficit de cobalamina C. Se inició tratamiento con hidroxocobalamina, betaína, carnitina y ácido fólico. El paciente pudo recibir un trasplante renal. Discusión: el establecimiento de un diagnóstico precoz y un tratamiento adecuado mejora la evolución clínica de los pacientes con déficit de Cbl C. La determinación de homocisteína, ácidos orgánicos y otros aminoácidos debe incluirse en el diagnóstico diferencial de los pacientes con síntomas nefrológico-neurológicos sin una etiología clara.

Arterial Blood Pressure Variability and Other Vascular Factors Contribution to the Cognitive Decline in Parkinson's Disease.

Dementia is one of the most disabling non-motor symptoms in Parkinson's disease (PD). Unlike in Alzheimer's disease, the vascular pathology in PD is less documented. Due to the uncertain role of commonly investigated metabolic or vascular factors, e.g., hypertension or diabetes, other factors corresponding to PD dementia have been proposed. Associated dysautonomia and dopaminergic treatment seem to have an impact on diurnal blood pressure (BP) variability, which may presumably contribute to white matter hyperintensities (WMH) development and cognitive decline. We aim to review possible vascular and metabolic factors: Renin-angiotensin-aldosterone system, vascular endothelial growth factor (VEGF), hyperhomocysteinemia (HHcy), as well as the dopaminergic treatment, in the etiopathogenesis of PD dementia. Additionally, we focus on the role of polymorphisms within the genes for catechol-O-methyltransferase (COMT), apolipoprotein E (APOE), vascular endothelial growth factor (VEGF), and for renin-angiotensin-aldosterone system components, and their contribution to cognitive decline in PD. Determining vascular risk factors and their contribution to the cognitive impairment in PD may result in screening, as well as preventive measures.

Genes and genetics in hyperhomocysteinemia and the "1-carbon metabolism": implications for retinal structure and eye functions.

Homocysteine (Hcy), a sulfur-containing nonproteinogenic amino acid, is generated as a metabolic intermediate. Hcy constitutes an important part of the "1-carbon metabolism" during methionine turnover. Elevated levels of Hcy known as hyperhomocysteinemia (HHcy) results from vitamin B deficiency, lack of exercise, smoking, excessive alcohol intake, high-fat and methionine-rich diet, and the underlying genetic defects. These factors directly affect the "1-carbon metabolism (methionine-Hcy-folate)" of a given cell. In fact, the Hcy levels are determined primarily by dietary intake, vitamin status, and the genetic blueprint of the susceptible individual. Although Hcy performs an important role in cellular functions, genetic alterations in any of the key enzymes responsible for the "1-carbon metabolism" could potentially upset the metabolic cycle, thus causing HHcy environment in susceptible people. As such, HHcy relates to several clinical conditions like atherosclerosis, myocardial infarction, stroke, cognitive impairment, dementia, Parkinson's disease, multiple sclerosis, epilepsy, and ocular disorders, among others. This article summarizes the findings from our laboratory and public database regarding genetics of HHcy and its effects on ocular disorders, their respective management during dysregulation of the 1-carbon metabolism.

Effect of Intensive Blood Pressure Control on Carotid Morphology and Hemodynamics in Chinese Patients with Hyperhomocysteinemia-Type Hypertension and High Risk of Stroke.

BACKGROUND Different blood pressure targets should be formulated for different groups of people. This study aimed to assess the effectiveness of intensive blood control in improving the carotid morphology and hemodynamics in Chinese patients with hyperhomocysteinemia-type hypertension and high risk of stroke. MATERIAL AND METHODS Chinese hypertensive patients with high risk of stroke were randomized to intensive (n=187) and standard (n=192; controls) blood pressure management groups. Systolic blood pressure (SBP) targets were 100< SBP ≤120 and 120< SBP ≤140 mmHg, respectively. All patients received folic acid 0.8 mg/d and atorvastatin 20 mg/d. Calcium antagonist was first used. If blood pressure was still uncontrolled, angiotensin-converting enzyme inhibitor or angiotensin receptor antagonist, ß-receptor blocker, and diuretics were added successively. Follow-up was 12 months. Carotid features, hemodynamics, and adverse events were examined. RESULTS There were no differences in sex, age, body mass index, blood lipids, baseline carotid parameters, and histories of smoking, diabetes, statin use, and stroke between the 2 groups. Carotid plaques after 12 months of treatment were 19.4±2.1 and 23.6±3.1 cm² for the intensive and control groups, respectively (P=0.038). Plaque scores were lower in the intensive group (1.75±0.52 vs. 2.45±0.47, P=0.023). Compared with controls, intensive management resulted in relatively higher Vd and significantly lower Vs/Vd, PI, and RI (all P<0.05). Major adverse events such as hypotension (n=5 (2.7%) vs. 3 (1.6%), P=0.020) and dizziness (n=20 (10.7%) vs. 16 (8.3%), P=0.041) were more frequent in the intensive group. CONCLUSIONS Intensive blood pressure management could be beneficial for Chinese patients with hyperhomocysteinemia-type hypertension and high risk of stroke.

