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1
Latteri, Saverio, Giulia Malaguarnera, Vito Emanuele Catania, Gaetano La Greca, Gaetano Bertino, Antonio Maria Borzì, Filippo Drago, and Michele Malaguarnera. "Homocysteine Serum Levels as Prognostic Marker of Hepatocellular Carcinoma with Portal Vein Thrombosis." Current Molecular Medicine 19, no. 7 (August 2, 2019): 532–38. http://dx.doi.org/10.2174/1566524019666190610120416.
Повний текст джерелаАнотація:
Background: Portal vein thrombosis (PVT) is a common complication of endstage hepatocellular carcinoma (HCC). : The aim of our study was to evaluate the role of Homocysteine (Hcy) in HCC patient with PVT. Hcy is a sulphur amino-acid involved in two pathways, trans-sulphuration and remethylation, that involve vitamins B6, B12 and folates. Methods: We recruited 54 patients with HCC and PVT, 60 patients with HCC and without PVT and 60 control subjects. We measured serum levels of Hcy, folate, vitamins B6 and B12. Results: The comparison between HCC patients with PVT versus HCC without PVT was shown that mean values of Hcy were 6.4 nmol/L (p<0.0073) higher, LDL cholesterol were 4.8 mg/dl (p<0.0079) lower, vitamin B6 were 4.6 nmol/L(p=0.0544) lower, vitamins B 12 were 22.1 pg/ml (p=0.0001) lower. Conclusion: High serum levels of Hcy are an established thrombotic risk factor in the general population. We found significantly higher levels of Hcy in HCC patients with PVT versus both HCC patients without PVT and controls.
2
Quinn, C. T., J. C. Griener, T. Bottiglieri, K. Hyland, A. Farrow, and B. A. Kamen. "Elevation of homocysteine and excitatory amino acid neurotransmitters in the CSF of children who receive methotrexate for the treatment of cancer." Journal of Clinical Oncology 15, no. 8 (August 1997): 2800–2806. http://dx.doi.org/10.1200/jco.1997.15.8.2800.
Повний текст джерелаАнотація:
PURPOSE Folate deficiency, either by diet or drug, increases plasma homocysteine (Hcy). Hcy damages cerebrovascular endothelium, and hyperhomocysteinemia is a risk factor for stroke. Hcy is metabolized to excitatory amino acid (EAA) neurotransmitters, such as homocysteic acid (HCA) and cysteine sulfinic acid (CSA), which may cause seizures and excitotoxic neuronal death. We postulated that excess Hcy and EAA neurotransmitters may partly mediate methotrexate (MTX)-associated neurotoxicity. PATIENTS AND METHODS In this retrospective analysis, we used high-performance liquid chromatography (HPLC) to measure Hcy, HCA, and CSA in CSF from two groups of children: (1) a control group of patients with no MTX exposure, and (2) a treatment group of patients who had received MTX no more than 7 days before a scheduled lumbar puncture. RESULTS The treatment group had a significantly (P = .0255) greater concentration of Hcy in CSF (0.814 micromol/L +/- 0.215 [mean +/- SEM], n = 23) than the control group (0.210 micromol/L +/- 0.028, n = 34). HCA and CSA were not detected in CSF from control patients (n = 29); however, MTX caused marked accumulation of CSF HCA (119.1 micromol/L +/- 32.0, n = 16) and CSA (28.4 micromol/L +/- 7.7, n = 16) in the treatment group. Patients with neurologic toxicity at the time of lumbar puncture had many of the highest concentrations of Hcy, HCA, and CSA. CONCLUSION These data support our hypothesis that MTX-associated neurotoxicity may be mediated by Hcy and excitotoxic neurotransmitters.
3
Yang, Modan, Winyen Tan, Xinyu Yang, Jianyong Zhuo, Zuyuan Lin, Beini Cen, Zhengxing Lian, et al. "Homocysteine: A novel prognostic biomarker in liver transplantation for alpha-fetoprotein- negative hepatocellular carcinoma." Cancer Biomarkers 29, no. 2 (October 9, 2020): 197–206. http://dx.doi.org/10.3233/cbm-201545.
Повний текст джерелаАнотація:
BACKGROUND: Precise recipient selection optimizes the prognosis of liver transplantation (LT) for hepatocellular carcinoma (HCC). Alpha-fetoprotein (AFP) is the most commonly used biomarker for diagnosis and prognosis of HCC in the clinical context. As a crucial molecule in methionine cycle, homocysteine (Hcy) level has been proved to be related to HCC progression and metastasis. OBJECTIVE: We aimed to explore the prognostic capacity of pre-transplant serum Hcy level in LT for HCC. METHODS: This study retrospectively enrolled 161 HCC patients who had underwent LT from donation after cardiac death (DCD) in the First Affiliated Hospital of Zhejiang University from 2015.01.01 to 2018.09.01. Pre-transplant serum Hcy level was incorporated into statistical analysis together with other clinical parameters and pathological features. RESULTS: From an overall perspective, significant difference was observed in Hcy level between recurrence (n= 61) and non-recurrence group (n= 100) though subsequent analysis showed unsatisfactory predicting performance. In the whole cohort, multivariate analysis showed that lnAFP (p= 0.010) and Milan criteria (MC, p< 0.001) were independent risk factors of HCC recurrence after LT. MA score based on MC and lnAFP performed well in predicting post-LT tumor recurrence with the AUROC at 0.836 (p< 0.001) and 3-year recurrence-free survival rate at 96.8% (p< 0.001) in the low risk group (n= 69). According to the clinical practice, serum concentration lower than 20 μg/L is considered as normal range of AFP. Elevated pre-transplant serum AFP (> 20 μg/L) predicts high HCC recurrence after LT. We further divided the 161 recipients into AFP- group (n= 77, AFP ⩽ 20 μg/L) and AFP+ group (n= 84, AFP > 20 μg/L). MA score was still well presented in the AFP+ group and the AUROC for tumor recurrence was 0.823 (p< 0.001), whereas the predicting accuracy was reduced in AFP- group (AUROC: 0.754, P< 0.001). After subsequent analysis, we found that elevated pre-transplant Hcy level (> 12.75 μmol/L) predicted increased tumor recurrence risk in AFP- group. The 3-year recurrence-free survival rates were 92.0% and 53.7% (p< 0.001) in low Hcy subgroup (n= 40) and high Hcy subgroup (n= 37) respectively. Multivariate analysis showed that Hcy (p= 0.040) and Milan criteria (p= 0.003) were independent risk factors for post-transplant tumor recurrence in AFP- group. Further combination of Hcy level and Milan criteria identified a subgroup of AFP- recipients with acceptable outcomes even though beyond Milan criteria (3-year recurrence-free survival rate: 77.7%, p< 0.001). CONCLUSION: As a classic predictor in HCC prognosis, AFP performed well in our study cohort when combined with Milan criteria. Homocysteine was an effective prognostic biomarker in LT for AFP- hepatocellular carcinoma. In recipients exceeding Milan criteria, acceptable post-transplant outcome could be seen in those with low Hcy and AFP level.
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Sikora, Marta, and Hieronim Jakubowski. "Homocysteine editing and growth inhibition in Escherichia coli." Microbiology 155, no. 6 (June 1, 2009): 1858–65. http://dx.doi.org/10.1099/mic.0.026609-0.
Повний текст джерелаАнотація:
In Escherichia coli homocysteine (Hcy) is metabolically converted to the thioester Hcy-thiolactone in ATP-consuming reactions catalysed by methionyl-, isoleucyl- and leucyl-tRNA synthetases. Here we show that growth inhibition caused by supplementation of E. coli cultures with Hcy is accompanied by greatly increased accumulation of Hcy-thiolactone. Energy dissipation for Hcy editing increases 100-fold in the presence of exogenous Hcy and reaches one mole of ATP unproductively dissipated for Hcy-thiolactone synthesis per each mole of ATP that is consumed for methionine activation. Inhibiting Hcy-thiolactone synthesis with isoleucine, leucine or methionine accelerates bacterial growth in Hcy-supplemented cultures. Growth rates in Hcy-inhibited cultures are inversely related to the accumulation of Hcy-thiolactone. We also show that the levels of protein N-linked Hcy modestly increase in E. coli cells in Hcy-supplemented cultures. The results suggest that Hcy editing restrains bacterial growth.
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Nozari, Samira, Nazila Fathi Maroufi, Mohammad Nouri, Mirhamid Paytakhti Oskouei, Javad Shiralizade, Farshid Yekani, Mina Mamipour, and Yousef Faridvand. "Decreasing serum homocysteine and hypocholesterolemic effects of bovine lactoferrin in male rat fed with high-cholesterol diet." Journal of Cardiovascular and Thoracic Research 10, no. 4 (December 11, 2018): 203–8. http://dx.doi.org/10.15171/jcvtr.2018.35.
Повний текст джерелаАнотація:
Introduction: Lipid metabolism disorder or hyperlipidemia is known as a risk factor for cardiovascular disease, the increase in serum homocysteine and leptin are associated with atherosclerotic disease. The purpose of the present study was to examine the effects of bovine lactoferrin (bLF) on serum homocysteine (Hcy), apolipoproteinA-I (ApoA-I) and B (ApoB), leptin and lipid profile changes in high-cholesterol-diet (HCD) fed rats. Methods: The Healthy Adult Sprague-Dawley (SD) male rats were randomly assigned into three experimental groups. Each group consisted of eleven male rats including control group, HCD rats and hypercholesterolemic rats, which were treated with bLF (HCD+bLF). bLF was given by gavage (200 mg/kg/d). After 4 weeks of feeding and overnight fasting, total blood samples were collected. Results: The results showed the elevated level of Hcy, leptin, total cholesterol, low density lipoprotein cholesterol (LDL-C), ApoB and decrease in ApoA-I in non-treated HCD group compared to the control rats. Administration of bLF significantly ameliorated the Hcy and leptin levels with decrease in LDL-C and total cholesterol in rats fed with a high-cholesterol diet. bLF also tended to increase low serum concentration of ApoA-I and high density lipoprotein cholesterol (HDL-C) in HCD rats. Meanwhile, upon bLF-treated rats, there was a significant decrease in ApoB in HCD group. Conclusion: The findings indicated that bLF can improve the alteration of serum Hcy, leptin, apolipproteins and lipid changes in male rats fed with high-cholesterol diet. So, bLF can counteract with HCD elicited hyper-homocysteinemia and hyper-leptinemia, suggesting it to have the useful therapeutic potential in patients with atherosclerosis and lipid disorder.
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Chwatko, Grazyna, and Hieronim Jakubowski. "Urinary Excretion of Homocysteine-Thiolactone in Humans." Clinical Chemistry 51, no. 2 (February 1, 2005): 408–15. http://dx.doi.org/10.1373/clinchem.2004.042531.
Повний текст джерелаАнотація:
Abstract Background: A metabolite of homocysteine (Hcy), the thioester Hcy-thiolactone, has been implicated in coronary heart disease in humans. Because inadvertent reactions of Hcy-thiolactone with proteins can lead to cell and tissue damage, the ability to detoxify or eliminate Hcy-thiolactone is essential for biological integrity. We examined the hypothesis that the human body eliminates Hcy-thiolactone by urinary excretion. Methods: We used a sensitive HPLC method with postcolumn derivatization and fluorescence detection to examine Hcy-thiolactone concentrations in human urine and plasma. Results: We discovered a previously unknown pool of Hcy-thiolactone in human urine. Urinary concentrations of Hcy-thiolactone (11–485 nmol/L; n = 19) were ∼100-fold higher than those in plasma (<0.1–22.6 nmol/L; n = 20). Urinary Hcy-thiolactone accounted for 2.5–28.3% of urinary total Hcy, whereas plasma Hcy-thiolactone accounted for <0.002–0.29% of plasma total Hcy. Urinary concentrations of Hcy-thiolactone, but not of total Hcy, were negatively correlated with urinary pH. Clearance of Hcy-thiolactone, relative to creatinine, was 0.21–6.96. In contrast, relative clearance of Hcy was 0.001–0.003. Conclusions: The analytical methods described here can be used to quantify Hcy-thiolactone in biological fluids. Using these methods we showed that the human body eliminates Hcy-thiolactone by urinary excretion. Our data also suggest that the protonation status of its amino group affects Hcy-thiolactone excretion.
