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1.
Biochemistry (Mosc) ; 85(2): 213-223, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32093597

RESUMO

Prenatal hyperhomocysteinemia (PHHC) in pregnant rats was induced by chronic L-methionine loading, resulting in a significant increase in the L-homocysteine content both in the mothers' blood and blood and brain of fetuses. Significant decrease in the weight of the placenta, fetus, and fetal brain was detected by the morphometric studies on day 20 of pregnancy. PHHC also activated maternal immune system due to the increase in the content of proinflammatory interleukin-1ß in the rat blood and fetal part of the placenta. PHHC elevated the levels of the brain-derived neurotrophic factor (BDNF, 29 kDa) and nerve growth factor (NGF, 31 kDa) precursors in the placenta and the content of the BDNF isoform (29 kDa) in the fetal brain. The content of neuregulin 1 (NRG1) decreased in the placenta and increased in the fetal brain on day 20 of embryonic development. An increase in the caspase-3 activity was detected in the brains of fetuses subjected to PHHC. It was suggested that changes in the processing of neurotrophins induced by PPHC, oxidative stress, and inflammatory processes initiated by it, as well as apoptosis, play an important role in the development of brain disorders in the offspring.


Assuntos
Encéfalo/metabolismo , Hiper-Homocisteinemia/metabolismo , Fatores de Crescimento Neural/metabolismo , Sistema Nervoso/química , Placenta/metabolismo , Animais , Encéfalo/embriologia , Citocinas/metabolismo , Feminino , Hiper-Homocisteinemia/induzido quimicamente , Hiper-Homocisteinemia/patologia , Metionina/administração & dosagem , Sistema Nervoso/embriologia , Sistema Nervoso/metabolismo , Gravidez , Ratos , Ratos Wistar
2.
Postgrad Med ; 132(2): 109-125, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31615302

RESUMO

Diabetes mellitus and cardiovascular diseases are part of the metabolic syndrome and share similar risk factors, including obesity, arterial hypertension, and dyslipidemia. Atherosclerosis and insulin resistance contribute to the development of the diseases, and subclinical inflammation is observed in both conditions. There are many proofs about the connection between epigenetic factors and different diseases, including diabetes and cardiovascular diseases. Interestingly, recent studies show that at least some anti-diabetic drugs, as well as blockers of the renin-angiotensin-aldosterone system (RAAS), exert epigenetic effects aside from their hypoglycemic and antihypertensive functions, respectively. More studies are needed to discover other positive effects of the medications established through epigenetic mechanisms and to find out more about the epigenetic role in the development of diabetes mellitus and cardiovascular diseases.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Epigênese Genética , Alarminas/metabolismo , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Cromatina/metabolismo , Metilação de DNA/fisiologia , Diabetes Mellitus Tipo 2/epidemiologia , Endotélio Vascular/metabolismo , Armadilhas Extracelulares/metabolismo , Microbioma Gastrointestinal/genética , Histonas/metabolismo , Homocisteína/metabolismo , Humanos , Hiper-Homocisteinemia/epidemiologia , Hiper-Homocisteinemia/metabolismo , Hipertensão/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/genética , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , RNA não Traduzido , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Fatores de Risco
3.
Int J Mol Sci ; 20(24)2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31835644

RESUMO

Hyperhomocysteinemia (hHcy) is regarded as an independent and strong risk factor for cerebrovascular diseases, stroke, and dementias. The hippocampus has a crucial role in spatial navigation and memory processes and is being constantly studied for neurodegenerative disorders. We used a moderate methionine (Met) diet at a dose of 2 g/kg of animal weight/day in duration of four weeks to induce mild hHcy in adult male Wistar rats. A novel approach has been used to explore the hippocampal metabolic changes using proton magnetic resonance spectroscopy (1H MRS), involving a 7T MR scanner in combination with histochemical and immunofluorescence analysis. We found alterations in the metabolic profile, as well as remarkable histo-morphological changes such as an increase of hippocampal volume, alterations in number and morphology of astrocytes, neurons, and their processes in the selective vulnerable brain area of animals treated with a Met-enriched diet. Results of both methodologies suggest that the mild hHcy induced by Met-enriched diet alters volume, histo-morphological pattern, and metabolic profile of hippocampal brain area, which might eventually endorse the neurodegenerative processes.