Culprit Lesion Characteristics in Young Patients with Hyperhomocysteinemia.

BACKGROUND The relationships between culprit coronary plaque characteristics and hyperhomocysteinemia (HHcy) are not fully understood in young patients. In this study we investigated the relationship between culprit atherosclerotic plaque phenotype assessed by optical coherence tomography (OCT) and hyperhomocysteinemia (HHcy) in young patients. MATERIAL AND METHODS We investigated the OCT imaging and HHcy of 123 lesions in 123 young patients (≤45 years of age). According to OCT images, culprit lesions were classified as thin-cap fiber atheroma (TCFA), thrombus, and other. The 123 patients were grouped as: HHcy group (53 cases, HHcy ≥15.5 µmol/l) and control group (70 cases, HHcy <15.5 µmol/l). RESULTS Compared with the control group, the HHcy group had a higher proportion of OCT-TCFA (p=0.03), OCT-vasa vasorum (p=0.013), and OCT-thrombus (p=0.012), and a larger lipid arc (p=0.002). HHcy (P=0.037) and metabolic syndrome (MetS) (P=0.016) remained independent predictors of TCFAs. HHcy (P=0.026) and smoking (P=0.005) remained independent determinants of thrombus. CONCLUSIONS HHcy and MetS are associated with TCFAs, and HHcy and smoking are associated with thrombus in young patients with coronary artery disease.

Communication: Melatonin, Hyperhomocysteinemia, Thioretinaco Ozonide, Adenosylmethionine and Mitochondrial Dysfunction in Aging and Dementia.

The indoleamine hormone melatonin is synthesized by the pineal gland, controls circadian rhythm, and is dependent upon adenosyl methionine for enzymatic synthesis of melatonin from N-acetyl serotonin. Pineal melatonin secretion declines dramatically with aging and dementia. Elevated plasma homocysteine is a risk factor for atherosclerosis and Alzheimer's disease, and the marked decline in adenosyl methionine with aging leads to dysregulation of methionine metabolism and hyperhomocysteinemia. Thioretinaco ozonide is a disulfonium complex formed from thioretinamide, cobalamin, and ozone, which binds the alpha and gamma-phosphate groups of adenosine triphosphate (ATP) and oxygen in the process of oxidative phosphorylation within mitochondria. Decreased adenosyl methionine concentrations with aging are attributed to the loss of thioretinaco ozonide from mitochondria, impairing adenosyl methionine synthesis from thioretinaco ozonide and ATP. Melatonin is present in mitochondria, where it inhibits the opening of the mitochondrial permeability transition pore, explaining its anti-oxidant and anti-apoptotic effects by reducing oxygen consumption, restoration of membrane potential and reduction of superoxide production. In aging, the enzyme cyclic nucleotide phosphodiesterase is lost from mitochondria by the opening of the permeability transition pore and disruption of the outer mitochondrial membrane, a process that is inhibited by melatonin. Thioretinaco ozonide is progressively lost from dysfunctional mitochondria by disruption of the outer mitochondrial membrane, explaining its depletion during the aging process. Accordingly, the anti-aging effects of diallyl trisulfide and metformin are attributable to inhibition of the opening of the mitochondrial permeability transition pore, preventing loss of thioretinaco ozonide from mitochondria. The hyperhomocysteinemia and suppressed immunity that are observed in atherosclerosis and dementia are attributed to the deficiency of adenosylmethionine caused by increased polyamine synthesis and decreased nitric oxide synthesis by host cells infected with pathogenic microbes. According to this analysis, the critical loss of thioretinaco ozonide from mitochondria through the opening of the permeability transition pore and disruption of the outer mitochondrial membrane by decreased melatonin secretion leads to the impaired oxidative phosphorylation, oxidative stress, calcium influx, apoptosis and mitochondrial dysfunction observed in aging and dementia.

