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1.
Biomed Khim ; 67(4): 338-346, 2021 Jul.
Artigo em Russo | MEDLINE | ID: mdl-34414892

RESUMO

Hyperhomocysteinemia is a risk factor for many diseases, including reproductive disorders in men. L-carnitine is used in medical practice to correct impaired bioenergetic conditions; in patients with idiopathic forms of infertility its effects are associated with improvement of the sperm parameters. However, the effect of exogenous L-carnitine on the level of homocysteine in the gonadal tissues, as a risk factor for impaired fertility, has not been investigated yet. The aim of this study was to investigate activity of bioenergetic enzymes in the epididymal mitochondrial fraction, the dynamics of changes in the cytoplasmic and mitochondrial lactate levels and LDH activity, the total carnitine content, as well as the oxidative status of these cells under conditions of oxidative stress caused by hyperhomocysteinemia, and to assess the effect of carnitine chloride on these parameters under conditions of methionine administration to male Wistar rats. Methionine administration to animals for three weeks at a dose of 3 g/kg, resulted in development of the severe forms of hyperhomocysteinemia with serum homocysteine concentrations exceeding 100 µmol/L. This was accompanied by a decrease in the activity of enzymes involved in the bioenergetic processes of the cell: tissue respiration (succinate dehydrogenase) and oxidative phosphorylation (H+-ATPase) in the epididymal head and tail. The change in lactate metabolism included an increase in its level in both the mitochondrial and cytoplasmic fractions of the epididymal head and mitochondria of the epididymal tail, and also simultaneous statistically significant decrease in LDH activity in the mitochondria and cytoplasm of the epididymal head. In male rats with severe hyperhomocysteinemia, an increase in the activity of mitochondrial SOD accompanied by an increase in the carbonylation of mitochondrial proteins in the head and tail of the epididymis was noted. Modeling of hyperhomocysteinemia under conditions of carnitine chloride of administration led to different reactions of the cells of the studied tissues assayed in the epididymal head and tail homogenate. In the epididymal head, carnitine chloride promoted an increase in the mitochondrial lactate concentration and a decrease in the cytoplasmic lactate concentration, as well as an increase in the LDH activity associated with the mitochondrial fraction. These changes were accompanied by an increase in the activity of H+-ATPase in the epididymal, thus suggesting that carnitine chloride stimulated lactate transport of into the mitochondria and its use as an energy substrate under conditions of oxidative stress caused by hyperhomocysteinemia. In the tail tissues, the changes were protective in nature and were associated with a decrease in the formation of oxidatively modified proteins.


Assuntos
Epididimo , Hiper-Homocisteinemia , Animais , Carnitina/metabolismo , Cloretos/metabolismo , Epididimo/metabolismo , Humanos , Hiper-Homocisteinemia/tratamento farmacológico , Hiper-Homocisteinemia/metabolismo , Ácido Láctico/metabolismo , Masculino , Mitocôndrias , Ratos , Ratos Wistar
2.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202757

RESUMO

The aim of this study was to investigate the effect of the application of homocysteine as well as its effect under the condition of aerobic physical activity on the activities of matrix metalloproteinases (MMP), lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) in cardiac tissue and on hepato-renal biochemical parameters in sera of rats. Male Wistar albino rats were divided into four groups (n = 10, per group): C: 0.9% NaCl 0.2 mL/day subcutaneous injection (s.c.); H: homocysteine 0.45 µmol/g b.w./day s.c.; CPA saline (0.9% NaCl 0.2 mL/day s.c.) and a program of physical activity on a treadmill; and HPA homocysteine (0.45 µmol/g b.w./day s.c.) and a program of physical activity on a treadmill. Subcutaneous injection of substances was applied 2 times a day at intervals of 8 h during the first two weeks of experimental protocol. Hcy level in serum was significantly higher in the HPA group compared to the CPA group (p < 0.05). Levels of glucose, proteins, albumin, and hepatorenal biomarkers were higher in active groups compared with the sedentary group. It was demonstrated that the increased activities of LDH (mainly caused by higher activity of isoform LDH2) and mMDH were found under the condition of homocysteine-treated rats plus aerobic physical activity. Independent application of homocysteine did not lead to these changes. Physical activity leads to activation of MMP-2 isoform and to increased activity of MMP-9 isoform in both homocysteine-treated and control rats.


Assuntos
Hiper-Homocisteinemia/metabolismo , Rim/metabolismo , L-Lactato Desidrogenase/metabolismo , Fígado/metabolismo , Malato Desidrogenase/metabolismo , Metaloproteinases da Matriz/metabolismo , Miocárdio/metabolismo , Condicionamento Físico Animal , Animais , Biomarcadores , Pesos e Medidas Corporais , Ativação Enzimática , Hiper-Homocisteinemia/etiologia , Miocárdio/enzimologia , Especificidade de Órgãos , Ratos , Fatores de Tempo
3.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200792

RESUMO

Hyperhomocysteinemia (HHcy) is remarkably common among the aging population. The relation between HHcy and the development of neurodegenerative diseases, such as Alzheimer's disease (AD) and eye diseases, and age-related macular degeneration (AMD) and diabetic retinopathy (DR) in elderly people, has been established. Disruption of the blood barrier function of the brain and retina is one of the most important underlying mechanisms associated with HHcy-induced neurodegenerative and retinal disorders. Impairment of the barrier function triggers inflammatory events that worsen disease pathology. Studies have shown that AD patients also suffer from visual impairments. As an extension of the central nervous system, the retina has been suggested as a prominent site of AD pathology. This review highlights inflammation as a possible underlying mechanism of HHcy-induced barrier dysfunction and neurovascular injury in aging diseases accompanied by HHcy, focusing on AD.