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Huang, An, John T. Pinto, Ghezal Froogh, Sharath Kandhi, Jun Qin, Michael S. Wolin, Thomas H. Hintze, and Dong Sun. "Role of homocysteinylation of ACE in endothelial dysfunction of arteries." American Journal of Physiology-Heart and Circulatory Physiology 308, no. 2 (January 15, 2015): H92—H100. http://dx.doi.org/10.1152/ajpheart.00577.2014.
Повний текст джерелаАнотація:
The direct impact of de novo synthesis of homocysteine (Hcy) and its reactive metabolites, Hcy-S-S-Hcy and Hcy thiolactone (HCTL), on vascular function has not been fully elucidated. We hypothesized that Hcy synthesized within endothelial cells affects activity of angiotensin-converting enzyme (ACE) by direct homocysteinylation of its amino- and/or sulfhydryl moieties. This covalent modification enhances ACE reactivity toward angiotensin II (ANG II)-NADPH oxidase-superoxide-dependent endothelial dysfunction. Mesenteric and coronary arteries isolated from normal rats were incubated for 3 days with or without exogenous methionine (Met, 0.1–0.3 mM), a precursor to Hcy. Incubation of arteries in Met-free media resulted in time-dependent decreases in vascular Hcy formation. By contrast, vessels incubated with Met produced Hcy in a dose-dependent manner. There was a notably greater de novo synthesis of Hcy from endothelial than from smooth muscle cells. Enhanced levels of Hcy production significantly impaired shear stress-induced dilation and release of nitric oxide, events that are associated with elevated production of vascular superoxide. Each of these processes was attenuated by ANG II type I receptor blocker or ACE and NADPH oxidase inhibitors. In addition, in vitro exposure of purified ACE to Hcy-S-S-Hcy/HCTL resulted in formation of homocysteinylated ACE and an enhanced ACE activity. The enhanced ACE activity was confirmed in isolated coronary and mesenteric arteries that had been exposed directly to Hcy-S-S-Hcy/HCTL or after Met incubation. In conclusion, vasculature-derived Hcy initiates endothelial dysfunction that, in part, may be mediated by ANG II-dependent activation of NADPH oxidase in association with homocysteinylation of ACE.
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Kornjaca, Dusko, Vladimir Zivkovic, Danijela Krstic, Mirjana Colovic, Marko Djuric, Sanja Stankovic, Slavica Mutavdzin, Vladimir Jakovljevic, and Dragan Djuric. "The effects of acute hyperhomocysteinemia induced by DL-homocysteine or DL-homocysteine thiolactone on serum biochemical parameters, plasma antioxidant enzyme and cardiac acetylcholinesterase activities in the rat." Archives of Biological Sciences 70, no. 2 (2018): 241–48. http://dx.doi.org/10.2298/abs170731041k.
Повний текст джерелаАнотація:
The aim of this study was to assess the effects of DL-homocysteine (DL-Hcy) and DL-homocysteine thiolactone (DL-Hcy TLHC) on selected serum biochemical parameters, markers of oxidative stress and the activities of antioxidant enzymes (catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD)) in the plasma, as well as on acetylcholinesterase (AChE) activity in the cardiac tissue homogenate in the rat. Male Wistar rats were divided into three groups as follows: control group (1 mL 0.9% NaCl, intraperitoneal (i.p.) injection), DL-Hcy group (8 mmol/kg body mass (b.m.), i.p.) or DL-Hcy TLHC group (8 mmol/kg b.m., i.p.). One hour after administration, the rats were euthanized, whole blood was collected for biochemical analysis, and the heart was excised. Following the i.p. administration of DL-Hcy and DL-Hcy TLHC, the activities of antioxidant enzymes were mostly significantly increased, while plasma malondialdehyde (MDA) was decreased. Administration of DL-Hcy and DL-Hcy TLHC significantly inhibited AChE activity in rat cardiac tissue. Our findings suggest that DL-Hcy and DL-Hcy TLHC exerted prooxidant effects; however, the decrease in MDA points to an inverse response to the increase in antioxidant enzyme activities. While both substances inhibited AChE activity in rat cardiac tissue, DL-Hcy TLHC induced stronger effects than DL-Hcy.
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Lominadze, David, Andrew M. Roberts, Neetu Tyagi, Karni S. Moshal, and Suresh C. Tyagi. "Homocysteine causes cerebrovascular leakage in mice." American Journal of Physiology-Heart and Circulatory Physiology 290, no. 3 (March 2006): H1206—H1213. http://dx.doi.org/10.1152/ajpheart.00376.2005.
Повний текст джерелаАнотація:
Elevated plasma homocysteine (Hcy) is associated with cerebrovascular disease and activates matrix metalloproteinases (MMPs), which lead to vascular remodeling that could disrupt the blood-brain barrier. To determine whether Hcy administration can increase brain microvascular leakage secondary to activation of MMPs, we examined pial venules by intravital video microscopy through a craniotomy in anesthetized mice. Bovine serum albumin labeled with fluorescein isothiocyanate (BSA-FITC) was injected into a carotid artery to measure extravenular leakage. Hcy (30 μM/total blood volume) was injected 10 min after FITC-BSA injection. Four groups of mice were examined: 1) wild type (WT) given vehicle; 2) WT given Hcy (WT + Hcy); 3) MMP-9 gene knockout given Hcy (MMP-9−/− + Hcy); and 4) MMP-9−/− with topical application of histamine (10−4 M) (MMP-9−/− + histamine). In the WT + Hcy mice, leakage of FITC-BSA from pial venules was significantly ( P < 0.05) greater than in the other groups. There was no significant leakage of pial microvessels in MMP-9−/− + Hcy mice. Increased cerebrovascular leakage in the MMP-9−/− + histamine group showed that microvascular permeability could still increase by a mechanism independent of MMP-9. Treatment of cultured mouse microvascular endothelial cells with 30 μM Hcy resulted in significantly greater F-actin formation than in control cells without Hcy. Treatment with a broad-range MMP inhibitor (GM-6001; 1 μM) ameliorated Hcy-induced F-actin formation. These data suggest that Hcy increases microvascular permeability, in part, through MMP-9 activation.
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Tuite, Nina L., Katy R. Fraser, and Conor P. O'Byrne. "Homocysteine Toxicity in Escherichia coli Is Caused by a Perturbation of Branched-Chain Amino Acid Biosynthesis." Journal of Bacteriology 187, no. 13 (July 1, 2005): 4362–71. http://dx.doi.org/10.1128/jb.187.13.4362-4371.2005.
Повний текст джерелаАнотація:
ABSTRACT In Escherichia coli the sulfur-containing amino acid homocysteine (Hcy) is the last intermediate on the methionine biosynthetic pathway. Supplementation of a glucose-based minimal medium with Hcy at concentrations greater than 0.2 mM causes the growth of E. coli Frag1 to be inhibited. Supplementation of Hcy-treated cultures with combinations of branched-chain amino acids containing isoleucine or with isoleucine alone reversed the inhibitory effects of Hcy on growth. The last intermediate of the isoleucine biosynthetic pathway, α-keto-β-methylvalerate, could also alleviate the growth inhibition caused by Hcy. Analysis of amino acid pools in Hcy-treated cells revealed that alanine, valine, and glutamate levels are depleted. Isoleucine could reverse the effects of Hcy on the cytoplasmic pools of valine and alanine. Supplementation of the culture medium with alanine gave partial relief from the inhibitory effects of Hcy. Enzyme assays revealed that the first step of the isoleucine biosynthetic pathway, catalyzed by threonine deaminase, was sensitive to inhibition by Hcy. The gene encoding threonine deaminase, ilvA, was found to be transcribed at higher levels in the presence of Hcy. Overexpression of the ilvA gene from a plasmid could overcome Hcy-mediated growth inhibition. Together, these data indicate that in E. coli Hcy toxicity is caused by a perturbation of branched-chain amino acid biosynthesis that is caused, at least in part, by the inhibition of threonine deaminase.
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Borowczyk, Kamila, Jacek Wróblewski, Joanna Suliburska, Noriyuki Akahoshi, Isao Ishii, and Hieronim Jakubowski. "Mutations in Homocysteine Metabolism Genes Increase Keratin N-Homocysteinylation and Damage in Mice." International Journal of Genomics 2018 (September 23, 2018): 1–7. http://dx.doi.org/10.1155/2018/7570850.
Повний текст джерелаАнотація:
Genetic or nutritional deficiencies in homocysteine (Hcy) metabolism increase Hcy-thiolactone, which causes protein damage by forming isopetide bonds with lysine residues, generating N-Hcy-protein. In the present work, we studied the prevalence and genetic determinants of keratin damage caused by homocysteinylation. We found that in mammals and birds, 35 to 98% of Hcy was bound to hair keratin via amide or isopeptide bond (Hcy-keratin), while 2 to 65% was S-Hcy-keratin. A major fraction of hair Hcy-keratin (56% to 93%), significantly higher in birds than in mammals, was sodium dodecyl sulfate-insoluble. Genetic hyperhomocysteinemia significantly increased N-Hcy-keratin levels in the mouse pelage. N-Hcy-keratin was elevated 3.5-, 6.3-, and 11.7-fold in hair from Mthfr−/−, Cse−/−, or Cbs−/− mice, respectively. The accumulation of N-Hcy in hair keratin led to a progressive reduction of N-Hcy-keratin solubility in sodium dodecyl sulfate, from 0.39 ± 0.04 in wild-type mice to 0.19 ± 0.03, 0.14 ± 0.01, and 0.07 ± 0.03 in Mthfr−/−, Cse−/−, or Cbs−/−animals, respectively. N-Hcy-keratin accelerated aggregation of unmodified keratin in Cbs−/− mouse hair. Keratin methionine, copper, and iron levels in mouse hair were not affected by hyperhomocysteinemia. These findings provide evidence that pelage keratin is N-homocysteinylated in vivo in mammals and birds, and that this process causes keratin damage, manifested by a reduced solubility.
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Chen, Jiaxi, Tongtian Zhuang, Jianru Chen, Yangzi Tian, Xiuli Yi, Qingrong Ni, Weigang Zhang та ін. "Homocysteine induces melanocytes apoptosis via PERK–eIF2α–CHOP pathway in vitiligo". Clinical Science 134, № 10 (травень 2020): 1127–41. http://dx.doi.org/10.1042/cs20200218.
Повний текст джерелаАнотація:
Abstract Vitiligo is a depigmentation disorder that develops as a result of the progressive disappearance of epidermal melanocytes. The elevated level of amino acid metabolite homocysteine (Hcy) has been identified as circulating marker of oxidative stress and known as a risk factor for vitiligo. However, the mechanism underlying Hcy-regulated melanocytic destruction is currently unknown. The present study aims to elucidate the effect of Hcy on melanocytic destruction and its involvement in the pathogenesis of vitiligo. Our results showed that Hcy level was significantly elevated in the serum of progressive vitiligo patients. Notably, Hcy induced cell apoptosis in melanocytes via activating reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress protein kinase RNA-like ER kinase (PERK)–eukaryotic translation initiation factor 2α (eIF2α)–C/EBP homologous protein (CHOP) pathway. More importantly, folic acid, functioning in the transformation of Hcy, could lower the intracellular Hcy level and further reverse the apoptotic effect of Hcy on melanocytes. Additionally, Hcy disrupted melanogenesis whereas folic acid supplementation could reverse the melanogenesis defect induced by Hcy in melanocytes. Taken together, Hcy is highly increased in vitiligo patients at progressive stage, and our in vitro studies revealed that folic acid could protect melanocytes from Hcy-induced apoptosis and melanin synthesis inhibition, indicating folic acid as a potential benefit agent for patients with progressive vitiligo.