Assuntos
Hipocampo/diagnóstico por imagem , Hiper-Homocisteinemia/diagnóstico por imagem , Metaboloma/efeitos dos fármacos , Metionina/efeitos adversos , Animais , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hiper-Homocisteinemia/induzido quimicamente , Hiper-Homocisteinemia/metabolismo , Masculino , Tamanho do Órgão/efeitos dos fármacos , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Ratos Wistar
4.
Georgian Med News ; (295): 127-132, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31804214

RESUMO

The effect of experimental HHCy on the processes of transsulfuration of sulfur amino acids in the tissues of heart and brain, the levels of HCy, cysteine, H2S in blood serum of experimental animals with hyperthyroidism and hypothyroidism has been studied in the research. The experiment was performed on white male rats with simulated HHCy, hyper- and hypothyroidism, HHCy with different thyroid function. In the heart, the activity of cysteine aminotransferase (CAT), γ-glutamate cysteine ligase (γ-GCL), sulfite oxidase (SO) was determined. In the brain, the activity of cystathionine-ß-synthase (CBS), cysteine ​​dioxygenase (CDO), GCL and SO was determined. In serum the total level of HCy, cysteine ​​and H2S was evaluated. HHCy caused inhibition of transsulfuration pathway of cysteine in the brain that was evidenced by decreased activity of CBS and CAT in heart that caused increase in the level of HCy and cysteine ​​as well as decrease in the level of H2S in blood serum. Hyperthyroidism causes increased activity of CBS in brain and of CAT in heart. Hyperthyroidism leads to decrease in the level of HCy in blood serum compare to the control, as well as increase in the level of H2S compare to the group of animals with HHCy. Hypothyroidism causes inhibition of cysteine ​​metabolism, decrease in of HCy and cysteine levels. In cases of HHCy simulated by administration of thiolactone-HCy the activity of CBS and SO in the brain of rats, and CAT in the heart is increased. Hyperthyroidism causes increase of the activity of the CBS, CDO, and SO in the brain, as well as CAT in the heart. At the same time, the simultaneous administration of L-tyroxysin into the animals with HHCy leads to increase in the enzyme activity of CBS, CDO, γ-GCL and SO in the brain of the animals and increase of CAT and γ-GCL in the myocardium. Hypothyroidism in the brain of animals causes a decrease in the activity of the CBS, CAT and SO, and at the same time, the activity of SO only decreases in the myocardium of animals. An increase in the level of HCy and cysteine, a decrease in the level of H2S in the blood of experimental animals during hypothyroidism, as well as inhibition of the transsulfuration enzyme activity in the brain and heart are significant markers of the development of cardiovascular pathologies and mortality associated with hypothyroidism.


Assuntos
Aminoácidos , Sulfeto de Hidrogênio , Hiper-Homocisteinemia , Aminoácidos/metabolismo , Animais , Encéfalo/metabolismo , Homocisteína , Sulfeto de Hidrogênio/metabolismo , Hiper-Homocisteinemia/metabolismo , Masculino , Miocárdio/metabolismo , Enxofre
5.
Oxid Med Cell Longev ; 2019: 7629673, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885816

RESUMO

While the role of hyperhomocysteinemia in cardiovascular pathogenesis continuously draws attention, deficiency of hydrogen sulfide (H2S) has been growingly implicated in cardiovascular diseases. Generation of H2S is closely associated with the metabolism of homocysteine via key enzymes such as cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CSE). The level of homocysteine and H2S is regulated by each other. Metabolic switch in the activity of CBS and CSE may occur with a resultant operating preference change of these enzymes in homocysteine and H2S metabolism. This paper presented an overview regarding (1) linkage between the metabolism of homocysteine and H2S, (2) mutual regulation of homocysteine and H2S, (3) imbalance of homocysteine and H2S in cardiovascular disorders, (4) mechanisms underlying the protective effect of H2S against homocysteine-induced vascular injury, and (5) the current status of homocysteine-lowering and H2S-based therapies for cardiovascular disease. The metabolic imbalance of homocysteine and H2S renders H2S/homocysteine ratio a potentially reliable biomarker for cardiovascular disease and development of drugs or interventions targeting the interplay between homocysteine and H2S to maintain the endogenous balance of these two molecules may hold an even bigger promise for management of vascular disorders than targeting homocysteine or H2S alone.