Assuntos
Doenças do Sistema Nervoso Central/patologia , Homocisteína/metabolismo , Hiper-Homocisteinemia/patologia , Inflamação/fisiopatologia , Fatores Etários , Animais , Doenças do Sistema Nervoso Central/etiologia , Doenças do Sistema Nervoso Central/metabolismo , Humanos , Hiper-Homocisteinemia/etiologia , Hiper-Homocisteinemia/metabolismo
4.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066973

RESUMO

L-methionine, an essential amino acid, plays a critical role in cell physiology. High intake and/or dysregulation in methionine (Met) metabolism results in accumulation of its intermediate(s) or breakdown products in plasma, including homocysteine (Hcy). High level of Hcy in plasma, hyperhomocysteinemia (hHcy), is considered to be an independent risk factor for cerebrovascular diseases, stroke and dementias. To evoke a mild hHcy in adult male Wistar rats we used an enriched Met diet at a dose of 2 g/kg of animal weight/day in duration of 4 weeks. The study contributes to the exploration of the impact of Met enriched diet inducing mild hHcy on nervous tissue by detecting the histo-morphological, metabolomic and behavioural alterations. We found an altered plasma metabolomic profile, modified spatial and learning memory acquisition as well as remarkable histo-morphological changes such as a decrease in neurons' vitality, alterations in the morphology of neurons in the selective vulnerable hippocampal CA 1 area of animals treated with Met enriched diet. Results of these approaches suggest that the mild hHcy alters plasma metabolome and behavioural and histo-morphological patterns in rats, likely due to the potential Met induced changes in "methylation index" of hippocampal brain area, which eventually aggravates the noxious effect of high methionine intake.


Assuntos
Comportamento Animal , Hipocampo/patologia , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/metabolismo , Metabolômica , Animais , Homocisteína/sangue , Hiper-Homocisteinemia/patologia , Marcação In Situ das Extremidades Cortadas , Espectroscopia de Ressonância Magnética , Masculino , Metionina , Ratos Wistar , Coloração e Rotulagem
5.
Biomed Res Int ; 2021: 6652231, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34036101

RESUMO

Homocysteine (Hct) is a substance produced in the metabolism of methionine. It is an essential type of amino acid gained from the daily diet. Methylenetetrahydrofolate reductase (MTHFR) gene mutation is related to elevated total homocysteine (tHct) expressions, in particular, among women with low folate intake. Hyperhomocysteinemia (HHct) is caused by numerous factors, such as genetic defects, lack of folic acid, vitamin B6 and B12 deficiency, hypothyroidism, drugs, aging, and renal dysfunction. Increased Hct in peripheral blood may lead to vascular illnesses, coronary artery dysfunction, atherosclerotic changes, and embolic diseases. Compared to nonpregnant women, the Hct level is lower in normal pregnancies. Recent studies have reported that HHct was associated with numerous pregnancy complications, including recurrent pregnancy loss (RPL), preeclampsia (PE), preterm delivery, placental abruption, fetal growth restriction (FGR), and gestational diabetes mellitus (GDM). Besides, it was discovered that neonatal birth weight and maternal Hct levels were negatively correlated. However, a number of these findings lack consistency. In this review, we summarized the metabolic process of Hct in the human body, the levels of Hct in different stages of normal pregnancy reported in previous studies, and the relationship between Hct and pregnancy complications. The work done is helpful for obstetricians to improve the likelihood of a positive outcome during pregnancy complications. Reducing the Hct level with a high dosage of folic acid supplements during the next pregnancy could be helpful for females who have suffered pregnancy complications due to HHct.


Assuntos
Homocisteína/sangue , Complicações na Gravidez , Aborto Habitual , Envelhecimento , Peso ao Nascer , Diabetes Gestacional , Suplementos Nutricionais , Feminino , Retardo do Crescimento Fetal , Ácido Fólico/sangue , Homocisteína/metabolismo , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/metabolismo , Placenta , Pré-Eclâmpsia , Gravidez , Vitamina B 12/sangue , Deficiência de Vitamina B 12 , Vitamina B 6/sangue , Deficiência de Vitamina B 6
6.
Eur J Pharmacol ; 905: 174168, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-33984300

RESUMO

Cardiovascular disease is one of the most common diseases in the elderly population, and its incidence has rapidly increased with the prolongation of life expectancy. Hyperhomocysteinemia is an independent risk factor for various cardiovascular diseases, including atherosclerosis, and damage to vascular function plays an initial role in its pathogenesis. This review presents the latest knowledge on the mechanisms of vascular injury caused by hyperhomocysteinemia, including oxidative stress, endoplasmic reticulum stress, protein N-homocysteinization, and epigenetic modification, and discusses the therapeutic targets of natural polyphenols. Studies have shown that natural polyphenols in plants can reduce homocysteine levels and regulate DNA methylation by acting on oxidative stress and endoplasmic reticulum stress-related signaling pathways, thus improving hyperhomocysteinemia-induced vascular injury. Natural polyphenols obtained via daily diet are safer and have more practical significance in the prevention and treatment of chronic diseases than traditional drugs.