Vitamin B complex mitigates cardiac dysfunction in high-methionine diet-induced hyperhomocysteinemia.

This research is designed to test the hypothesis that elevated homocysteine (Hcy) levels in vivo, caused by a deficit in vitamin B complex, promote changes in cardiac function and redox status that lead to heart failure. In order to conduct the study, we used adult male Wistar albino rats (n = 30; 4 weeks old; 100 ± 15 g body weight). Hyperhomocysteinaemia (HHcy) in these animals was achieved by dietary manipulation. For 4 weeks, the animals were fed with a standard rodent chow (control, CF), a diet enriched in methionine with no deficiency in B vitamins (i.e., folic acid, B6 and B12) (HMNV) or a diet enriched in methionine and deficient in B vitamins (HMLV). After 28 days of dietary manipulation, all animals were killed. The rat hearts were isolated and retrogradely perfused according to the Langendorff technique at a gradually increasing perfusion pressure. We found a negative correlation between elevated serum Hcy and total body and heart weight. The maximum rate of left ventricular pressure development was significantly increased in the HMNV group compared with in the other groups. Systolic left ventricular pressure was significantly changed in all groups. HHcy induces remodelling of the cardiac tissues, as moderate HHcy is associated with more prominent interstitial and perivascular fibrosis. Our results suggest that a high methionine diet without vitamin B complex causes profound negative effects associated with HHcy.

[THE DIFFERENTIATED APPROACH TO PREVENTION OF NEURAL TUBE DEFECTS IN CHILDREN].

Neural tube defects occupy second place in frequency after the defects of the cardiovascular system. The folate metabolism violation and hyperhomocysteinemia in women are proved to be the leading risk factors for the NTD of the fetus. Polymorphism of the 5,10-methylenetetrahydrofolate reductase gene (MTHFR) is a genetic determinant of folate metabolism violation. Admission of folic acid in a standard dose of 0.4 mg and / or the use of fortified foods does not allow reaching the protective level of folic acid if there is a mutation of the MTHFR gene or when several risk factors combine, which requires a higher dose of folic acid. The aim of the study is to develop an algorithm for the identification of women of reproductive age with the risk of having a child with NTD and to apply differentiated approach to the choice of a preventive dose of folic acid. A retrospective analysis of NTD cases in the Odessa region (Ukraine) for 2000-2013 was carried out. The frequency of the birth of children with CNS defects and NTD, risk factors of NTD in children were studied. Mothers and their children with NTD were evaluated for the level of folic acid, homocysteine and the presence of C677T and A1298C MTHFR polymorphisms. The incidence of spina bifida aperta is 4.9 per 10,000 newborns. Two groups of significant risk factors for the NTD in children were identified: 1) risk factors that can be eliminated - the absence of preconceptional prevention of NTD with folic acid (AR 0.4), second-hand tobacсo smoking (AR 0.33), fever/hot baths in the first trimester of pregnancy (AR 0.64), use of well water for cooking (AP 0.44); 2) risk factors that can not be eliminated, and which indicate a genetic risk of NTD - a family history of a stroke, heart attack, thrombosis, congenital malformations, malignant tumors (AR 0.54-0.7), an obstetrical history of miscarriage (AR 0.56 ), mother's diseases (varicose disease, obesity), NTD in other children in this family (AR 0.74). The mothers of children with NTD showed a decreased level of folic acid and an increased level of homocysteine in addition to the correlation of hyperhomocysteinemia with the mutations of the MTHFR gene. The algorithm for assessing the individual risk of having a child with NTD includes the evaluation of risk factors. If a genetic factor of folate metabolism violation or environmental risk factors that can not be eliminated are found, we recommend an additional examination. It includes determining the level of homocysteine and the MTHFR polymorphisms (in the case of hyperhomocysteinemia), which will identify the required dose of folic acid.

Endothelial factors in the pathogenesis and treatment of chronic kidney disease Part II: Role in disease conditions: a joint consensus statement from the European Society of Hypertension Working Group on Endothelin and Endothelial Factors and the Japanese Society of Hypertension.