Assuntos
Vasos Sanguíneos/patologia , Homocisteína/metabolismo , Sulfeto de Hidrogênio/metabolismo , Hiper-Homocisteinemia/metabolismo , Lesões do Sistema Vascular/metabolismo , Animais , Vasos Sanguíneos/metabolismo , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Humanos , Sulfeto de Hidrogênio/uso terapêutico , Hiper-Homocisteinemia/terapia , Transdução de Sinais , Lesões do Sistema Vascular/terapia
6.
Georgian Med News ; (292-293): 92-95, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31560671

RESUMO

The aim of the research was the experimental study of one of the possible mechanisms performing contractile activity of arterioles in hyperhomocysteinemic animals. Moderate hyperhomocysteinemia was induced in male rats (120-160 g., n=12) by adding L-methionine to the drinking water during 4 weeks. Control animals (n=12) administered the normal water without limitation. The experiments were performed on the isolated arterioles of first line of the rat's soft muscle (Gracilis). Reactions were studied on normal and deendothelized segments of arterioles. Increased homocysteine has been found to be associated with noradrenaline-induced vascular constriction and decreased endothelium-dependent dilatation in the arterioles of the muscle. It has been suggested that the increased reactivity of blood to noradrenaline in animals in the group of hyperhomocysteinemia must have been due to impaired endothelial nitric oxide synthesis.


Assuntos
Arteríolas/fisiopatologia , Hiper-Homocisteinemia/fisiopatologia , Óxido Nítrico/fisiologia , Animais , Arteríolas/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Hiper-Homocisteinemia/metabolismo , Masculino , Metionina , Óxido Nítrico/metabolismo , Norepinefrina , Ratos
7.
Acta Histochem ; 121(7): 823-832, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377002

RESUMO

OBJECTIVE: Numerous studies have shown that a methionine-rich diet induces hyperhomocysteinemia (Hhcy), a risk factor for cardiovascular diseases. The objective of the present study was to determine the involvement of Hhcy in cardiac remodeling in the sand rat Psammomys obesus. MATERIALS AND METHODS: An experimental Hhcy was induced, in the sand rat Psammomys obesus, by intraperitoneal injection of 300 mg/kg of body weight/day of methionine for 1 month. The impact of Hhcy on the cellular and matricial structures of the myocardium was analyzed with histological techniques (Masson trichrome and Sirius red staining). Immunohistochemistry allowed us to analyze several factors involved in myocardial remodeling, such as fibrillar collagen I and III, metalloproteases (MMP-2 and -9) and their inhibitors (TIMP-1 and -2), TGF-ß1 and activated caspase 3. RESULTS: Our results show that Hhcy induced by an excess of methionine causes, in the myocardium of Psammomys obesus, a significant accumulation of fibrillar collagens I and III at the interstitial and perivascular scales, indicating the appearance of fibrosis, which is associated with an immuno-expression increase of TGF-ß1, MMP-9 and TIMP-2 and an immuno-expression decrease of MMP-2 and TIMP-1. Also, Hhcy induces apoptosis of some cardiomyocytes and cardiac fibroblasts by increasing of activated caspase 3 expression. These results highlight a remodeling of cardiac tissue in hyperhomocysteinemic Psammomys obesus.