Assuntos
Hiper-Homocisteinemia/complicações , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Lesões do Sistema Vascular/tratamento farmacológico , Lesões do Sistema Vascular/etiologia , Animais , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Homocisteína/fisiologia , Humanos , Hiper-Homocisteinemia/metabolismo , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Lesões do Sistema Vascular/metabolismo
7.
Molecules ; 26(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33802165

RESUMO

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


Assuntos
Disfunção Cognitiva/fisiopatologia , Doença de Parkinson/fisiopatologia , Apolipoproteínas E/genética , Pressão Arterial/fisiologia , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/metabolismo , Disfunção Cognitiva/sangue , Humanos , Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/fisiopatologia , Doença de Parkinson/sangue , Sistema Renina-Angiotensina/fisiologia , Fatores de Risco , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/fisiologia , Substância Branca/patologia
8.
J Cell Mol Med ; 25(7): 3437-3448, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33675119

RESUMO

Hyperhomocysteinaemia (HHcy)-impaired endothelial dysfunction including endoplasmic reticulum (ER) stress plays a crucial role in atherogenesis. Hydrogen sulphide (H2 S), a metabolic production of Hcy and gasotransmitter, exhibits preventing cardiovascular damages induced by HHcy by reducing ER stress, but the underlying mechanism is unclear. Here, we made an atherosclerosis with HHcy mice model by ApoE knockout mice and feeding Pagien diet and drinking L-methionine water. H2 S donors NaHS and GYY4137 treatment lowered plaque area and ER stress in this model. Protein disulphide isomerase (PDI), a modulation protein folding key enzyme, was up-regulated in plaque and reduced by H2 S treatment. In cultured human aortic endothelial cells, Hcy dose and time dependently elevated PDI expression, but inhibited its activity, and which were rescued by H2 S. H2 S and its endogenous generation key enzyme-cystathionine γ lyase induced a new post-translational modification-sulfhydration of PDI. Sulfhydrated PDI enhanced its activity, and two cysteine-terminal CXXC domain of PDI was identified by site mutation. HHcy lowered PDI sulfhydration association ER stress, and H2 S rescued it but this effect was blocked by cysteine site mutation. Conclusively, we demonstrated that H2 S sulfhydrated PDI and enhanced its activity, reducing HHcy-induced endothelial ER stress to attenuate atherosclerosis development.


Assuntos
Aterosclerose/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Endoteliais/metabolismo , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Hiper-Homocisteinemia/metabolismo , Isomerases de Dissulfetos de Proteínas/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Células HEK293 , Homocisteína/metabolismo , Humanos , Masculino , Camundongos , Camundongos Knockout para ApoE , Isomerases de Dissulfetos de Proteínas/química , Regulação para Cima
9.
Front Immunol ; 12: 632333, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717169

RESUMO

Background: Murine monocytes (MC) are classified into Ly6Chigh and Ly6Clow MC. Ly6Chigh MC is the pro-inflammatory subset and the counterpart of human CD14++CD16+ intermediate MC which contributes to systemic and tissue inflammation in various metabolic disorders, including hyperhomocysteinemia (HHcy). This study aims to explore molecule signaling mediating MC subset differentiation in HHcy and control mice. Methods: RNA-seq was performed in blood Ly6Chigh and Ly6Clow MC sorted by flow cytometry from control and HHcy cystathionine ß-synthase gene-deficient (Cbs -/-) mice. Transcriptome data were analyzed by comparing Ly6Chigh vs. Ly6Clow in control mice, Ly6Chigh vs. Ly6Clow in Cbs-/- mice, Cbs-/- Ly6Chigh vs. control Ly6Chigh MC and Cbs-/- Ly6Clow vs. control Ly6Clow MC by using intensive bioinformatic strategies. Significantly differentially expressed (SDE) immunological genes and transcription factor (TF) were selected for functional pathways and transcriptional signaling identification. Results: A total of 7,928 SDE genes and 46 canonical pathways derived from it were identified. Ly6Chigh MC exhibited activated neutrophil degranulation, lysosome, cytokine production/receptor interaction and myeloid cell activation pathways, and Ly6Clow MC presented features of lymphocyte immunity pathways in both mice. Twenty-four potential transcriptional regulatory pathways were identified based on SDE TFs matched with their corresponding SDE immunological genes. Ly6Chigh MC presented downregulated co-stimulatory receptors (CD2, GITR, and TIM1) which direct immune cell proliferation, and upregulated co-stimulatory ligands (LIGHT and SEMA4A) which trigger antigen priming and differentiation. Ly6Chigh MC expressed higher levels of macrophage (MΦ) markers, whereas, Ly6Clow MC highly expressed lymphocyte markers in both mice. HHcy in Cbs -/- mice reinforced inflammatory features in Ly6Chigh MC by upregulating inflammatory TFs (Ets1 and Tbx21) and strengthened lymphocytes functional adaptation in Ly6Clow MC by increased expression of CD3, DR3, ICOS, and Fos. Finally, we established 3 groups of transcriptional models to describe Ly6Chigh to Ly6Clow MC subset differentiation, immune checkpoint regulation, Ly6Chigh MC to MΦ subset differentiation and Ly6Clow MC to lymphocyte functional adaptation. Conclusions: Ly6Chigh MC displayed enriched inflammatory pathways and favored to be differentiated into MΦ. Ly6Clow MC manifested activated T-cell signaling pathways and potentially can adapt the function of lymphocytes. HHcy reinforced inflammatory feature in Ly6Chigh MC and strengthened lymphocytes functional adaptation in Ly6Clow MC.