: After examining in Part I the general mechanisms of endothelial cell injury in the kidney, the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension and the Japanese Society of Hypertension will herein review current knowledge on the role of endothelial dysfunction in multiple disease conditions that affect the kidney, including diabetes mellitus, preeclampsia, solid organ transplantation, hyperhomocysteinemia and antiangiogenic therapy in cancer. The few available randomized controlled clinical trials specifically designed to evaluate strategies for correcting endothelial dysfunction in patients with hypertension and/or chronic kidney disease are also discussed alongside their cardiovascular and renal outcomes.

Hyperhomocysteinemia and cardiovascular disease in animal model.

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease and is associated with primary causes of mortality and morbidity throughout the world. Several studies have been carried out to evaluate the effects of a diet inducing cystathionine-ß-synthase, methyltetrafolate, folic acid, and vitamin B supplemented with methionine on the homocysteine metabolism and in lowering the plasma total homocysteine levels. A large number of molecular and biomedical studies in numerous animals, such as mice, rabbits, and pigs, have sought to elevate the plasma total homocysteine levels and to identify a disease model for human hyperhomocysteinemia. However, a specific animal model is not suitable for hyperhomocysteinemia in terms of all aspects of cardiovascular disease. In this review article, the experimental progress of animal models with plasma total homocysteine levels is examined to identify a feasible animal model of hyperhomocysteinemia for different aspects.

Prevalence of hyperhomocysteinemia and its associated factors in patients with primary hypertension in Chinese urban communities: A cross-sectional study from Nanjing.

OBJECTIVE: This study aimed to investigate the prevalence of hyperhomocysteinemia (Hhcy) and its major determinants in Chinese urban population with new-onset hypertension. METHODS: A total of 574 adults (404 men and 170 women) with newly diagnosed primary hypertension were recruited from seven communities in Nanjing, China. Data on lifestyle factors, such as physical activities, current smoking and drinking status, dietary habits, and familial factors were collected in interviews, and laboratory examinations were performed by well-trained personnel. Potential factors related to the prevalence of Hhcy in this population were analyzed using a logistic regression model. RESULTS: Of the 574 participants, 421 (73.3%) were diagnosed with Hhcy whereas the remainder were only hypertensive. The study highlighted a number of factors that were significantly correlated (p < 0.001) with the prevalence of Hhcy. Subjects with Hhcy were more likely to be male (odds ratio [OR] 3.007, 95% confidence interval [CI] 1.781-5.079), have a smoking history (OR 1.052, 95% CI 1.031-1.074), older (OR 1.052, 95% CI 1.031-1.074), have an elevated Body Mass Index BMI (OR 1.160, 95% CI 1.080-1.246) and higher levels of low density lipoprotein cholesterol (LDL-c) (OR 1.590, 95% CI 1.226-2.063). Regular and adequate physical activity was associated with normal homocysteine levels in both male and female groups (p < 0.05). For males only, having a higher BMI, higher LDL-c or being older significantly (p < 0.05) affected the chances of Hhcy. Whereas for females, lower levels of eGFR could be related to Hhcy (p < 0.05). CONCLUSIONS: Our present study reported a high prevalence of Hhcy in the Nanjing population with new-onset hypertension. Associated factors like physical activity, gender, smoking history, age, BMI, and LDL-c were important modifiers of plasma homocysteine concentration. Management and intervention of the above associated factors should be implicated to improve H type hypertension control.

Adropin levels in women with polycystic ovaries undergoing ovarian stimulation: correlation with lipoprotein lipid profiles.

This study aimed to investigate serum and follicular fluid (FF) adropin levels in polycystic ovary syndrome (PCOS) and normal women undergoing controlled ovarian stimulation and correlate them with the lipid and lipoprotein levels. We included 60 women (30 lean and 30 overweight) with diagnosed PCOS, and 60 age and weight-matched non-PCOS controls (30 lean and 30 overweight), under in vitro fertilization (IVF) treatment. Serum lipid and lipoprotein levels were assessed by the Abbott Architect c8000 autoanalyzer while adropin levels were determined by enzyme immunoassay. Serum and FF adropin levels were significantly lower in PCOS women compared with controls and FF adropin levels were lower than serum levels. Significantly higher serum levels of total cholesterol, LDL-C, triglycerides, apolipoprotein B, lipoprotein(a) and homocysteine were encountered in PCOS subjects, while HDL-C and apolipoprotein A1 were significantly lower compared with controls. According to univariate and multivariate analysis, serum and FF adropin levels were positively correlated with BMI and HDL-C levels and negatively correlated with LDL-C levels. Women with polycystic ovaries exhibit lipid lipoprotein alterations increasing the risk of cardiovascular diseases later in life. Our findings suggest a probable involvement of adropin both in human metabolism and in the pathophysiology of PCOS.