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FRIEDMAN, ALLON N., ANDREW G. BOSTOM, JACOB SELHUB, ANDREW S. LEVEY, and IRWIN H. ROSENBERG. "The Kidney and Homocysteine Metabolism." Journal of the American Society of Nephrology 12, no. 10 (October 2001): 2181–89. http://dx.doi.org/10.1681/asn.v12102181.
Повний текст джерелаАнотація:
Abstract. Homocysteine (Hcy) is an intermediate of methionine metabolism that, at elevated levels, is an independent risk factor for vascular disease and atherothrombosis. Patients with renal disease, who exhibit unusually high rates of cardiovascular morbidity and death, tend to be hyperhomocysteinemic, particularly as renal function declines. This observation and the inverse relationship between Hcy levels and GFR implicate the kidney as an important participant in Hcy handling. The normal kidney plays a major role in plasma amino acid clearance and metabolism. The existence in the kidney of specific Hcy uptake mechanisms and Hcy-metabolizing enzymes suggests that this role extends to Hcy. Dietary protein intake may affect renal Hcy handling and should be considered when measuring Hcy plasma flux and renal clearance. The underlying cause of hyperhomocysteinemia in renal disease is not entirely understood but seems to involve reduced clearance of plasma Hcy. This reduction may be attributable to defective renal clearance and/or extrarenal clearance and metabolism, the latter possibly resulting from retained uremic inhibitory substances. Although the currently available evidence is not conclusive, it seems more likely that a reduction in renal Hcy clearance and metabolism is the cause of the hyperhomocysteinemic state. Efforts to resolve this important issue will advance the search for effective Hcy-lowering therapies in patients with renal disease.
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Alam, Mohammad Murshedul, Askar A. Mohammad, Umar Shuaib, Chenxu Wang, Usman Ghani, Brenda Schwindt, Kathryn G. Todd, and Ashfaq Shuaib. "Homocysteine Reduces Endothelial Progenitor Cells in Stroke Patients through Apoptosis." Journal of Cerebral Blood Flow & Metabolism 29, no. 1 (September 3, 2008): 157–65. http://dx.doi.org/10.1038/jcbfm.2008.99.
Повний текст джерелаАнотація:
Homocysteine (Hcy) is a risk factor for vascular dysfunction. High levels of Hcy may result in vascular injury accelerating atherosclerosis leading to ischemia. After ischemia, endothelial progenitor cells (EPCs) migrate from bone marrow to repair damaged sites either through direct incorporation of EPCs or by repopulating mature endothelial cells. This study looks into the relationship between increased Hcy in patients with cerebrovascular disease (CVD) and EPCs. Some patients with hyperhomocysteinemia were treated with B vitamins to evaluate if the treatment reverses the elevated Hcy and its impact on their EPC levels. EPCs were treated with Hcy to determine the in vitro effects of Hcy. Our clinical findings show that elevated Hcy levels have an inverse relationship with EPC levels and B vitamin intervention can reverse this effect. Our in vitro work shows that Hcy-mediated EPC toxicity is due to apoptosis involving caspase-8, cytochrome c release, and caspase-3 activation. Vitamin B6, and B9 significantly impair Hcy-mediated EPC caspase-3 activation in vitro. Our clinical and in vitro data together indicate that increased Hcy results in a decrease in EPC numbers. This decrease in EPC by Hcy may be occurring through increased apoptosis and B vitamins (B6, B9) intervention can attenuate such effects.
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Kurz, Katharina, Barbara Frick, Christina Fürhapter, Günter Weiss, Barbara Wirleitner, Norbert Sepp, and Dietmar Fuchs. "Homocysteine metabolism in different human cells." Pteridines 24, no. 3 (December 1, 2013): 183–89. http://dx.doi.org/10.1515/pterid-2013-0039.
Повний текст джерелаАнотація:
AbstractThe effects of cytokine and mitogen stimulation on homocysteine (HCY) metabolism in different cells were investigated: in human dermal microvascular endothelial cells (HDMEC), T lymphocytes, mature and immature dendritic cells, and myelomonocytic (THP-1) and monocytic cell lines (U-937). Furthermore, the influence of supplementation of cells with folate acid, methionine and the combination of both on HCY metabolism was investigated. Unstimulated HDMEC and dendritic cells only produced very little amounts of HCY, and stimulation did not change HCY formation significantly either. However, higher HCY concentrations were detected in HDMEC and dendritic cells under supplementation with methionine and slightly less under supplementation with folate. Proliferating T lymphocytes showed an increase in HCY production on stimulation with increasing doses of mitogens; proliferative activity was associated with HCY formation. THP-1 and U-937 cells produced significantly more HCY than endothelial cells; U-937 cells produced most HCY, which was mainly due to their high proliferation rate. Stimulation of both cell lines with lipopolysaccharide and interferon-γ, respectively, showed a significant effect on HCY production of cells; in THP-1 cells, stimulation with IFN-γ and lipopolysaccharide induced neopterin formation. Methionine supplementation strongly increased and folate supplementation slightly decreased HCY formation in both cell lines. Thus, inflammation may play a role in moderate hyperhomocysteinemia.
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Montecinos-Oliva, Carla, Macarena S. Arrázola, Claudia Jara, Cheril Tapia-Rojas та Nibaldo C. Inestrosa. "Hormetic-Like Effects of L-Homocysteine on Synaptic Structure, Function, and Aβ Aggregation". Pharmaceuticals 13, № 2 (2 лютого 2020): 24. http://dx.doi.org/10.3390/ph13020024.
Повний текст джерелаАнотація:
Alzheimer’s Disease (AD) is the primary cause of dementia among the elderly population. Elevated plasma levels of homocysteine (HCy), an amino acid derived from methionine metabolism, are considered a risk factor and biomarker of AD and other types of dementia. An increase in HCy is mostly a consequence of high methionine and/or low vitamin B intake in the diet. Here, we studied the effects of physiological and pathophysiological HCy concentrations on oxidative stress, synaptic protein levels, and synaptic activity in mice hippocampal slices. We also studied the in vitro effects of HCy on the aggregation kinetics of Aβ40. We found that physiological cerebrospinal concentrations of HCy (0.5 µM) induce an increase in synaptic proteins, whereas higher doses of HCy (30–100 µM) decrease their levels, thereby increasing oxidative stress and causing excitatory transmission hyperactivity, which are all considered to be neurotoxic effects. We also observed that normal cerebrospinal concentrations of HCy slow the aggregation kinetic of Aβ40, whereas high concentrations accelerate its aggregation. Finally, we studied the effects of HCy and HCy + Aβ42 over long-term potentiation. Altogether, by studying an ample range of effects under different HCy concentrations, we report, for the first time, that HCy can exert beneficial or toxic effects over neurons, evidencing a hormetic-like effect. Therefore, we further encourage the use of HCy as a biomarker and modifiable risk factor with therapeutic use against AD and other types of dementia.
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Huang, Tao, Katherine L. Tucker, Yu-Chi Lee, Jimmy W. Crott, Laurence D. Parnell, Jian Shen, Caren E. Smith, Jose M. Ordovas, Duo Li, and Chao-Qiang Lai. "Interactions between genetic variants of folate metabolism genes and lifestyle affect plasma homocysteine concentrations in the Boston Puerto Rican population." Public Health Nutrition 14, no. 10 (February 22, 2011): 1805–12. http://dx.doi.org/10.1017/s1368980011000140.
Повний текст джерелаАнотація:
AbstractObjectiveTo investigate genetic and lifestyle factors and their interactions on plasma homocysteine (Hcy) concentrations in the Boston Puerto Rican population.DesignCross-sectional study. Plasma concentrations of Hcy, folate, vitamin B12and pyridoxal phosphate were measured, and genetic polymorphisms were determined. Data on lifestyle factors were collected in interviews.SettingA population survey of health and nutritional measures.SubjectsA total of 994 Puerto Rican men and women residing in the Boston metropolitan area.ResultsSmoking status was positively associated with plasma Hcy. Genetic polymorphismsMTHFR677C→T,FOLH11561C→T,FOLH1rs647370 andPCFT928A→G interacted significantly with smoking for Hcy.MTHFR1298A→C (P= 0·040) andPCFT928A→G (P= 0·002) displayed significant interactions with alcohol intake in determining plasma Hcy. Subjects withPCFT928GGgenotype had significantly higher plasma Hcy concentrations compared with carriers of theAallele (AA+AG;P= 0·030) among non-drinking subjects. When consuming alcohol,GGsubjects had lower plasma Hcy levels compared withAA+AGsubjects. Physical activity interacted significantly withMTR2756A→G in determining plasma Hcy (Pfor interaction = 0·002). Smoking interacted with physical activity for plasma Hcy (Pfor interaction = 0·023).ConclusionsSmoking and drinking were associated plasma Hcy concentrations. Genetic variants involved in folate metabolism further modify the effects of lifestyle on plasma Hcy.
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Holmen, Marte, Anne-Mette Hvas, and Johan F. H. Arendt. "Hyperhomocysteinemia and Ischemic Stroke: A Potential Dose-Response Association—A Systematic Review and Meta-analysis." TH Open 05, no. 03 (July 2021): e420-e437. http://dx.doi.org/10.1055/s-0041-1735978.
Повний текст джерелаАнотація:
Abstract Background and Purpose Previous studies suggest an association between increased homocysteine (Hcy) and risk of ischemic stroke. Yet, it remains unknown whether a dose-response association exists between Hcy levels and risk of ischemic stroke. Methods Systematic literature searches were performed in PubMed, Embase, Scopus, and Web of Science. Inclusion criteria were studies investigating ischemic stroke risk in an adult population with measured Hcy levels. We computed odds ratios (ORs) for a 5 µmol/L increase in Hcy levels using a random effects meta-analysis. Results In total, 108 studies met the inclusion criteria of which 22 were rated as high-quality studies, and 20 studies included a dose-response analysis. Hcy levels were analyzed either as a continuous or categorical variable. The majority of the studies found an increased risk of ischemic stroke when comparing the highest-to-lowest Hcy strata. A graded association was observed over the Hcy strata, indicating a dose-response association, with the most apparent effect when Hcy levels exceeded approximately 15 µmol/L. No studies explored a potential nonlinear association between Hcy levels and ischemic stroke. Six studies were included in a meta-analysis, showing an OR of 1.43 (95% confidence interval [CI]: 1.28–1.61) per 5 µmol/L increase in Hcy levels. Conclusion This review and meta-analysis indicate a dose-response association between Hcy levels and ischemic stroke. An evident increase in effect measures was observed when Hcy levels exceeded 15 µmol/L, indicating a nonlinear association between ischemic stroke and Hcy levels. This nonlinear association warrants further study.This study is registered with clinical trial ( https://www.crd.york.ac.uk/prospero/ ; unique identifier: CRD42019130371).
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Slattery, J. T., T. F. Kalhorn, G. B. McDonald, K. Lambert, C. D. Buckner, W. I. Bensinger, C. Anasetti, and F. R. Appelbaum. "Conditioning regimen-dependent disposition of cyclophosphamide and hydroxycyclophosphamide in human marrow transplantation patients." Journal of Clinical Oncology 14, no. 5 (May 1996): 1484–94. http://dx.doi.org/10.1200/jco.1996.14.5.1484.