Assuntos
Antígenos Ly/imunologia , Hiper-Homocisteinemia/imunologia , Monócitos/imunologia , Animais , Antígenos Ly/metabolismo , Diferenciação Celular/imunologia , Cistationina beta-Sintase/deficiência , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hiper-Homocisteinemia/metabolismo , Proteínas de Checkpoint Imunológico/genética , Inflamação , Linfócitos/imunologia , Lisossomos/imunologia , Macrófagos/imunologia , Camundongos , Monócitos/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética
10.
Int J Mol Sci ; 22(4)2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33567540

RESUMO

The influence of hyperhomocysteinemia (HHCy) on cardiovascular disease (CVD) remains unclear. HHCy is associated with inflammation and atherosclerosis, and it is an independent risk factor for CVD, stroke and myocardial infarction. However, homocysteine (HCy)-lowering therapy does not affect the inflammatory state of CVD patients, and it has little influence on cardiovascular risk. The HCy degradation product hydrogen sulfide (H2S) is a cardioprotector. Previous research proposed a positive role of H2S in the cardiovascular system, and we discuss some recent data suggesting that HHCy worsens CVD by increasing the production of H2S, which decreases the expression of adenosine A2A receptors on the surface of immune and cardiovascular cells to cause inflammation and ischemia, respectively.


Assuntos
Doenças Cardiovasculares/etiologia , Homocisteína/metabolismo , Sulfeto de Hidrogênio/metabolismo , Hiper-Homocisteinemia/complicações , Receptor A2A de Adenosina/metabolismo , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Humanos , Hiper-Homocisteinemia/metabolismo
11.
Biochem Biophys Res Commun ; 547: 125-130, 2021 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-33610040

RESUMO

ABJECTIVE: Interaction of hypertension and hyperhomocysteinemia (HHcy) leads to enhanced cardiac remodeling in hypertensive heart disease. However, the mechanism of collagen accumulation and cardiac remodeling remains unclear. In this study, we attempted to evaluate the relationship between hypertension and HHcy in the context of cardiac remodeling and to explore its mechanism of action. METHODS: Wistar Kyoto (WKY) and spontaneous hypertension rats (SHR) were randomly divided into four groups, namely WKY group, WKY + HHcy group, SHR group and SHR + HHcy group. We measured blood pressure (BP), plasma homocysteine (Hcy), serum superoxide dismutase (SOD) and serum malondialdehyde (MDA). We also examined cardiac histopathology and gene and protein expression levels of Nrf2 and HO-1. RESULTS: Compared with the WKY group, myocardial interstitial and perivascular collagen deposition in the WKY + HHcy group, the SHR group and the SHR + HHcy group increased successively, indicating that cardiac remodeling gradually increased, and HHcy aggravated cardiac remodeling was more serious in hypertensive rats. SOD decreased gradually in the four groups, while MDA was on the contrary. WKY + HHcy and SHR + HHcy groups both suppressed Nrf2 and HO-1 expression and inhibited the translocation of Nrf2 from cytoplasm to nucleus compared with their control groups, and the SHR + HHcy group had a stronger inhibitory effect. CONCLUSION: HHcy enhanced cardiac remodeling in rats by enhancing oxidative stress, suppressing the Nrf2/HO-1 pathway and Nrf2 nuclear transport, and this inhibitory effect was stronger in the context of hypertension.