Assuntos
Apoptose , Cardiomiopatias , Hiper-Homocisteinemia , Proteínas Musculares/biossíntese , Miocárdio , Miócitos Cardíacos , Animais , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Gerbillinae , Hiper-Homocisteinemia/induzido quimicamente , Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/patologia , Metionina/efeitos adversos , Metionina/farmacologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia
8.
Kidney Blood Press Res ; 44(4): 513-532, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31266025

RESUMO

Elevated homocysteine (Hcy) levels have been shown to activate nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome leading to podocyte dysfunction and glomerular injury. However, it remains unclear how this inflammasome activation in podocytes is a therapeutic target for reversal of glomerular injury and ultimate sclerosis. The present study tested whether inhibition of Rac1 GTPase activity suppresses NLRP3 inflammation activation and thereby blocks podocyte injury induced by elevated Hcy. In cultured podocytes, we found that L-Hcy (the active Hcy form) stimulated the NLRP3 inflammasome formation, as shown by increased colocalization of NLRP3 with apoptosis-associated speck-like protein (ASC) or caspase-1, which was accompanied by increased interleukin-1ß production and caspase-1 activity, indicating NLRP3 inflammasome activation. Rac1 activator, uridine triphosphate (UTP), mimicked L-Hcy-induced NLRP3 inflammasome activation, while Rac1 inhibitor NSC23766 blocked it. This Rac1 inhibition also prevented L-Hcy-induced podocyte dysfunction. All these effects were shown to be mediated via lipid raft redox signaling platforms with nicotinamide adenine dinucleotide phosphate oxidase subunits and consequent O2- production. In animal studies, hyperhomocysteinemia (hHcy) induced by folate-free diet was shown to induce NLRP3 inflammasome formation and activation in glomeruli, which was also mimicked by UTP and inhibited by NSC23766 to a comparable level seen in Nlrp3 gene knockout mice. These results together suggest that Rac1 inhibition protects the kidney from hHcy-induced podocyte injury and glomerular sclerosis due to its action to suppress NLRP3 inflammasome activation in podocytes.


Assuntos
GTP Fosfo-Hidrolases/antagonistas & inibidores , Hiper-Homocisteinemia/metabolismo , Inflamassomos/metabolismo , Glomérulos Renais/patologia , Podócitos/patologia , Animais , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Humanos , Hiper-Homocisteinemia/complicações , Inflamassomos/química , Inflamassomos/efeitos dos fármacos , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Podócitos/efeitos dos fármacos , Substâncias Protetoras , Esclerose/prevenção & controle , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores
9.
Int J Mol Sci ; 20(13)2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31252610

RESUMO

Hyperhomocysteinemia (HHcy) exerts a wide range of biological effects and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. Although mechanisms of HHcy toxicity are not fully uncovered, there has been a significant progress in their understanding. The picture emerging from the studies of homocysteine (Hcy) metabolism and pathophysiology is a complex one, as Hcy and its metabolites affect biomolecules and processes in a tissue- and sex-specific manner. Because of their connection to one carbon metabolism and editing mechanisms in protein biosynthesis, Hcy and its metabolites impair epigenetic control of gene expression mediated by DNA methylation, histone modifications, and non-coding RNA, which underlies the pathology of human disease. In this review we summarize the recent evidence showing that epigenetic dysregulation of gene expression, mediated by changes in DNA methylation and histone N-homocysteinylation, is a pathogenic consequence of HHcy in many human diseases. These findings provide new insights into the mechanisms of human disease induced by Hcy and its metabolites, and suggest therapeutic targets for the prevention and/or treatment.


Assuntos
Epigênese Genética , Hiper-Homocisteinemia/genética , Animais , Metilação de DNA , Código das Histonas , Homocisteína/metabolismo , Humanos , Hiper-Homocisteinemia/metabolismo , RNA não Traduzido/genética
10.
Artigo em Inglês | MEDLINE | ID: mdl-31202182