Повний текст джерелаАнотація:
PURPOSE The pharmacokinetics of cyclophosphamide (CY) and 4-hydroxycyclophosphamide (HCY) were studied in 14 patients being prepared for bone marrow transplantation with either busulfan (BU)/CY (n = 7) or CY/total-body irradiation (TBI) (n = 7) to determine whether exposure to CY and its proximate toxic metabolite HCY is modulated by other agents used in the preparative regimen. PATIENTS AND METHODS HCY was assayed by a new method that stabilized the metabolite at bedside. In BU/CY patients (who also received phenytoin), CY clearance was 112% greater (P = .0014), half-life 54% less (P = .0027), peak HCY concentration in plasma/CY dose 113% greater (P = .0006), and the ratio of area under the plasma concentration-time curves (AUCs) of HCY to CY 166% greater (P = .0116) than in CY/TBI patients. The ratio of the AUC of HCY/CY dose was 48% greater in BU/CY patients than in CY/TBI patients when one CY/TBI patient with an apparent impaired ability to eliminate HCY was excluded from analysis. In CY/TBI patients, there was an inverse correlation between the AUC of HCY and that of CY (R2 = .740, P = .028). Also, the ratio of the AUC of HCY/CY dose was correlated with the average concentration of BU at steady-state (Css, Bu) (R2 = .646, P = 0.29). Variability in CY and HCY pharmacokinetics among the 14 patients overall was pronounced, with the highest variability (15-fold) observed in the ratio of the AUC of HCY to that of CY. CONCLUSION Prior administration of BU and/or phenytoin significantly alters exposure to CY and HCY. Interpatient variability in HCY exposure at a given CY dose is substantial.
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Botelho, João, Vanessa Machado, Yago Leira, Luís Proença, and José João Mendes. "Periodontal Inflamed Surface Area Mediates the Link between Homocysteine and Blood Pressure." Biomolecules 11, no. 6 (June 12, 2021): 875. http://dx.doi.org/10.3390/biom11060875.
Повний текст джерелаАнотація:
Here, we assess the association between homocysteine (Hcy) serum levels and periodontal status in a large representative sample of the National Health and Nutrition Examination Survey (NHANES). Using the 2001–2002 and 2003–2004 NHANES databases, participants with a periodontal examination, medical self-reported data, blood pressure (BP) and blood samples to determine complete blood count, C-reactive protein (CRP) and Hcy levels. We then calculated the periodontal inflamed surface area (PISA) and the periodontal epithelial surface area (PESA). Multivariable regression analysis explored the association between Hcy, periodontal measures and BP. Mediation analysis was performed to understand the effect of PISA and PESA in the link between Hcy and BP. 4021 participants fulfilled the inclusion criteria. Hcy levels showed significant correlations with systolic BP, diastolic BP, PISA, PESA and age. PESA showed to be significantly associated with Hcy both for the crude and adjusted models (p < 0.01), but not PISA (p > 0.05). In the association of Hcy with systolic BP, PISA significantly mediated 17.4% and PESA 0.9%. In the association of Hcy with diastolic BP, PISA significantly mediated 16.3% and PESA 47.2%. In conclusion, Hcy and periodontitis are associated. Further, both PISA and PESA significantly mediated the association of Hcy with systolic BP and diastolic BP. Future studies shall deepen the mechanisms by which Hcy levels increase in a clinical situation of periodontitis.
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Sibarov, Dmitry A., Sergei I. Boikov, Tatiana V. Karelina, and Sergei M. Antonov. "GluN2 Subunit-Dependent Redox Modulation of NMDA Receptor Activation by Homocysteine." Biomolecules 10, no. 10 (October 14, 2020): 1441. http://dx.doi.org/10.3390/biom10101441.
Повний текст джерелаАнотація:
Homocysteine (HCY) molecule combines distinct pharmacological properties as an agonist of N-methyl-d-aspartate receptors (NMDARs) and a reducing agent. Whereas NMDAR activation by HCY was elucidated, whether the redox modulation contributes to its action is unclear. Here, using patch-clamp recording and imaging of intracellular Ca2+, we study dithiothreitol (DTT) effects on currents and Ca2+ responses activated by HCY through native NMDARs and recombinant diheteromeric GluN1/2A, GluN1/2B, and GluN1/2C receptors. Within a wide range (1–800 μM) of [HCY]s, the concentration–activation relationships for recombinant NMDARs revealed a biphasicness. The high-affinity component obtained between 1 and 100 µM [HCY]s corresponding to the NMDAR activation was not affected by 1 mM DTT. The low-affinity phase observed at [HCY]s above 200 μM probably originated from thiol-dependent redox modulation of NMDARs. The reduction of NMDAR disulfide bonds by either 1 mM DTT or 1 mM HCY decreased GluN1/2A currents activated by HCY. In contrast, HCY-elicited GluN1/2B currents were enhanced due to the remarkable weakening of GluN1/2B desensitization. In fact, cleaving NMDAR disulfide bonds in neurons reversed the HCY-induced Ca2+ accumulation, making it dependent on GluN2B- rather than GluN2A-containing NMDARs. Thus, estimated concentrations for the HCY redox effects exceed those in the plasma during intermediate hyperhomocysteinemia but may occur during severe hyperhomocysteinemia.
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Li, Siming, Erland Arning, Chang Liu, Victor Vitvitsky, Carlos Hernandez, Ruma Banerjee, Teodoro Bottiglieri та Jiandie D. Lin. "Regulation of homocysteine homeostasis through the transcriptional coactivator PGC-1α". American Journal of Physiology-Endocrinology and Metabolism 296, № 3 (березень 2009): E543—E548. http://dx.doi.org/10.1152/ajpendo.90719.2008.
Повний текст джерелаАнотація:
Plasma homocysteine (Hcy) is an independent risk factor for cardiovascular disease. Hcy is a nonprotein amino acid derivative that is generated from the methionine cycle, which provides the methyl group for essentially all biological methylation reactions. Although plasma Hcy levels are elevated in patients with cardiovascular disease, the mechanisms that regulate Hcy homeostasis remain poorly defined. In this study, we found that the expression of key enzymes involved in Hcy metabolism is induced in the liver in response to fasting. This induction coincides with increased expression of peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, a transcriptional coactivator that regulates hepatic gluconeogenesis and mitochondrial function. PGC-1α stimulates the expression of genes involved in Hcy metabolism in cultured primary hepatocytes as well as in the liver. Adenoviral-mediated expression of PGC-1α in vivo leads to elevated plasma Hcy levels. In contrast, mice deficient in PGC-1α have lower plasma Hcy concentrations. These results define a novel role for the PGC-1α coactivator pathway in the regulation of Hcy homeostasis and suggest a potential pathogenic mechanism that contributes to hyperhomocysteinemia.
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Kartal Durmazlar, Selda Pelin, Ahmet Akgul, and Fatma Eskioglu. "Homocysteine May Involve in the Pathogenesis of Behcet's Disease by Inducing Inflammation." Mediators of Inflammation 2008 (2008): 1–9. http://dx.doi.org/10.1155/2008/407972.
Повний текст джерелаАнотація:
Objective. Our aim was to evaluate the significance of homocysteine (Hcy) in Behcet's disease (BD) and the association of elevated Hcy levels associated with the indices of inflammation in BD.Methods. Untreated 70 patients with BD and 33 healthy individuals were included into the study. Hcy, tumor necrosis alpha (TNF-), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were evaluated with respect to activity and specific individual clinical manifestations of the disease.Results. Hcy levels were found significantly elevated in active BD when compared to inactive BD and healthy controls. Hcy levels were found to have high correlation with the number of active clinical manifestations increased. A significant positive correlation was found between serum Hcy and TNF- levels, CRP, and ESR. Hcy was found to be the best predictor of TNF- among other parameters.Conclusion. Hcy may involve in the pathogenesis of BD by inducing inflammation.
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Righetti, Marco, Adalberto Tommasi, Cinzia Lagona, Lucia La Rosa, Mario Uccellini, and Adalberto Sessa. "Effective Homocysteine-Lowering Vitamin B Treatment in Peritoneal Dialysis Patients." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 24, no. 4 (July 2004): 373–77. http://dx.doi.org/10.1177/089686080402400413.
Повний текст джерелаАнотація:
Background Hyperhomocysteinemia, a risk factor for atherosclerosis, is frequently detected in patients with renal failure. Vitamin B supplementation reduces but rarely normalizes homocysteine (Hcy) levels in hemodialysis patients. There are no data about the effects of vitamin B therapy on Hcy levels in patients on peritoneal dialysis (PD). Aims We performed this trial both to observe baseline plasma Hcy levels in PD patients and to assess the effects of vitamin B therapy on Hcy levels in continuous ambulatory PD patients. Methods We conducted a 6-month prospective study of the effects of vitamin B therapy on plasma Hcy levels. Biochemical analyses were obtained at baseline and after every phase of treatment with folic acid, folic acid plus vitamin B12, and folic acid plus vitamin B12 plus vitamin B6. Eighteen of the 25 enrolled patients finished the study. Results Hyperhomocysteinemia was present in 83% of PD patients. We detected a trend toward a significant inverse relationship between baseline Hcy and folate levels. There were no significant correlations between baseline Hcy and vitamin B12, peritoneal membrane permeability, dialytic efficiency, or computed peritoneal Hcy clearance. We obtained an effective decrease in mean Hcy concentration from 20 to 14.8 μmol/L after folic acid and vitamin B12 treatment. We observed a further reduction in mean Hcy level to 12.8 μmol/L using the triple therapy; 72% of patients normalized their Hcy value. Conclusions High doses of folic acid, vitamin B6, and vitamin B12 normalize Hcy values in the majority of PD patients. This treatment may be important in reducing cardiovascular morbidity and mortality.
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Thaimory, Mohaddeseh, Iran Goudarzi, Taghi Lashkarbolouki, and Kataneh Abrari. "Quercetin fail to protect against the neurotoxic effects of chronic homocysteine administration on motor behavior and oxidative stress in the adult rat’s cerebellum." Toxicology Research 10, no. 4 (July 12, 2021): 810–16. http://dx.doi.org/10.1093/toxres/tfab065.
Повний текст джерелаАнотація:
Abstract Homocysteine (Hcy) is an excitatory amino acid that contains thiol group and derives from the methionine metabolism. It increases vulnerability of the neuronal cells to excitotoxic and oxidative damage. This study aimed to investigate the hyperhomocysteinemia (hHcy) effects on rat cerebellum and the possible protective role of quercetin administration in Hcy-treated rats, using behavioral and biochemical analyzes. To this end, the adult male rats were divided randomly into the control group that received vehicle, Hcy group received Hcy (400 μg/kg), Hcy + Que group received Hcy + quercetin (50 mg/kg), quercetin group received quercetin for 14 days. On Day 14 after the final treatment, lipid peroxidation level, the superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities were evaluated in the cerebellum. After completion of treatment, the rat’s performance on rotarod and locomotor activity was evaluated. The results showed that Hcy treatment elicited cerebellar lipid peroxidation, impaired locomotor activity and increased latency to fall on the rotarod. Quercetin failed to attenuate significantly motoric impairment, increased significantly the cerebellar lipid peroxidation and GPx activity in the Hcy + Que group. Our results suggest that Hcy induced cerebellar toxicity and quercetin had no significant protective effects against Hcy toxicity in the cerebellum of adult rats.
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Moshal, Karni S., Utpal Sen, Neetu Tyagi, Brooke Henderson, Mesia Steed, Alexander V. Ovechkin, and Suresh C. Tyagi. "Regulation of homocysteine-induced MMP-9 by ERK1/2 pathway." American Journal of Physiology-Cell Physiology 290, no. 3 (March 2006): C883—C891. http://dx.doi.org/10.1152/ajpcell.00359.2005.