Assuntos
Cardiopatias/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Hiper-Homocisteinemia/metabolismo , Hipertensão/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Remodelação Ventricular , Animais , Modelos Animais de Doenças , Cardiopatias/etiologia , Cardiopatias/patologia , Hiper-Homocisteinemia/patologia , Hipertensão/patologia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Transdução de Sinais
12.
Phytomedicine ; 81: 153410, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33285470

RESUMO

BACKGROUND: Homocysteine (Hcy) induced vascular endothelial dysfunction is known to be closely associated with oxidative stress and impaired NO system. 1,8-Dihydroxy-3-methoxy-6-methylanthracene-9,10-dione (physcion) has been known to has antioxidative and anti-inflammatory properties. PURPOSE: The purpose of the present study was to define the protective effect of physcion on Hcy-induced endothelial dysfunction and its mechanisms involved. STUDY DESIGN AND METHODS: Hyperhomocysteinemia (HHcy) rat model was induced by feeding 3% methionine. A rat thoracic aortic ring model was used to investigate the effects of physcion on Hcy-induced impairment of endothelium-dependent relaxation. Two doses, low (L, 30 mg/kg/day) and high (H, 50 mg/kg/day) of physcion were used in the present study. To construct Hcy-injured human umbilical vein endothelial cells (HUVECs) model, the cells treated with 3 mM Hcy. The effects of physcion on Hcy-induced HUVECs cytotoxicity and apoptosis were studied using MTT and flow cytometry. Confocal analysis was used to determine the levels of intracellular Ca2+. The levels of protein expression of the apoptosis-related markers Bcl-2, Bax, caspase-9/3, and Akt and endothelial nitric oxide synthase (eNOS) were evaluated by western blot. RESULTS: In the HHcy rat model, plasma levels of Hcy and malondialdehyde (MDA) were elevated (20.45 ± 2.42 vs. 4.67 ± 1.94 µM, 9.42 ± 0.48 vs. 3.47 ± 0.59 nM, p < 0.001 for both), whereas superoxide dismutase (SOD) and nitric oxide (NO) levels were decreased (77.11 ± 4.78 vs. 115.02 ± 5.63 U/ml, 44.51 ± 4.45 vs. 64.18 ± 5.34 µM, p < 0.001 and p < 0.01, respectively). However, treatment with physcion significantly reversed these changes (11.82 ± 2.02 vs. 20.45 ± 2.42 µM, 5.97 ± 0.72 vs. 9.42 ± 0.48 nM, 108.75 ± 5.65 vs. 77.11 ± 4.78 U/ml, 58.14 ± 6.02 vs. 44.51 ± 4.45 µM, p < 0.01 for all). Physcion also prevented Hcy-induced impairment of endothelium-dependent relaxation in HHcy rats (1.56 ± 0.06 vs. 15.44 ± 2.53 nM EC50 for ACh vasorelaxation, p < 0.05 vs. HHcy). In Hcy-injured HUVECs, physcion inhibited the impaired viability, apoptosis and reactive oxygen species. Hcy treatment significantly increased the protein phosphorylation levels of p38 (2.26 ± 0.20 vs. 1.00 ± 0.12, p <0.01), ERK (2.11 ± 0.21 vs. 1.00 ± 0.11, p <0.01) and JNK. Moreover, physcion reversed the Hcy-induced apoptosis related parameter changes such as decreased mitochondrial membrane potential (MMP) and Bcl-2/Bax protein ratio, and increased protein expression of caspase-9/3 in HUVECs. Furthermore, the downregulation of Ca2+, Akt, eNOS and NO caused by Hcy were recovered with physcion treatment in HUVECs. CONCLUSION: Physcion prevents Hcy-induced endothelial dysfunction by activating Ca2+- and Akt-eNOS-NO signaling pathways. This study provides the first evidence that physcion might be a candidate agent for the prevention of cardiovascular disease induced by Hcy.


Assuntos
Cálcio/metabolismo , Emodina/análogos & derivados , Endotélio Vascular/efeitos dos fármacos , Homocisteína/metabolismo , Hiper-Homocisteinemia/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Caspase 9/metabolismo , Emodina/farmacologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Hiper-Homocisteinemia/metabolismo , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Vasodilatação/efeitos dos fármacos
13.
Biochem Biophys Res Commun ; 537: 7-14, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33383564

RESUMO

Hydrogen sulfide (H2S) prevents platelet activation and neutrophils extracellular traps (NETs) formation. However, the mechanism of sodium hydrosulfide (NaHS, a donor that produces H2S) inhibits the formation of NETs in hyperhomocysteinemia (HHcy) rats has not been previously investigated. In the experiment, the expressions of HMGB1 of platelets, the expressions of TLR4, PAD4 and the phosphor-p38 of neutrophils were measured. The NETs formations, the concentration of DNA in the serum and the culture solution of cultured neutrophils which was stimulated by platelet-rich plasma (PRP) were tested. Additionally, the cellular ROS level and SOD activity were detected. The platelets were activated and the expression of HMGB1 of platelets and NETs formation, the concentration of DNA, and the expressions of TLR4, phosphor-p38 and PAD4, the ROS level were all increased while the activity of SOD decreased in the HHcy group compared to the control group. NaHS significantly inhibited the activation of platelets, the production of ROS and the formation of NETs in neutrophils, reversed the expressions of HMGB1, TLR4, phosphor-p38, PAD4 and decreased concentration of DNA which was caused by high homocysteine. Our results demonstrate that the donor of H2S inhibits NETs formation of neutrophils via the HMGB1/TLR4/p38 MAPK/ROS pathway in hyperhomocysteinemia.