RESUMO

The multifactorial nature of Late Onset Alzheimer's Disease (LOAD), the AD form of major relevance on epidemiological and social aspects, has driven the original investigation by LC-MS and top-down proteomics approach of the protein repertoire of the brain tissue of TgCRND8 model mice fed with a diet deficient in B vitamins. The analysis of the acid-soluble fraction of brain tissue homogenates identified a list of proteins and peptides, proteoforms and PTMs. In order to disclose possible modulations, their relative quantification in wild type and AD model mice under both B vitamin deficient and control diets was performed. The levels of metallothionein III, guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 and brain acid soluble protein 1 showed statistically significant alterations depending on genotype, diet or both effects, respectively. Particularly, metallothionein III exhibited increased levels in TgCRND8 mice under B vitamin deficient diet with respect to wild type mice under both diets. Brain acid soluble protein 1 showed the opposite, revealing decreased levels in all diet groups of AD model mice with respect to wild type mice in control diet. Lower levels of brain acid soluble protein 1 were also observed in wild type mice under deficiency of B vitamins. These results, besides contributing to increase the knowledge of AD at molecular level, give new suggestions for deeply investigating metallothionein III and brain acid soluble protein 1 in AD.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Hiper-Homocisteinemia/metabolismo , Proteoma/metabolismo , Complexo Vitamínico B/análise , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Química Encefálica , Proteínas de Ligação a Calmodulina/genética , Proteínas de Ligação a Calmodulina/metabolismo , Cromatografia Líquida , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Hiper-Homocisteinemia/etiologia , Hiper-Homocisteinemia/genética , Masculino , Espectrometria de Massas , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteoma/química , Proteoma/genética , Complexo Vitamínico B/metabolismo
11.
Cell Mol Neurobiol ; 39(5): 687-700, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30949917

RESUMO

Homocysteine (HCY) has been linked to oxidative stress and varied metabolic changes that are dependent on its concentration and affected tissues. In the present study we evaluate parameters of energy metabolism [succinate dehydrogenase (SDH), complex II and IV (cytochrome c oxidase), and ATP levels] and oxidative stress [DCFH oxidation, nitrite levels, antioxidant enzymes and lipid, protein and DNA damages, as well as nuclear factor erythroid 2-related (Nrf2) protein abundance] in amygdala and prefrontal cortex of HCY-treated rats. Wistar male rats were treated with a subcutaneous injection of HCY (0.03 µmol/g of body weight) from the 30th to 60th post-natal day, twice a day, to induce mild hyperhomocysteinemia (HHCY). The rats were euthanatized without anesthesia at 12 h after the last injection, and amygdala and prefrontal cortex were dissected for biochemical analyses. In the amygdala, mild HHCY increased activities of SDH and complex II and decreased complex IV and ATP level, as well as increased antioxidant enzymes activities (glutathione peroxidase and superoxide dismutase), nitrite levels, DNA damage, and Nrf 2 protein abundance. In the prefrontal cortex, mild HHCY did not alter energy metabolism, but increased glutathione peroxidase, catalase and DNA damage. Other analyzed parameters were not altered by HCY-treatment. Our findings suggested that chronic mild HHCY changes each brain structure, particularly and specifically. These changes may be associated with the mechanisms by which chronic mild HHCY has been linked to the risk factor of fear, mood disorders and depression, as well as in neurodegenerative diseases.


Assuntos
Encéfalo/metabolismo , Encéfalo/patologia , Dano ao DNA , Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Tonsila do Cerebelo/enzimologia , Tonsila do Cerebelo/patologia , Animais , Antioxidantes/metabolismo , Núcleo Celular/metabolismo , Doença Crônica , Metabolismo Energético , Masculino , Modelos Biológicos , Córtex Pré-Frontal/enzimologia , Córtex Pré-Frontal/patologia , Ratos Wistar
12.
Redox Biol ; 24: 101199, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31026769