Hyperhomocysteinemia-Induced Gene Expression Changes in the Cell Types of the Brain.

High plasma levels of homocysteine, termed hyperhomocysteinemia, are a risk factor for vascular cognitive impairment and dementia, which is the second leading cause of dementia. While hyperhomocysteinemia induces microhemorrhages and cognitive decline in mice, the specific effect of hyperhomocysteinemia on each cell type remains unknown. We took separate cultures of astrocytes, microglia, endothelial cells, and neuronal cells and treated each with moderate levels of homocysteine for 24, 48, 72, and 96 hr. We then determined the gene expression changes for cell-specific markers and neuroinflammatory markers including the matrix metalloproteinase 9 system. Astrocytes had decreased levels of several astrocytic end feet genes, such as aquaporin 4 and an adenosine triphosphate (ATP)-sensitive inward rectifier potassium channel at 72 hr, as well as an increase in matrix metalloproteinase 9 at 48 hr. Gene changes in microglia indicated a peak in proinflammatory markers at 48 hr followed by a peak in the anti-inflammatory marker, interleukin 1 receptor antagonist, at 72 hr. Endothelial cells had reduced occludin expression at 72 hr, while kinases and phosphatases known to alter tau phosphorylation states were increased in neuronal cells. This suggests that hyperhomocysteinemia induces early proinflammatory changes in microglia and astrocytic changes relevant to their interaction with the vasculature. Overall, the data show how hyperhomocysteinemia could impact Alzheimer's disease and vascular cognitive impairment and dementia.

Homocysteine Induces Hepatic Steatosis Involving ER Stress Response in High Methionine Diet-Fed Mice.

Elevated circulating homocysteine (Hcy) has been proposed to be associated with non-alcoholic fatty liver disease (NAFLD). It is also reported that Hcy causes protein misfolding in the endoplasmic reticulum (ER). In this study, we used a high methionine diet (HMD)-fed mouse model and cultured primary hepatocytes to investigate the effects of Hcy on hepatic lipids metabolism. C57BL/6J mice received either standard chow diet (CT, n = 10) or diet supplemented with 2% methionine (MET, n = 10) for 16 weeks. In in vitro experiments, cultured mouse primary hepatocytes were treated with Hcy, or Hcy combined with 4-phenylbutyric acid (4-PBA), or tunicamycin (TM), respectively. HMD-fed mice exhibited a mild increase in plasma Hcy level. There was no significant difference of body weight gain between the two groups. Nevertheless, HMD feeding increased epididymal fat/body weight ratio, elevated plasma triglyceride (TG) level, and decreased high-density lipoprotein cholesterol (HDL) level. Similarly, mice on HMD displayed higher liver/body weight ratio, plasma aspartate aminotransferase (AST) and its ratio to alanine aminotransferase (ALT), which was supported by the morphological observations of hepatic triglyceride accumulation in liver tissue as well as primary hepatocytes. Activation of the sterol response element-binding protein 1c (SREBP1c) in Hcy-treated hepatocytes with increased expression of genes involved in hepatic de novo lipogenesis was partially reduced by pretreatment of 4-PBA. Hcy-induced ER stress was also ameliorated by 4-PBA pretreatment, thus demonstrating an important role of Hcy-induced ER stress response in hepatic steatosis. These findings suggest that elevated Hcy was a critical factor in the pathogenesis of NAFLD. Activation of the ER stress response may be involved in Hcy-induced hepatic steatosis.

Prenatal Hyperhomocysteinemia Impairs Hypothalamic Regulation of Reproductive Cycles in Rat Progeny.

Effects of prenatal hyperhomocysteinemia on hypothalamic regulation of estrous cycles were studied in female rats. In mature rats exposed to prenatal hyperhomocysteinemia, changes in the catecholamine content in hypothalamic areas responsible for the formation of the preovulatory surge of gonadotropin-releasing hormone were revealed: the level of norepinephrine in the medial preoptic area decreased and concentration of dopamine in the median eminence with arcuate nuclei increased. Administration of melatonin attenuated the observed changes, which can be related to neuroprotective effects of this hormone determined by its antioxidant properties.