Assuntos
Armadilhas Extracelulares/metabolismo , Proteína HMGB1/metabolismo , Sulfeto de Hidrogênio/farmacologia , Hiper-Homocisteinemia/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor 4 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Plaquetas/ultraestrutura , Modelos Animais de Doenças , Armadilhas Extracelulares/efeitos dos fármacos , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Fosforilação/efeitos dos fármacos , Plasma Rico em Plaquetas/metabolismo , Proteína-Arginina Desiminase do Tipo 4/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
14.
J Nutr ; 150(Suppl 1): 2524S-2531S, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33000164

RESUMO

The metabolism of methionine and cysteine in the body tissues determines the concentrations of several metabolites with various biologic activities, including homocysteine, hydrogen sulfide (H2S), taurine, and glutathione. Hyperhomocysteinemia, which is correlated with lower HDL cholesterol in blood in volunteers and animal models, has been associated with an increased risk for cardiovascular diseases. In humans, the relation between methionine intake and hyperhomocysteinemia is dependent on vitamin status (vitamins B-6 and B-12 and folic acid) and on the supply of other amino acids. However, lowering homocysteinemia by itself is not sufficient for decreasing the risk of cardiovascular disease progression. Other compounds related to methionine metabolism have recently been identified as being involved in the risk of atherosclerosis and steatohepatitis. Indeed, the metabolism of sulfur amino acids has an impact on phosphatidylcholine (PC) metabolism, and anomalies in PC synthesis due to global hypomethylation have been associated with disturbances of lipid metabolism. In addition, impairment of H2S synthesis from cysteine favors atherosclerosis and steatosis in animal models. The effects of taurine on lipid metabolism appear heterogeneous depending on the populations of volunteers studied. A decrease in the concentration of intracellular glutathione, a tripeptide involved in redox homeostasis, is implicated in the etiology of cardiovascular diseases and steatosis. Last, supplementation with betaine, a compound that allows remethylation of homocysteine to methionine, decreases basal and methionine-stimulated homocysteinemia; however, it adversely increases plasma total and LDL cholesterol. The study of these metabolites may help determine the range of optimal and safe intakes of methionine and cysteine in dietary proteins and supplements. The amino acid requirement for protein synthesis in different situations and for optimal production of intracellular compounds involved in the regulation of lipid metabolism also needs to be considered for dietary attenuation of atherosclerosis and steatosis risk.


Assuntos
Aterosclerose/etiologia , Cisteína/metabolismo , Fígado Gorduroso/etiologia , Metabolismo dos Lipídeos , Metionina/metabolismo , Estado Nutricional , Enxofre/metabolismo , Aminoácidos Sulfúricos/metabolismo , Animais , Aterosclerose/metabolismo , Betaína/metabolismo , Betaína/farmacologia , Colesterol/sangue , Proteínas na Dieta/química , Suplementos Nutricionais , Fígado Gorduroso/metabolismo , Glutationa/metabolismo , Humanos , Sulfeto de Hidrogênio/metabolismo , Hiper-Homocisteinemia/etiologia , Hiper-Homocisteinemia/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Necessidades Nutricionais , Fosfatidilcolinas/metabolismo , Compostos de Enxofre/metabolismo , Taurina/metabolismo , Taurina/farmacologia
15.
J Nutr ; 150(Suppl 1): 2538S-2547S, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33000166

RESUMO

The central position of methionine (Met) in protein metabolism indicates the importance of this essential amino acid for growth and maintenance of lean body mass. Therefore, Met might be a tempting candidate for supplementation. However, because Met is also the precursor of homocysteine (Hcy), a deficient intake of B vitamins or excessive intake of Met may result in hyperhomocysteinemia (HHcy), which is a risk factor for cardiovascular disease. This review discusses the evidence generated in preclinical and clinical studies on the importance and potentially harmful effects of Met supplementation and elaborates on potential clinical applications of supplemental Met with reference to clinical studies performed over the past 20 y. Recently acquired knowledge about the NOAEL (no observed adverse effect level) of 46.3 mg · kg-1 · d-1 and the LOAEL (lowest observed adverse effect level) of 91 mg · kg-1 · d-1 of supplemented Met will guide the design of future studies to further establish the role of Met as a potential (safe) candidate for nutritional supplementation in clinical applications.


Assuntos
Compartimentos de Líquidos Corporais/metabolismo , Doenças Cardiovasculares/etiologia , Suplementos Nutricionais , Homocisteína/metabolismo , Hiper-Homocisteinemia/etiologia , Metionina , Deficiência de Vitaminas do Complexo B/complicações , Animais , Doenças Cardiovasculares/metabolismo , Feminino , Humanos , Hiper-Homocisteinemia/metabolismo , Masculino , Metionina/efeitos adversos , Metionina/metabolismo , Metionina/farmacologia , Metionina/uso terapêutico , Proteínas/metabolismo , Complexo Vitamínico B/sangue , Deficiência de Vitaminas do Complexo B/sangue
16.
Biochem Biophys Res Commun ; 532(4): 640-646, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-32912629