Повний текст джерелаАнотація:
Homocysteine (Hcy) induces matrix metalloproteinase (MMP)-9 in microvascular endothelial cells (MVECs). We hypothesized that the ERK1/2 signaling pathway is involved in Hcy-mediated MMP-9 expression. In cultured MVECs, Hcy induced activation of ERK, which was blocked by PD-98059 and U0126 (MEK inhibitors). Pretreatment with BAPTA-AM, staurosporine (PKC inhibitor), or Gö6976 (specific inhibitor for Ca2+-dependent PKC) abrogated ERK phosphorylation, suggesting the role of Ca2+ and Ca2+-dependent PKC in Hcy-induced ERK activation. ERK phosphorylation was suppressed by pertussis toxin (PTX), suggesting the involvement of G protein-coupled receptors (GPCRs) in initiating signal transduction by Hcy and leading to ERK activation. Pretreatment of MVECs with genistein, BAPTA-AM, or thapsigargin abrogated Hcy-induced ERK activation, suggesting the involvement of the PTK pathway in Hcy-induced ERK activation, which was mediated by intracellular Ca2+ pool depletion. ERK activation was attenuated by preincubation with N-acetylcysteine (NAC) and SOD, suggesting the role of oxidation in Hcy-induced ERK activation. Pretreatment with an ERK1/2 blocker (PD-98059), staurosporine, folate, or NAC modulated Hcy-induced MMP-9 activation as measured using zymography. Our results provide evidence that Hcy triggers the PTX-sensitive ERK1/2 signaling pathway, which is involved in the regulation of MMP-9 in MVECs.
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Valjevac, Amina, Alen Džubur, Emina Nakaš-Ićindić, Almira Hadžović-Džuvo, Asija Zaćiragić, Orhan Lepara, and Amila Arslanagić. "Changes in Serum Homocysteine Level Follow Two Different Trends in Patients During Early Post Myocardial Infarction Period." Bosnian Journal of Basic Medical Sciences 9, no. 2 (May 20, 2009): 161–73. http://dx.doi.org/10.17305/bjbms.2009.2837.
Повний текст джерелаАнотація:
The evolution of homocysteine (Hcy) changes after acute myocardial infarction is still not elucidated. Serum Hcy concentration has been shown to increase between acute and convalescent period after myocardial infarction and stroke, Also a decrease in serum Hcy during acute phase was observed, It is still not clear whether the Hcy is a culprit or an innocent bystander in cardiovascular diseases, Addressing the discrepancies in Hcy changes in patients with acute myocardial infarction might give insight in Hcy role in cardiovascular diseases and offer implications both for the clinical interpretation and patients risk stratification, The aim of the study was to evaluate serum Hcy concentration changes during early post myocardial infarction, The study included 55 patients with AMI from the Clinics for Heart Diseases and Rheumatism at University of Sarajevo Clinics Centre, For Hcy analysis blood was collected on day 2 and 5 after the AMI onset, Serum Hcy concentration was determined quantitatively with fluorescent polarisation immunoassay on AxSYM system, Cluster analysis revealed two groups ofAMI patients with different trends of serum Hcy changes, Increase in serum Hcy concentration was observed in 33 (60,0%) patients (AMI 1 group), while in 22 (40,0%) patients a decrease was observed (AMI 2 group), On day 2, patients in AMI 2 group had significantly higher mean Hcy concentration compared to AMI 1 group of patients (15,27±0,96 and 11,59±0,61 μmol/L p<0,05), On day 5, no significant difference in mean Hcy level between AMI 1 and AMI 2 group of patients was observed (14,86±1,1 vs, 12,75±0,74 μmol/L respectively), Significant differences between AMI 1 and AMI 2 patients were observed in VLDLC levels and CK-MB activity on day 2,Patients in AMI 1 group had significant increase in platelets count from day 2 to day 5 (230,1±11,6 vs. 244,2±11,0; p<0,05). Our study of serial Hcy changes in patients with AMI revealed two different patterns of Hcy changes in early post infarction period which might reflect two distinct populations of AMI patients. Although further research is necessary, possible explanation for the observed findings could be a different genetic background, vitamin and oxidative status of patients with AMI.
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Undas, Anetta, Milosz Jankowski, Magdalena Twardowska, Agnieszka Padjas, Hieronim Jakubowski, and Andrzej Szczeklik. "Antibodies to N-homocysteinylated albumin as a marker for earlyonset coronary artery disease in men." Thrombosis and Haemostasis 93, no. 02 (2005): 346–50. http://dx.doi.org/10.1160/th04-08-0493.
Повний текст джерелаАнотація:
Summary N-homocysteinylated (Nε-Hcy) proteins and corresponding antibodies have recently been discovered in humans and animals. Increased autoimmune response to Nε -Hcy-proteins has been reported in stroke patients. The aim of the present study was to investigate whether antibodies against N-homocysteinylated albumin are associated with coronary artery disease (CAD).We studied 88 male patients aged 50 years or under with angiographically documented CAD and 100 age-matched apparently healthy men as controls. Serum levels of IgG antibodies against Nε-Hcy-albumin were determined using an enzymelinked immunosorbent assay. Seropositivity to anti-Nε -Hcy-albumin antibodies was 5-fold more frequent in CAD patients than in controls (52.3 % vs 10.0 %; p<0.0001). Plasma Hcy levels in CAD patients were also significantly higher in the former than in the latter group (medians, 13.0 μ M vs 12.1 μ M; p=0.026). Importantly, 41.2% of subjects with plasma total Hcy >14.5 mM were seropositive compared with 25.5 % of normohomocysteinemic individuals (p=0.048).There was a weak correlation between anti-Nε-Hcy-albumin antibodies and Hcy levels (r=0.16; p=0.03). By multivariate logistic regression analysis, seropositivity to anti-Nε-Hcy-albumin antibodies was an independent predictor of early CAD (OR, 14.82; 95% CI, 4.47 to 49.19; p=0.00002). Interestingly, anti-Nε-Hcy-albumin antibodies were associated with C-reactive protein levels (r=0.24; p=0.002). Seropositivity to anti-Nε-Hcy-albumin antibodies showed no association with the MTHFR C677T polymorphism. Our results suggest that seropositivity to antibodies against Nε-homocysteinylated albumin is associated with early-onset CAD. An autoimmune response to Nε-Hcy-albumin may represent a novel mechanism involved in the early development of CAD.
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Chan, Crystal Yin Tung, and Stephen Wing Keung Cheng. "Elevated homocysteine in human abdominal aortic aneurysmal tissues." Vascular Medicine 22, no. 5 (July 14, 2017): 370–77. http://dx.doi.org/10.1177/1358863x17718260.
Повний текст джерелаАнотація:
An abnormally high level of homocysteine (Hcy) has been consistently observed in the blood of abdominal aortic aneurysm (AAA) patients. However, the expression of Hcy in human AAA tissues has not been investigated. In this study, the expression of Hcy in aneurysmal tissues from AAA patients ( n=30) was compared with non-aneurysmal tissues from organ donors ( n=31) by dot blotting and immunohistochemistry. A significantly higher expression of Hcy was observed in AAA than control tissues ( p<0.001). Furthermore, the associations of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, detected by polymerase chain reaction-restriction fragment length polymorphism, with both AAA and tissue Hcy expression were evaluated. Our results showed MTHFR C677T polymorphism was not significantly associated with AAA or tissue Hcy expression. Lastly, the expression of Hcy in vascular smooth muscle cells (VSMCs), which were isolated from human aortic tissues by explant culture, and their release to cultured media was investigated by dot blotting. The AAA VSMCs expressed and released a significantly higher level of Hcy than the control VSMCs ( p<0.001). In summary, our novel findings showed Hcy expression was abnormally elevated in human AAA tissues, which may not be dependent on MTHFR C677T polymorphism.
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Pan, Qingrong, Shuxin Gao, Xia Gao, Ning Yang, Zhi Yao, Yanjin Hu, Li Miao, Zhe Chen, and Guang Wang. "Relation of kidney function and homocysteine in patients with hypothyroidism." Endocrine Connections 10, no. 5 (May 1, 2021): 502–10. http://dx.doi.org/10.1530/ec-21-0069.
Повний текст джерелаАнотація:
Objective It has been found that both serum homocysteine (Hcy) and serum creatinine levels were increased in hypothyroidism patients. The aim of this study was to investigate the correlation between serum Hcy and kidney function in patients with subclinical hypothyroidism or hypothyroidism. Methods A total of 448 subjects were enrolled and divided into three groups: hypothyroidism (n = 129), subclinical hypothyroidism (n = 141), and control group (n = 168). Anthropometric information, metabolic parameters, serum Hcy and creatinine levels, and estimated glomerular filtration rate (eGFR) were analyzed. Results Compared with healthy subjects, patients with subclinical hypothyroidism or hypothyroidism had significantly higher serum Hcy and creatinine levels and lower eGFR level (all P < 0.001). Serum Hcy was negatively correlated with eGFR in subclinical hypothyroidism patients (r = −0.220, P = 0.009), and in hypothyroidism patients (r = −0.422, P < 0.001). After adjusting for age, sex and BMI, eGFR was still significantly correlated with serum Hcy in subclinical hypothyroidism or hypothyroidism patients (both P < 0.05). Levothyroxine treatment resulted in significantly decreased Hcy and increased eGFR in hypothyroidism patients (both P < 0.001). The decrease in Hcy was correlated with the increased eGFR after treatment (P = 0.001). Conclusion Serum Hcy was negatively correlated with eGFR in subclinical hypothyroidism or hypothyroidism patients. After levothyroxine treatment, a correlation was found between the decrease in serum Hcy and the increase in eGFR in hypothyroidism patients.
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Akalin, Aysen, Ozkan Alatas, and Omer Colak. "Relation of plasma homocysteine levels to atherosclerotic vascular disease and inflammation markers in type 2 diabetic patients." European Journal of Endocrinology 158, no. 1 (January 2008): 47–52. http://dx.doi.org/10.1530/eje-07-0470.
Повний текст джерелаАнотація:
ObjectiveBoth hyperhomocysteinemia and increased inflammatory activity are shown to be associated with atherosclerosis. The relation of inflammatory activity to homocysteine (Hcy) levels is not well established. In the present study, we aimed to evaluate the relation of plasma Hcy levels to atherosclerotic vascular disease and inflammatory activity in type 2 diabetic patients.Design and methodsIn total 90 type 2 diabetic patients were included in the study. Of these patients, 41 had established atherosclerotic vascular disease and 49 had no evidence of atherosclerotic vascular disease. Hcy levels and markers of inflammation, namely C-reactive protein, fibrinogen, erythrocyte sedimentation rate, interleukin-6, and tumor necrosis factor α (TNFα), were measured. Glucose regulation, C-peptide, lipid parameters, and renal functions were also studied.ResultsBoth Hcy levels and inflammation markers were all significantly elevated in patients with atherosclerotic vascular disease when compared with patients without vascular disease. Reduced renal functions were responsible for the majority of Hcy elevation in patients with vascular disease. Also, renal functions were significantly associated with both Hcy levels and inflammatory markers. There was no correlation between Hcy levels and inflammation markers except for TNFα.ConclusionsInflammatory activity and Hcy levels are increased in type 2 diabetic patients with atherosclerotic vascular disease. Impairment of renal functions is the key factor that affects both Hcy levels and inflammation markers. Inflammation is not involved in the process by which Hcy leads atherosclerosis in type 2 diabetes.
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Zhang, Zhimin, Congying Wei, Yanfen Zhou, Tao Yan, Zhengqiang Wang, Wei Li, and Lianyou Zhao. "Homocysteine Induces Apoptosis of Human Umbilical Vein Endothelial Cells via Mitochondrial Dysfunction and Endoplasmic Reticulum Stress." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/5736506.