Homocysteine as a Pathological Biomarker for Bone Disease.

In the last few decades, perturbation in methyl-group and homocysteine (Hcy) balance have emerged as independent risk factors in a number of pathological conditions including neurodegenerative disease, cardiovascular dysfunction, cancer development, autoimmune disease, and kidney disease. Recent studies report Hcy to be a newly recognized risk factor for osteoporosis. Elevated Hcy levels are known to modulate osteoclastgenesis by causing detrimental effects on bone via oxidative stress induced metalloproteinase-mediated extracellular matrix degradation and decrease in bone blood flow. Evidence from previous studies also suggests that the decreased chondrocytes mediated bone mineralization in chick limb-bud mesenchymal cells and during the gestational period of ossification in rat model. However, Hcy imbalance and its role in bone loss, regression in vascular invasion, and osteoporosis, are not clearly understood. More investigations are required to explore the complex interplay between Hcy imbalance and onset of bone disease progression. This article reviews the current body of knowledge on regulation of Hcy mediated oxidative stress and its role in bone remodeling, vascular blood flow and progression of bone disease. J. Cell. Physiol. 232: 2704-2709, 2017. © 2016 Wiley Periodicals, Inc.

Potential Links between Impaired One-Carbon Metabolism Due to Polymorphisms, Inadequate B-Vitamin Status, and the Development of Alzheimer's Disease.

Alzheimer's disease (AD) is the major cause of dementia and no preventive or effective treatment has been established to date. The etiology of AD is poorly understood, but genetic and environmental factors seem to play a role in its onset and progression. In particular, factors affecting the one-carbon metabolism (OCM) are thought to be important and elevated homocysteine (Hcy) levels, indicating impaired OCM, have been associated with AD. We aimed at evaluating the role of polymorphisms of key OCM enzymes in the etiology of AD, particularly when intakes of relevant B-vitamins are inadequate. Our review indicates that a range of compensatory mechanisms exist to maintain a metabolic balance. However, these become overwhelmed if the activity of more than one enzyme is reduced due to genetic factors or insufficient folate, riboflavin, vitamin B6 and/or vitamin B12 levels. Consequences include increased Hcy levels and reduced capacity to synthetize, methylate and repair DNA, and/or modulated neurotransmission. This seems to favor the development of hallmarks of AD particularly when combined with increased oxidative stress e.g., in apolipoprotein E (ApoE) ε4 carriers. However, as these effects can be compensated at least partially by adequate intakes of B-vitamins, achieving optimal B-vitamin status for the general population should be a public health priority.

Prospective study of serum cysteine and cysteinylglycine and cancer of the head and neck, esophagus, and stomach in a cohort of male smokers.

BACKGROUND: The nonessential amino acid cysteine is known to be involved in many antioxidant and anticarcinogenic pathways. Cysteinylglycine is a pro-oxidant metabolite of glutathione and a precursor of cysteine. OBJECTIVE: To examine the relation between serum cysteine and cysteinylglycine and risk of gastric adenocarcinomas, esophageal squamous cell carcinomas, and head and neck squamous cell carcinomas, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention study of male Finnish smokers aged 50-69 y at baseline. DESIGN: In total, 170 gastric adenocarcinomas, 68 esophageal squamous cell carcinomas, and 270 head and neck squamous cell carcinomas (identified from the Finnish Cancer Registry) were matched one-to-one with cancer-free control subjects on age and the date of serum collection. We calculated ORs and 95% CIs with the use of a multivariate-adjusted conditional logistic regression. RESULTS: Cysteine had a U-shaped association with gastric adenocarcinomas; a model that included a linear and a squared term had a significant global P-test (P = 0.036). Serum cysteinylglycine was inversely associated with adenocarcinomas of the gastric cardia (OR for above the median compared with below the median: 0.07; 95% CI: 0.01, 0.70; n = 38 cases) but not for other sites. Both cysteine and cysteinylglycine were not associated with esophageal squamous cell carcinoma or head and neck squamous cell carcinoma. CONCLUSIONS: We observed associations between serum cysteine and cysteinylglycine with upper gastrointestinal cancer risk. Future studies are needed to replicate these findings. This trial was registered at clininicaltrials.gov as NCT00342992.