RESUMO

Endothelial cells injury and pro-inflammation cytokines release are the initial steps of hyperhomocysteinemia (HHcy)-associated vascular inflammation. Pyroptosis is a newly identified pro-inflammation form of programmed cell death, causing cell lysis and IL-1ß release, and characterized by the caspases-induced cleavage of its effector molecule gasdermins (GSDMs). However, the effect of homocysteine (Hcy) on endothelial cells pyroptosis and the underlying mechanisms have not been fully defined. We have previously reported that Hcy induces vascular endothelial inflammation accompanied by the increase of high mobility group box-1 protein (HMGB1) and lysosomal cysteine protease cathepsin V in endothelial cells, and other studies have shown that HMGB1 or cathepsins are involved in activation of NLRP3 inflammasome and caspase-1. Here, we investigated the role of HMGB1 and cathepsin V in the process of Hcy-induced pyroptosis. We observed an increase in plasma IL-1ß levels in HHcy patients and mice models, cathepsin V inhibitor reduced the plasma IL-1ß levels and cleavage of GSDMD full-length into GSDMD N-terminal in the thoracic aorta of hyperhomocysteinemia mice. Using cultured HUVECs, we observed that Hcy promoted GSDMD N-terminal expression, silencing GSDMD or HMGB1 rescued Hcy-induced pyroptosis. HMGB1 also increased GSDMD N-terminal expression, and silencing cathepsin V reversed HMGB1-induced pyroptosis. HMGB1 could increase lysosome permeability, and silencing cathepsin V attenuated HMGB1-induced activation of caspase-1. In conclusion, this study has delineated a novel mechanism that HMGB1 mediated Hcy-induced endothelial cells pyroptosis partly via cathepsin V-dependent pathway.


Assuntos
Catepsinas/fisiologia , Cisteína Endopeptidases/fisiologia , Endotélio Vascular/citologia , Proteína HMGB1/fisiologia , Homocisteína/fisiologia , Piroptose , Idoso , Animais , Caspase 1/metabolismo , Linhagem Celular , Feminino , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/metabolismo , Interleucina-1beta/sangue , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteínas de Ligação a Fosfato/metabolismo , Artérias Torácicas/metabolismo
17.
Free Radic Biol Med ; 160: 552-565, 2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-32896601

RESUMO

Homocysteine (Hcy) is an amino acid involved in gene methylation. Plasma concentration of Hcy is elevated in the pathological condition hyperhomocysteinemia (HHcy), which increases the risk of disorders of the vascular, nervous and musculoskeletal systems, including chondrocyte dysfunction. The present study aimed to explore the role of Hcy in intervertebral disc degeneration (IVDD), using a range of techniques. A clinical epidemiological study showed that HHcy is an independent risk factor for human IVDD. Cell culture using rat nucleus pulposus cells showed that Hcy promotes a degenerative cell phenotype (involving increased oxidative stress and cell death by ferroptosis) which is mediated by upregulated methylation of GPX4. An in-vivo mouse 'puncture' model of IVDD showed that folic acid (which is used to treat HHcy in humans) reduced the ability of diet-induced HHcy to promote IVDD. We conclude that Hcy upregulates oxidative stress and ferroptosis in the nucleus pulposus via enhancing GPX4 methylation, and is a new contributing factor in IVDD.


Assuntos
Ferroptose , Hiper-Homocisteinemia , Núcleo Pulposo , Animais , Homocisteína/metabolismo , Hiper-Homocisteinemia/metabolismo , Metilação , Camundongos , Núcleo Pulposo/metabolismo , Estresse Oxidativo , Ratos
18.
Biomolecules ; 10(8)2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32751132

RESUMO

Elevated plasma homocysteine (Hcy) level, known as hyperhomocysteinemia (HHcy) has been linked to different systemic and neurological diseases, well-known as a risk factor for systemic atherosclerosis and cardiovascular disease (CVD) and has been identified as a risk factor for several ocular disorders, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Different mechanisms have been proposed to explain HHcy-induced visual dysfunction, including oxidative stress, upregulation of inflammatory mediators, retinal ganglion cell apoptosis, and extracellular matrix remodeling. Our previous studies using in vivo and in vitro models of HHcy have demonstrated that Hcy impairs the function of both inner and outer blood retinal barrier (BRB). Dysfunction of BRB is a hallmark of vision loss in DR and AMD. Our findings highlighted oxidative stress, ER stress, inflammation, and epigenetic modifications as possible mechanisms of HHcy-induced BRB dysfunction. In addition, we recently reported HHcy-induced brain inflammation as a mechanism of blood-brain barrier (BBB) dysfunction and pathogenesis of Alzheimer's disease (AD). Moreover, we are currently investigating the activation of glutamate receptor N-methyl-d-aspartate receptor (NMDAR) as the molecular mechanism for HHcy-induced BRB dysfunction. This review focuses on the studied effects of HHcy on BRB and the controversial role of HHcy in the pathogenesis of aging neurological diseases such as DR, AMD, and AD. We also highlight the possible mechanisms for such deleterious effects of HHcy.