Повний текст джерелаАнотація:
Homocysteine- (Hcy-) induced endothelial cell apoptosis has been suggested as a cause of Hcy-dependent vascular injury, while the proposed molecular pathways underlying this process are unclear. In this study, we investigated the adverse effects of Hcy on human umbilical vein endothelial cells (HUVEC) and the underlying mechanisms. Our results demonstrated that moderate-dose Hcy treatment induced HUVEC apoptosis in a time-dependent manner. Furthermore, prolonged Hcy treatment increased the expression of NOX4 and the production of intracellular ROS but decreased the ratio of Bcl-2/Bax and mitochondrial membrane potential (MMP), resulting in the leakage of cytochrome c and activation of caspase-3. Prolonged Hcy treatment also upregulated glucose-regulated protein 78 (GRP78), activated protein kinase RNA-like ER kinase (PERK), and induced the expression of C/EBP homologous protein (CHOP) and the phosphorylation of NF-κb. The inhibition of NOX4 decreased the production of ROS and alleviated the Hcy-induced HUVEC apoptosis and ER stress. Blocking the PERK pathway partly alleviated Hcy-induced HUVEC apoptosis and the activation of NF-κb. Taken together, our results suggest that Hcy-induced mitochondrial dysfunction crucially modulated apoptosis and contributed to the activation of ER stress in HUVEC. The excessive activation of the PERK pathway partly contributed to Hcy-induced HUVEC apoptosis and the phosphorylation of NF-κb.
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O, Karmin, and Yaw L. Siow. "Metabolic Imbalance of Homocysteine and Hydrogen Sulfide in Kidney Disease." Current Medicinal Chemistry 25, no. 3 (January 30, 2018): 367–77. http://dx.doi.org/10.2174/0929867324666170509145240.
Повний текст джерелаАнотація:
Homocysteine (Hcy) and hydrogen sulfide (H2S) are important molecules produced during the metabolism of sulfur-containing amino acids. Hcy metabolism is central to the supply of methyl groups that are essential for biological function. Hcy can be either regenerated to methionine or metabolized to cysteine, a precursor for glutathione synthesis. Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) play a crucial role in metabolizing Hcy to cysteine through the transsulfuration pathway. These two enzymes are also responsible for H2S generation through desulfuration reactions. H2S, at physiological levels serves as a gaseous mediator and has multifaceted effects. Metabolic imbalance of Hcy and H2S has been implicated in pathological conditions including oxidative stress, inflammation, cardiovascular and cerebral dysfunction, fatty liver disease and ischemiareperfusion injury. Organs such as liver, kidney, gut and pancreas contain all the enzymes that are required for Hcy metabolism. The kidney plays an important role in removing Hcy from the circulation. Hyperhomocysteinemia, a condition of elevated blood Hcy level, is a common clinical finding in patients with chronic kidney disease (CKD) or acute kidney injury (AKI), the latter is often caused by ischemia-reperfusion. This paper reviews exiting literatures regarding (1) the role of kidney in regulating Hcy and H2S metabolism; (2) disruption of sulfur-containing amino acid metabolism during ischemiareperfusion; (3) impact of metabolic imbalance of Hcy and H2S on kidney function. Better understanding of molecular mechanisms that regulate Hcy and H2S metabolism under physiological and pathophysiological conditions will help improve therapeutic strategies for patients with kidney disease or other organ injuries.
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Parada-Turska, Jolanta, Grażyna Wójcicka, and Jerzy Beltowski. "Paraoxonase 1 Phenotype and Protein N-Homocysteinylation in Patients with Rheumatoid Arthritis: Implications for Cardiovascular Disease." Antioxidants 9, no. 9 (September 21, 2020): 899. http://dx.doi.org/10.3390/antiox9090899.
Повний текст джерелаАнотація:
Paraoxonase 1 (PON1) is the high density lipoprotein-associated esterase which inhibits the development of atherosclerosis by metabolizing lipid peroxidation products as well as hydrolyzing proatherogenic metabolite of homocysteine (Hcy), Hcy thiolactone, which otherwise reacts with lysine groups of proteins, thus forming N-Hcy-protein in a process referred to as protein N-homocysteinylation. Rheumatoid arthritis (RA) is the chronic inflammatory autoimmune disease associated with increased risk of cardiovascular complications, but the underlying mechanisms are incompletely understood. We examined PON1 status and N-homocysteinylation of serum proteins in patients with RA. Blood was collected from 74 RA patients and 70 control subjects. PON1 activity was measured toward synthetic (paraoxon, phenyl acetate) and natural (Hcy thiolactone) substrates. PON1 protein concentration was measured by ELISA. Total Hcy as well as N-Hcy-protein were measured in serum as well. PON1 activity toward Hcy thiolactone was lower in RA patients than in control subjects which was accompanied by increased concentration of N-Hcy-protein despite normal total Hcy concentration. PON1 protein concentration was unchanged in the RA group, but the specific enzyme activity was reduced. When RA patients were categorized according to the DAS28-ESR score, PON1 concentration and enzymatic activity were lower whereas N-Hcy-protein was higher in those with high disease activity. PON1 activity and Hcy thiolactone were correlated with DAS28-ESR score and myeloperoxidase concentration. In conclusion, RA is associated with deficiency of PON1 activity and increased protein N-homocyseinylation which may contribute to accelerated development of cardiovascular diseases.
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Fraser, Katy R., Nina L. Tuite, Arvind Bhagwat, and Conor P. O'Byrne. "Global effects of homocysteine on transcription in Escherichia coli: induction of the gene for the major cold-shock protein, CspA." Microbiology 152, no. 8 (August 1, 2006): 2221–31. http://dx.doi.org/10.1099/mic.0.28804-0.
Повний текст джерелаАнотація:
Homocysteine (Hcy) is a thiol-containing amino acid that is considered to be medically important because it is linked to the development of several life-threatening diseases in humans, including cardiovascular disease and stroke. It inhibits the growth of Escherichia coli when supplied in the growth medium. Growth inhibition is believed to arise as a result of partial starvation for isoleucine, which occurs because Hcy perturbs the biosynthesis of this amino acid. This study attempted to further elucidate the inhibitory mode of action of Hcy by examining the impact of exogenously supplied Hcy on the transcriptome. Using gene macroarrays the transcript levels corresponding to 68 genes were found to be reproducibly altered in the presence of 0.5 mM Hcy. Of these genes, the biggest functional groups affected were those involved in translation (25 genes) and in amino acid metabolism (19 genes). Genes involved in protection against oxidative stress were repressed in Hcy-treated cells and this correlated with a decrease in catalase activity. The gene showing the strongest induction by Hcy was cspA, which encodes the major cold-shock protein CspA. RT-PCR and reporter fusion experiments confirmed that cspA was induced by Hcy. Induction of cspA by Hcy was not caused by nutritional upshift, a stimulus known to induce CspA expression, nor was it dependent on the presence of a functional CspA protein. The induction of cspA by Hcy was suppressed when isoleucine was included in the growth medium. These data suggest that the induction of CspA expression in the presence of Hcy occurs because of a limitation for isoleucine. The possibility that Hcy-induced cspA expression is triggered by translational stalling that occurs when the cells are limited for isoleucine is discussed.
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Keller, Amy C., Jelena Klawitter, Kerry L. Hildreth, Uwe Christians, Kelly Putnam, Wendy M. Kohrt, Jane E. B. Reusch, and Kerrie L. Moreau. "Elevated plasma homocysteine and cysteine are associated with endothelial dysfunction across menopausal stages in healthy women." Journal of Applied Physiology 126, no. 6 (June 1, 2019): 1533–40. http://dx.doi.org/10.1152/japplphysiol.00819.2018.
Повний текст джерелаАнотація:
Hyperhomocysteinemia is associated with endothelial dysfunction and increased cardiovascular disease (CVD). We determined whether elevated homocysteine (Hcy) and markers of Hcy metabolism were associated with the previously reported endothelial dysfunction across stages of the menopause transition. Brachial artery flow-mediated dilation (FMD) and plasma concentrations of Hcy, cysteine, and methionine were measured in healthy women ( n = 128) 22–70 yr of age categorized as premenopausal ( n = 35), perimenopausal (early: n = 16; late: n = 21), and postmenopausal (early: n = 21; late: n = 35). Dietary intake of micronutrients involved in Hcy metabolism (e.g., vitamins B6, B12, folate) was assessed in a subpopulation of women. Hcy and cysteine concentrations were progressively higher, and methionine was progressively lower across menopausal stages (all P < 0.005). The higher Hcy and cysteine concentrations correlated with lower circulating estradiol levels ( r = −0.49 and −0.50, respectively, both P < 0.001). FMD was inversely correlated with Hcy ( r = −0.25, P = 0.004) and cysteine ( r = −0.39, P < 0.001) and positively correlated with methionine concentrations ( r = 0.25, P = 0.005). Dietary intake of vitamins B6 and B12 (both P < 0.05) were lower in postmenopausal women. Vitamin B12 intake correlated with FMD ( r = 0.22, P = 0.006). These data suggest that declines in estradiol across stages of the menopause transition may lead to elevations in Hcy and cysteine that may contribute to endothelial dysfunction in postmenopausal women. Future studies should examine whether targeting Hcy metabolism during the perimenopausal to early postmenopausal period with interventions, including diet, attenuates or reverses the decline in endothelial function in women.NEW & NOTEWORTHY Declines in circulating estradiol across the stages of the menopausal transition may lead to elevations in Hcy and cysteine concentrations that may contribute to endothelial dysfunction. Abnormalities in the Hcy metabolic pathways, possibly related to dietary deficiencies of vitamins B12 and B6 and folate, may contribute to elevations in Hcy and cysteine concentrations. Findings also suggest that higher cysteine levels may be more damaging to the vascular endothelium than Hcy.
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Prisco, Domenico, Tamara Brunelli, Guglielmina Pepe, Anna Gori, Sandra Fedi, Monia Capanni, Ignazio Simonetti, et al. "Tissue Factor and Homocysteine Levels in Ischemic Heart Disease Are Associated with Angiographically Documented Clinical Recurrences after Coronary Angioplasty." Thrombosis and Haemostasis 83, no. 06 (2000): 826–32. http://dx.doi.org/10.1055/s-0037-1613928.
Повний текст джерелаАнотація:
Summary Background In ischemic heart disease (IHD) patients high plasma levels of Tissue Factor (TF), the trigger of coagulation cascade, are present. Homocysteine (Hcy) is a risk factor for coronary artery disease, and several different pathophysiological mechanisms by which Hcy may play a role in thrombus formation have been postulated in “in vitro” studies. We investigated the “in vivo” role of Hcy in affecting plasma levels of TF, its inhibitor Tissue Factor Pathway Inhibitor (TFPI) and hypercoagulability. Methods and Results We investigated 119 IHD patients who underwent PTCA and compared them with 103 healthy subjects. TF, TFPI, Thrombin-Antithrombin complexes (TAT) and Hcy levels were significantly higher in the patients than in the controls. A positive correlation was found between Hcy and TF (r = 0.54; p < 0.0001), Hcy and TFPI (r = 0.26; p < 0.05) as well as Hcy and TAT (r = 0.33; p < 0.0001) levels. An inverse correlation existed between folate intake and Hcy levels (r = −0.28; p = 0.001). Hcy levels within the first quartile and in the highest quartile were associated with a lower (p < 0.001) and higher (p <0.0001) rate of clinical recurrences, respectively. Patients with TF values in the first quartile had a lower rate of angiographically documented clinical recurrences as compared to those in the fourth quartile (p < 0.01); those in the highest quartile of TF showed a higher rate of recurrences (p = 0.001). Multivariate analysis confirmed these results (first quartile of Hcy: OR 0.02, Cl 0.002–0.27; fourth quartile of Hcy: OR 36.5, Cl 3.6-365/first quartile of TF: OR 0.006, Cl 0.001–0.44; fourth quartile of TF: OR 16.4, Cl 3.0 – 90.0), also after adjustment for risk factors and Hcy and TF respectively. Conclusions In this study we show that TF, TFPI and TAT levels are correlated with Hcy plasma levels in IHD patients, providing evidence of an “in vivo” pathophysiological mechanism of hyperhomocysteinemia. The observed association between angiographically documented clinical recurrences and TF and Hcy values awaits confirmation in studies designated to evaluate this issue on a larger number of patients.