RESUMO

Hyperhomocysteinemia (Hhcy), or increased levels of the excitatory amino acid homocysteine (Hcy), is implicated in glaucoma, a disease characterized by increased oxidative stress and loss of retinal ganglion cells (RGCs). Whether Hhcy is causative or merely a biomarker for RGC loss in glaucoma is unknown. Here we analyzed the role of NRF2, a master regulator of the antioxidant response, in Hhcy-induced RGC death in vivo and in vitro. By crossing Nrf2-/- mice and two mouse models of chronic Hhcy (Cbs+/- and Mthfr+/- mice), we generated Cbs+/-Nrf2-/- and Mthfr+/-Nrf2-/- mice and performed systematic analysis of retinal architecture and visual acuity followed by assessment of retinal morphometry and gliosis. We observed significant reduction of inner retinal layer thickness and reduced visual acuity in Hhcy mice lacking NRF2. These functional deficits were accompanied by fewer RGCs and increased gliosis. Given the key role of Müller glial cells in maintaining RGCs, we established an ex-vivo indirect co-culture system using primary RGCs and Müller cells. Hhcy-exposure decreased RGC viability, which was abrogated when cells were indirectly cultured with wildtype (WT) Müller cells, but not with Nrf2-/- Müller cells. Exposure of WT Müller cells to Hhcy yielded a robust mitochondrial and glycolytic response, which was not observed in Nrf2-/- Müller cells. Taken together, the in vivo and in vitro data suggest that deleterious effects of Hhcy on RGCs are likely dependent upon the health of retinal glial cells and the availability of an intact retinal antioxidant response mechanism.


Assuntos
Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/patologia , Células Ganglionares da Retina/metabolismo , Animais , Biomarcadores , Contagem de Células , Técnicas de Cocultura , Modelos Animais de Doenças , Eletrorretinografia , Células Ependimogliais/metabolismo , Células Ependimogliais/patologia , Glicólise , Hiper-Homocisteinemia/genética , Pressão Intraocular , Camundongos , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Retina/diagnóstico por imagem , Retina/metabolismo , Células Ganglionares da Retina/patologia
13.
Int J Dev Neurosci ; 75: 1-12, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30946975

RESUMO

Enhanced levels of homocysteine during pregnancy induce oxidative stress and contribute to many age-related diseases. In this study, we analyzed age-dependent synaptic modifications in developing neuromuscular synapses of rats with prenatal hyperhomocysteinemia (hHCY). One of the main findings indicate that the intensity and the timing of transmitter release in synapses of neonatal (P6 and P10) hHCY rats acquired features of matured synaptic transmission of adult rats. The amplitude and frequency of miniature end-plate currents (MEPCs) and evoked transmitter release were higher in neonatal hHCY animals compared to the control group. Analysis of the kinetics of neurotransmitter release demonstrated more synchronized release in neonatal rats with hHCY. At the same time lower release probability was observed in adults with hHCY. Spontaneous transmitter release in neonates with hHCY was inhibited by hydrogen peroxide (H2O2) whereas in controls this oxidant was effective only in adult animals indicating a higher susceptibility of motor nerve terminals to oxidative stress. The morphology and the intensity of endocytosis of synaptic vesicles in motor nerve endings was assessed using the fluorescence dye FM 1-43. Adult-like synapses were found in neonates with hHCY which were characterized by a larger area of presynaptic terminals compared to controls. No difference in the intensity of FM 1-43 fluorescence was observed between two groups of animals. Prenatal hHCY resulted in reduced muscle strength assessed by the Paw Grip Endurance test. Using biochemical assays we found an increased level of H2O2 and lipid peroxidation products in the diaphragm muscles of hHCY rats. This was associated with a lowered activity of superoxide dismutase and glutathione peroxidase. Our data indicate that prenatal hHCY induces oxidative stress and apparent faster functional and morphological "maturation" of motor synapses. Our results uncover synaptic mechanisms of disrupted muscle function observed in hHCY conditions which may contribute to the pathogenesis of motor neuronal diseases associated with enhanced level of homocysteine.