Assuntos
Barreira Hematorretiniana/fisiopatologia , Hiper-Homocisteinemia/fisiopatologia , Envelhecimento , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Barreira Hematorretiniana/metabolismo , Retinopatia Diabética/etiologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/fisiopatologia , Estresse do Retículo Endoplasmático , Homocisteína/metabolismo , Humanos , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/metabolismo , Degeneração Macular/etiologia , Degeneração Macular/metabolismo , Degeneração Macular/fisiopatologia , Estresse Oxidativo
19.
Biomolecules ; 10(8)2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32722349

RESUMO

Pathological homocysteine (HCY) accumulation in the human plasma, known as hyperhomocysteinemia, exacerbates neurodegenerative diseases because, in the brain, this amino acid acts as a persistent N-methyl-d-aspartate receptor agonist. We studied the effects of 0.1-1 nM ouabain on intracellular Ca2+ signaling, mitochondrial inner membrane voltage (φmit), and cell viability in primary cultures of rat cortical neurons in glutamate and HCY neurotoxic insults. In addition, apoptosis-related protein expression and the involvement of some kinases in ouabain-mediated effects were evaluated. In short insults, HCY was less potent than glutamate as a neurotoxic agent and induced a 20% loss of φmit, whereas glutamate caused a 70% decrease of this value. Subnanomolar ouabain exhibited immediate and postponed neuroprotective effects on neurons. (1) Ouabain rapidly reduced the Ca2+ overload of neurons and loss of φmit evoked by glutamate and HCY that rescued neurons in short insults. (2) In prolonged 24 h excitotoxic insults, ouabain prevented neuronal apoptosis, triggering proteinkinase A and proteinkinase C dependent intracellular neuroprotective cascades for HCY, but not for glutamate. We, therefore, demonstrated here the role of PKC and PKA involving pathways in neuronal survival caused by ouabain in hyperhomocysteinemia, which suggests existence of different appropriate pharmacological treatment for hyperhomocysteinemia and glutamate excitotoxicity.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Neurônios/efeitos dos fármacos , Ouabaína/farmacologia , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ácido Glutâmico/farmacologia , Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/patologia , Transporte de Íons/efeitos dos fármacos , Neurônios/citologia , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Proteína Quinase C/metabolismo , Ratos Wistar
20.
Nutrients ; 12(8)2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32717800

RESUMO

Hyperhomocysteinemia (HHcy) is a risk factor for atherosclerosis through mechanisms which are still incompletely defined. One possible mechanism involves the hypomethylation of the nuclear histone proteins to favor the progression of atherosclerosis. In previous cell studies, hypomethylating stress decreased a specific epigenetic tag (the trimethylation of lysine 27 on histone H3, H3K27me3) to promote endothelial dysfunction and activation, i.e., an atherogenic phenotype. Here, we conducted a pilot study to investigate the impact of mild HHcy on vascular methylating index, atherosclerosis progression and H3K27me3 aortic content in apolipoprotein E-deficient (ApoE -/-) mice. In two different sets of experiments, male mice were fed high-fat, low in methyl donors (HFLM), or control (HF) diets for 16 (Study A) or 12 (Study B) weeks. At multiple time points, plasma was collected for (1) quantification of total homocysteine (tHcy) by high-performance liquid chromatography; or (2) the methylation index of S-adenosylmethionine to S-adenosylhomocysteine (SAM:SAH ratio) by liquid chromatography tandem-mass spectrometry; or (3) a panel of inflammatory cytokines previously implicated in atherosclerosis by a multiplex assay. At the end point, aortas were collected and used to assess (1) the methylating index (SAM:SAH ratio); (2) the volume of aortic atherosclerotic plaque assessed by high field magnetic resonance imaging; and (3) the vascular content of H3K27me3 by immunohistochemistry. The results showed that, in both studies, HFLM-fed mice, but not those mice fed control diets, accumulated mildly elevated tHcy plasmatic concentrations. However, the pattern of changes in the inflammatory cytokines did not support a major difference in systemic inflammation between these groups. Accordingly, in both studies, no significant differences were detected for the aortic methylating index, plaque burden, and H3K27me3 vascular content between HF and HFLM-fed mice. Surprisingly however, a decreased plasma SAM: SAH was also observed, suggesting that the plasma compartment does not always reflect the vascular concentrations of these two metabolites, at least in this model. Mild HHcy in vivo was not be sufficient to induce vascular hypomethylating stress or the progression of atherosclerosis, suggesting that only higher accumulations of plasma tHcy will exhibit vascular toxicity and promote specific epigenetic dysregulation.


Assuntos
Aterosclerose , Dieta/efeitos adversos , Progressão da Doença , Histonas/metabolismo , Hiper-Homocisteinemia/metabolismo , Animais , Aorta/diagnóstico por imagem , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/diagnóstico por imagem , Aterosclerose/genética , Citocinas , Metilação de DNA , Epigênese Genética , Hiper-Homocisteinemia/genética , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Knockout , Projetos Piloto , Placa Aterosclerótica , S-Adenosilmetionina/metabolismo
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