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Miroshnichenko, I. I., A. I. Platova, T. P. Safarova, and O. B. Yakovleva. "Determination of homocysteine by lc-ms-ms with atmospheric pressure chemical ionization." Biomeditsinskaya Khimiya 60, no. 2 (2014): 235–45. http://dx.doi.org/10.18097/pbmc20146002235.
Повний текст джерелаАнотація:
Homocysteine (Hcy) is an intermediate of methionine metabolism. High plasma Hcy concentrations are an independent risk factor for stroke, peripheral vascular disease, deep venous thrombosis, coronary disease, and cognitive deficiency. Apparently, it is a great importance to measure Hcy levels in human blood. A new method for the quantification of Hcy by means of reversed-phase LC/atmospheric pressure chemical ionization mass spectrometry has been developed. The MRM ion transition, m/z 136.0 ® 90.0 was used for Hcy quantification. The limit of detection was 0.4 mM, quantification was performed from 1 mM to 40 mM with coefficient of determination of R2=0,997. The method was applied successfully to Hcy determination in human blood.
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Li, Hong, Sergey Brodsky, Sindu Kumari, Virginijus Valiunas, Peter Brink, Jun-Ichi Kaide, Alberto Nasjletti, and Michael S. Goligorsky. "Paradoxical overexpression and translocation of connexin43 in homocysteine-treated endothelial cells." American Journal of Physiology-Heart and Circulatory Physiology 282, no. 6 (June 1, 2002): H2124—H2133. http://dx.doi.org/10.1152/ajpheart.01028.2001.
Повний текст джерелаАнотація:
Hyperhomocysteinemia is an established cause of defective vasorelaxation. Gene expression screening of human umbilical vein endothelial cells (HUVEC) treated with homocysteine (Hcy) revealed that connexin43 (Cx43) was upregulated. Expression of Cx43 was increased more than twofold in Hcy-treated HUVEC. Gap junctional communication (Lucifer yellow and whole cell patch clamp) was not enhanced in Hcy-treated HUVEC. HUVEC expressing chimeric Cx43-green fluorescent protein exhibited it at cell-cell contacts in control but showed redistribution to the intracellular compartment(s) in Hcy-treated cells. Confocal microscopy of HUVEC stained with anti-Cx43, mitochondrial, and endoplasmic reticulum fluorescent markers showed the localization of Cx43 to the plasma membrane of control cells and its colocalization with the mitochondrial marker in Hcy-treated HUVEC. Studies of isolated mitochondria confirmed overexpression of Cx43 in the mitochondria of Hcy-treated HUVEC. Microdissected renal interlobar arteries, which normally exhibit endothelium-derived hyperpolarizing factor-induced vasorelaxation, showed reduced nitric oxide synthase- and cyclooxygenase-independent vasorelaxation to acetylcholine after pretreatment with Hcy. In summary, Hcy-induced upregulation of Cx43 transcript and protein expression are associated with unaltered intercellular communication, redistribution of Cx43 in HUVEC, and reduced nitric oxide- and prostanoid-independent vascular responses to acetylcholine in Hcy-treated arteries.
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Mo, Tingting, Yufei Wang, Hui Gao, Wending Li, Lue Zhou, Yu Yuan, Xiaomin Zhang, et al. "Sleep Duration, Midday Napping, and Serum Homocysteine Levels: A Gene–Environment Interaction Study." Nutrients 15, no. 1 (January 1, 2023): 210. http://dx.doi.org/10.3390/nu15010210.
Повний текст джерелаАнотація:
The associations of sleep duration and midday napping with homocysteine (Hcy) levels, and whether these sleep behaviors modify the association between genetic predisposition and Hcy levels, has yet to be investigated. We included 19,426 participants without severe health conditions at baseline from the Dongfeng–Tongji cohort. In a subgroup of 15,126 participants with genetic data, a genetic risk score (GRS) based on 18 Hcy-related loci was constructed to test the gene–sleep interactions in Hcy. Hcy levels were higher in subjects with a long sleep duration (≥9 h) and midday napping (>90 min), as compared to those who reported a moderate sleep duration (7 to <8 h) and midday napping (1–30 min) (all p values < 0.05). A long sleep duration and midday napping showed a joint effect in increasing Hcy (p for trend < 0.001). Significant interactions regarding Hcy levels were observed for a long sleep duration with GRS and MTHFR rs1801133, and long midday napping with DPEP1 rs12921383 (all p values for interaction < 0.05). Overall findings indicated that a long sleep duration and midday napping were associated with elevated serum Hcy levels, independently and jointly, and amplified the genetic susceptibility to higher Hcy.
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Bełtowski, Jerzy, Grażyna Wójcicka, and Hieronim Jakubowski. "Modulation of paraoxonase 1 and protein N-homocysteinylation by leptin and the synthetic liver X receptor agonist T0901317 in the rat." Journal of Endocrinology 204, no. 2 (November 2, 2009): 191–98. http://dx.doi.org/10.1677/joe-09-0298.
Повний текст джерелаАнотація:
The adipose tissue hormone leptin and homocysteine (Hcy)-thiolactone are linked to the pathogenesis of atherosclerosis through their interactions with the anti-atherogenic enzyme paraoxonase 1 that has the ability to hydrolyze Hcy-thiolactone and minimizes protein N-homocysteinylation. Here we examined the relationships between hyperleptinemia, Hcy-thiolactonase, and protein N-homocysteinylation in rats. Hyperleptinemia was induced in adult rats by administration of leptin for 7 days (0.25 mg/kg twice daily s.c). We found that serum Hcy-thiolactonase was lower in hyperleptinemic than in control animals (−41.0%, P<0.001). Leptin administration increased the level of N-linked Hcy in plasma proteins (+92.9%, P<0.01), but had no effect on plasma total Hcy. These effects were not reproduced by pair-feeding. We also found that the synthetic liver X receptor (LXR) agonist, T0901317 (1 mg/kg per day) normalized Hcy-thiolactonase and protein N-homocysteinylation levels in leptin-treated rats. However, leptin-induced increase in plasma isoprostane levels (a marker of oxidative stress) was not normalized by T0901317. The NADPH oxidase inhibitor apocynin prevented leptin-induced increase in isoprostane levels but did not normalize Hcy-thiolactonase and protein N-homocysteinylation levels. These results suggest that the decreased capacity to metabolize Hcy-thiolactone and concomitant increase in protein N-homocysteinylation contribute to pro-atherogenic effect of chronic hyperleptinemia, independently of oxidative stress. LXR agonists normalize Hcy-thiolactonase levels and decrease protein N-homocysteinylation, especially under conditions associated with excess leptin such as metabolic syndrome.
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Zinellu, Angelo, Elisabetta Zinellu, Salvatore Sotgia, Marilena Formato, Gian Mario Cherchi, Luca Deiana, and Ciriaco Carru. "Factors Affecting S-Homocysteinylation of LDL Apoprotein B." Clinical Chemistry 52, no. 11 (November 1, 2006): 2054–59. http://dx.doi.org/10.1373/clinchem.2006.071142.
Повний текст джерелаАнотація:
Abstract Background: Hyperhomocysteinemia is an important risk factor for vascular disease and atherosclerosis, but the mechanisms by which homocysteine exerts its deleterious effects are not known. Because oxidation and/or homocysteinylation may increase atherogenicity of LDL, we investigated S-homocysteinylation of LDL as a possible contributor to atherosclerosis pathogenesis. Methods: We used capillary electrophoresis to measure LDL-bound thiols [homocysteine, cysteine (Cys), cysteinylglycine, glutathione, and glutamylcysteine] in 104 healthy study participants We also assessed total plasma thiol concentrations and lipid profiles. Results: Our data suggest that apoprotein B (apoB)-cysteinylglycine (CysGly), apoB-Hcy, and apoB-Cys concentrations are markedly higher in men than in women. The percentage of CysGly and glutathione on apoB was higher than that of the same thiols in plasma, whereas the other thiols were markedly less prevalent in lipoprotein than in plasma. Pearson correlation showed that among all thiols, only total plasma Hcy is related to apoB-Hcy concentrations. Multiple correlation analysis confirmed that total Hcy was the most important determinant of apoB-Hcy. Age and LDL cholesterol also showed positive associations, but Cys and, mainly, CysGly were negatively associated with apoB-Hcy concentrations. Conclusions: apoB-Hcy derivative formation is mainly dependent on total homocysteine concentration. Increased cholesterol concentrations are related to increased apoB-Hcy. CysGly seems to compete with Hcy for binding to LDL apoprotein, suggesting that CysGly may protect against atherosclerosis by decreasing the concentrations of Hcy transferred by LDL from plasma to endothelial and subendothelial spaces.
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Park, Eun Jung, Jihyun Je, Theodomir Dusabimana, Seung Pil Yun, Hye Jung Kim, Hwajin Kim, and Sang Won Park. "The Uremic Toxin Homocysteine Exacerbates the Brain Inflammation Induced by Renal Ischemia-Reperfusion in Mice." Biomedicines 10, no. 12 (November 25, 2022): 3048. http://dx.doi.org/10.3390/biomedicines10123048.
Повний текст джерелаАнотація:
Homocysteine (Hcy), a homologue of cysteine, is biosynthesized during methionine metabolism. Elevated plasma Hcy is associated with glomerular injury and considered as a risk factor for renal dysfunction, predicting incident chronic kidney disease. Hcy promotes oxidative stress, inflammation, and endothelial dysfunction. Acute kidney injury (AKI) is defined as a sudden decline in renal function and is important clinically due to the high mortality rate in AKI patients with multiple organs failure, including the brain. However, the cytotoxic role of Hcy on the brain following AKI is not directly shown. In this study, C57BL/6 mice were subjected to renal ischemia reperfusion (IR), one of the causes of AKI, and treated with vehicle or Hcy (0.2 mg/kg) to analyse the brain inflammation. IR mice showed a significant induction in plasma creatinine and Hcy levels, associated with tubular injury and neutrophil infiltration, and upregulation of pro-inflammatory cytokines and tubular apoptosis. Hcy treatment aggravated these renal damage and dysfunction by regulating cyclooxygenase-2 (COX-2), inhibitor of κB phosphorylation, and heme oxygenase-1. Consistently, Hcy treatment significantly increased expression of pro-inflammatory cytokines, glial fibrillary acidic protein, and COX-2 in the prefrontal cortex of IR mice. We conclude that Hcy treatment aggravated the renal dysfunction and enhanced IR-induced inflammatory cytokines and astrocyte activation in the brain. We propose that lowering plasma Hcy levels may attenuate neurological dysfunction found in patients with AKI.
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du Plessis, Jacomina P., Leandi Lammertyn, Aletta E. Schutte, and Cornelie Nienaber-Rousseau. "H-Type Hypertension among Black South Africans and the Relationship between Homocysteine, Its Genetic Determinants and Estimates of Vascular Function." Journal of Cardiovascular Development and Disease 9, no. 12 (December 9, 2022): 447. http://dx.doi.org/10.3390/jcdd9120447.
Повний текст джерелаАнотація:
Elevated homocysteine (Hcy) increases cardiovascular disease (CVD) risk. Our objective was to emphasize Hcy’s contribution in hypertension and CVD management by determining H-type hypertension (hypertension with Hcy ≥ 10 µmol/L) and associations between Hcy, blood pressure (BP) and estimates of vascular function among Black South Africans. We included 1995 adults (63% female). Plasma Hcy and cardiovascular measures (systolic and diastolic BP (SBP, DBP), pulse pressure, heart rate (HR), carotid-radialis pulse wave velocity (cr-PWV), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1) were quantified. Five Hcy-related polymorphisms (cystathionine β-synthase (CBS 844ins68, T833C, G9276A); methylenetetrahydrofolate reductase (MTHFR C677T) and methionine synthase (MTR A2756G)) were genotyped. Hcy was >10 µmol/L in 41% (n = 762), and of the 47% (n = 951) hypertensives, 45% (n = 425) presented with H-type. Hcy was higher in hypertensives vs. normotensives (9.86 vs. 8.78 µmol/L, p < 0.0001, effect size 0.56) and correlated positively with SBP, DBP, cr-PWV and ICAM-1 (r > 0.19, p < 0.0001). Over Hcy quartiles, SBP, DBP, HR, cr-PWV and ICAM-1 increased progressively (all p-trends ≤ 0.001). In multiple regression models, Hcy contributed to the variance of SBP, DBP, HR, cr-PWV and ICAM-1. H-type hypertensives also had the lowest MTHFR 677 CC frequency (p = 0.03). Hcy is positively and independently associated with markers of vascular function and raised BP.
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Razygraev, A. V. "Homocysteine peroxidase activity in rat blood plasma: stoichiometry and enzymatic character of the reaction." Biomeditsinskaya Khimiya 59, no. 6 (2013): 636–43. http://dx.doi.org/10.18097/pbmc20135906636.
Повний текст джерелаАнотація:
Recently it was shown that the presence of rat blood plasma (as well as of erythrocyte hemolysate) in the reaction mixture containing 43 mM Tris-HCl-buffer (pH 8.5), 0.29 mM EDTA, 19.2 mM sodium azide, 1 mM DL-homocysteine (Hcy), and 198 mM hydrogen peroxide (incubation at 37°C) results in a significant acceleration of the decrease in Hcy concentration caused by addition of H O . In this paper, we present data indicating that the observed activity is the homocysteine:H O -oxidoreductase (homocysteine peroxidase) activity. It has been found that the level of H O -dependent Hcy decrease observed in the presence of blood plasma corresponds to homocysteine:H O -oxidoreductase reaction stoichiometry of 2:1 (mole ratio). The activity observed belongs to the protein fraction isolated by saturation with ammonium sulfate to 50%; the specific activity in this protein fraction is significantly higher than that in the whole plasma. The results confirm the hypothesis that the reaction between Hcy and H O at the presence of plasma is catalyzed by the protein component of plasma and this is the homocysteine peroxidase reaction. This activity is not associated with serum albumin, which is known to function as thiol peroxidase, and probably belongs to extracellular glutathione peroxidase (Gpx3).
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Lu, Jingtong, Kegong Chen, Wei Chen, Chang Liu, XingPei Jiang, Zili Ma, Dong Li, Yanjiao Shen, and Hai Tian. "Association of Serum Homocysteine with Cardiovascular and All-Cause Mortality in Adults with Diabetes: A Prospective Cohort Study." Oxidative Medicine and Cellular Longevity 2022 (October 11, 2022): 1–11. http://dx.doi.org/10.1155/2022/2156483.
Повний текст джерелаАнотація:
Background. Homocysteine (Hcy) was implicated in oxidative stress and diabetes biologically. However, the clinical evidence on the link between Hcy level and diabetes is limited and controversial. This study is aimed at investigating the association of serum Hcy with all-cause and cardiovascular mortality in diabetic patients. Methods. Serum Hcy was measured among 2,286 adults with type 2 diabetes in NHANES 1999-2006. Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% CIs for the association of Hcy with all-cause and cause-specific mortality. Results. Over a median follow-up of 11.0 (interquartile range, 8.9-13.4) years, 952 of the 2286 patients with diabetes died, covering 269 (28.3%) cardiovascular deaths and 144 (15.2%) cancer deaths. Restricted cubic spline showed the linear relationship between Hcy and all-cause mortality risk. After multivariate adjustment, higher serum Hcy levels were independently associated with increased risk of all-cause and cardiovascular mortality. Compared with participants in the bottom tertile of Hcy, the multivariate-adjusted HRs and 95% CI for participants in the top quartile were 2.33 (1.64-3.30) for all-cause mortality ( p trend < 0.001 ), 2.24 (1.22-4.10) for CVD mortality ( p trend = 0.017 ), and 2.05 (0.90-4.69) for cancer mortality ( p trend = 0.096 ). The association with total mortality was especially stronger among patients with albuminuria. Serum Hcy significantly improved reclassification for 10-year mortality in diabetic patients (net reclassification index = 0.253 and integrated discrimination improvement = 0.011 ). Conclusions. Serum Hcy was associated with risks of all-cause and cardiovascular mortality in diabetic adults. Our results suggested that Hcy was a promising biomarker in risk stratification among diabetic patients.
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Prathapasinghe, Gamika A., Yaw L. Siow, and Karmin O. "Detrimental role of homocysteine in renal ischemia-reperfusion injury." American Journal of Physiology-Renal Physiology 292, no. 5 (May 2007): F1354—F1363. http://dx.doi.org/10.1152/ajprenal.00301.2006.
Повний текст джерелаАнотація:
Ischemia followed by reperfusion is a major cause for renal injury in both native kidney and renal allografts. Hyperhomocysteinemia, a condition of elevated plasma homocysteine (Hcy) level, is associated with cardiovascular diseases. Recent evidence suggests that Hcy, at higher levels, may be harmful to other organs such as the kidney. In this study, we investigated the role of Hcy in ischemia-reperfusion-induced renal injury. The left kidney of a Sprague-Dawley rat was subjected to either 30-min or 1-h ischemia followed by 1- or 24-h reperfusion. Ischemia-reperfusion caused a significant increase in peroxynitrite formation and lipid peroxidation in kidneys, which reflected oxidative stress. The number of apoptotic cells in those kidneys was also markedly increased. Hcy levels were elevated 2.9- and 1.5-fold in kidneys subjected to ischemia alone or ischemia-reperfusion, respectively. Further investigation revealed that elevation of Hcy level in the kidney upon ischemia-reperfusion was due to reduced activity of cystathionine-β-synthase, a key enzyme in Hcy metabolism. Administration of anti-Hcy antibodies into the kidney not only abolished ischemia-reperfusion-induced oxidative stress and cell death in the kidneys but also restored renal function after 1 h of reperfusion. However, such a protective effect was not sustained after 24 h of reperfusion. In conclusion, ischemia-reperfusion impairs Hcy metabolism in the kidney. Hcy, at elevated levels, is capable of inducing oxidative stress and renal injury. Neutralization of Hcy with antibodies offers transient functional benefit against ischemia-reperfusion-induced oxidative stress and renal injury. These results suggest that Hcy may play a detrimental role in the kidney during ischemia-reperfusion.
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Blum, Arnon, Ihsan Hijazi, Michal Mashiach Eizenberg, and Nava Blum. "Homocysteine (Hcy) Follow-Up Study." Clinical & Investigative Medicine 30, no. 1 (February 11, 2007): 21. http://dx.doi.org/10.25011/cim.v30i1.445.
Повний текст джерелаАнотація:
Background: Hyperhomocysteinemia confers an increased risk of coronary artery disease, stroke, and deep vein thrombosis, and is a strong predictor of mortality among patients with ischemic heart disease.
Purpose: To determne the long term clinical outcome of patients with risk factors to atherosclerosis with high concentrations of homocysteine (Hcy).
Methods: 89 patients with one or more risk factors for atherosclerosis, whose plasma total Hcy concentrations were measured, were followed for 5 years. Patients were interviewed and underwent a clinical examination in the outpatient clinic. Their medical records were reviewed in the last 5 years including smoking habits, medications, other diseases (hypertension, diabetes mellitus, hyperlipidemia) and their management. SPSS was used to describe and explore possible relationships between Hcy concentration, other diseases, medications and the clinical long term outcome.
Results: All men with normal Hcy concentrations (10.76±1.71µmol/L) survived during the 5 years’ follow up, while 5 of the men with high Hcy concentrations (21.27±5.37µmol/L), died (17%) (P< 0.05). In women Hcy concentration did not affect survival. No association was found between diabetes mellitus, hypercholesterolemia, hypertension and Hcy. Long term treatment with Beta Blockers, ACE inhibitors, Calcium Channel blockers, and especially with Aspirin prevented death and changed the natural history of patients with high Hcy concentrations (P < 0.05).
Conclusions – Hyperhomocysteinemia may have an effect on survival in men.
Long term treatment with Beta Blockers, ACE inhibitors, Calcium Channel Blockers, and especially with Aspirin – prevented death and changed the natural history of patients with high Hcy concentrations.
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Wang, Rui, Zhong-Ji Han, Ge Song, Yi Cui, Hong-Fei Xia, and Xu Ma. "Homocysteine-induced neural tube defects in chick embryos via oxidative stress and DNA methylation associated transcriptional down-regulation of miR-124." Toxicology Research 10, no. 3 (April 26, 2021): 425–35. http://dx.doi.org/10.1093/toxres/tfab020.
Повний текст джерелаАнотація:
Abstract Although moderate homocysteine (HCY) elevation is associated with neural tube defects (NTDs), the underlying mechanisms have not been elucidated. In this study, we aimed to investigate that whether HCY-induced NTDs were associated with oxidative stress and methyl metabolism in chick embryos. The potential role of miR-124 in neurogenesis was also investigated. In this study, increased intracellular oxidative species and alterations in DNA methylation were observed following HCY treatment. This alteration coincided with decreases of Mn superoxide dismutase and glutathione peroxidase activities, as well as the expression of anti-rabbit DNA methyltransferase (DNMT) 1 and 3a. In addition, HCY induced significant decreases of S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) (P < 0.05). N-acetyl-L-cysteine and choline ameliorated global DNA hypomethylation induced by HCY. MiR-124 levels were significantly suppressed by HCY (P < 0.05), while elevated by 5-aza-2′-deoxycytidine (5-aza-dC). MiR-124 knockdown resulted in spina bifida occulta. Our research suggests that HCY-induced NTDs were associated with oxidative stress and methyl metabolism in chick embryos. MiR-124 down-regulation may occur via epigenetic mechanisms and contribute to HCY-induced NTDs in chick embryo models.
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Liang, Shuang, Yuanpeng Zhou, Huijun Wang, Yanyan Qian, Duan Ma, Weidong Tian, Vishwani Persaud-Sharma, et al. "The Effect of Multiple Single Nucleotide Polymorphisms in the Folic Acid Pathway Genes on Homocysteine Metabolism." BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/560183.
Повний текст джерелаАнотація:
Objective. To investigate the joint effects of the single nucleotide polymorphisms (SNPs) of genes in the folic acid pathway on homocysteine (Hcy) metabolism.Methods. Four hundred women with normal pregnancies were enrolled in this study. SNPs were identified by MassARRAY. Serum folic acid and Hcy concentration were measured. Analysis of variance (ANOVA) and support vector machine (SVM) regressions were used to analyze the joint effects of SNPs on the Hcy level.Results. SNPs of MTHFR (rs1801133 and rs3733965) were significantly associated with maternal serum Hcy level. In the different genotypes of MTHFR (rs1801133), SNPs of RFC1 (rs1051266), TCN2 (rs9606756), BHMT (rs3733890), and CBS (rs234713 and rs2851391) were linked with the Hcy level adjusted for folic acid concentration. The integrated SNPs scores were significantly associated with the residual Hcy concentration (RHC) (r=0.247). The Hcy level was significantly higher in the group with high SNP scores than that in other groups with SNP scores of less than 0.2 (P=0.000). Moreover, this difference was even more significant in moderate and high levels of folic acid.Conclusion. SNPs of genes in the folic acid pathway possibly affect the Hcy metabolism in the presence of moderate and high levels of folic acid.