Assuntos
Hiper-Homocisteinemia/metabolismo , Músculo Esquelético/metabolismo , Junção Neuromuscular/fisiologia , Estresse Oxidativo/fisiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Transmissão Sináptica/fisiologia , Animais , Feminino , Peróxido de Hidrogênio/farmacologia , Peroxidação de Lipídeos/fisiologia , Neurônios Motores/metabolismo , Força Muscular/fisiologia , Junção Neuromuscular/efeitos dos fármacos , Oxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Transmissão Sináptica/efeitos dos fármacos
14.
Neurobiol Dis ; 127: 287-302, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30885791

RESUMO

Hyperhomocysteinemia has been implicated in several neurodegenerative disorders including ischemic stroke. However, the pathological consequences of ischemic insult in individuals predisposed to hyperhomocysteinemia and the associated etiology are unknown. In this study, we evaluated the outcome of transient ischemic stroke in a rodent model of hyperhomocysteinemia, developed by subcutaneous implantation of osmotic pumps containing L-homocysteine into male Wistar rats. Our findings show a 42.3% mortality rate in hyperhomocysteinemic rats as compared to 7.7% in control rats. Magnetic resonance imaging of the brain in the surviving rats shows that mild hyperhomocysteinemia leads to exacerbation of ischemic injury within 24 h, which remains elevated over time. Behavioral studies further demonstrate significant deficit in sensorimotor functions in hyperhomocysteinemic rats compared to control rats. Using pharmacological inhibitors targeting the NMDAR subtypes, the study further demonstrates that inhibition of GluN2A-containing NMDARs significantly reduces ischemic brain damage in hyperhomocysteinemic rats but not in control rats, indicating that hyperhomocysteinemia-mediated exacerbation of ischemic brain injury involves GluN2A-NMDAR signaling. Complementary studies in GluN2A-knockout mice show that in the absence of GluN2A-NMDARs, hyperhomocysteinemia-associated exacerbation of ischemic brain injury is blocked, confirming that GluN2A-NMDAR activation is a critical determinant of the severity of ischemic damage under hyperhomocysteinemic conditions. Furthermore, at the molecular level we observe GluN2A-NMDAR dependent sustained increase in ERK MAPK phosphorylation under hyperhomocysteinemic condition that has been shown to be involved in homocysteine-induced neurotoxicity. Taken together, the findings show that hyperhomocysteinemia triggers a unique signaling pathway that in conjunction with ischemia-induced pathways enhance the pathology of stroke under hyperhomocysteinemic conditions.


Assuntos
Isquemia Encefálica/metabolismo , Encéfalo/metabolismo , Hiper-Homocisteinemia/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Comportamento Animal/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Isquemia Encefálica/complicações , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Progressão da Doença , Homocisteína/sangue , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/diagnóstico por imagem , Hiper-Homocisteinemia/patologia , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Knockout , Atividade Motora/fisiologia , Neurônios/metabolismo , Neurônios/patologia , Fosforilação , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores de N-Metil-D-Aspartato/genética , Teste de Desempenho do Rota-Rod , Índice de Gravidade de Doença , Transdução de Sinais/fisiologia
15.
Am J Physiol Gastrointest Liver Physiol ; 316(4): G527-G538, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30789748

RESUMO

Hepatic steatosis is the beginning phase of nonalcoholic fatty liver disease, and hyperhomocysteinemia (HHcy) is a significant risk factor. Soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids, attenuating their cardiovascular protective effects. However, the involvement of sEH in HHcy-induced hepatic steatosis is unknown. The current study aimed to explore the role of sEH in HHcy-induced lipid disorder. We fed 6-wk-old male mice a chow diet or 2% (wt/wt) high-metnionine diet for 8 wk to establish the HHcy model. A high level of homocysteine induced lipid accumulation in vivo and in vitro, which was concomitant with the increased activity and expression of sEH. Treatment with a highly selective specific sEH inhibitor (0.8 mg·kg-1·day-1 for the animal model and 1 µM for cells) prevented HHcy-induced lipid accumulation in vivo and in vitro. Inhibition of sEH activated the peroxisome proliferator-activated receptor-α (PPAR-α), as evidenced by elevated ß-oxidation of fatty acids and the expression of PPAR-α target genes in HHcy-induced hepatic steatosis. In primary cultured hepatocytes, the effect of sEH inhibition on PPAR-α activation was further confirmed by a marked increase in PPAR-response element luciferase activity, which was reversed by knock down of PPAR-α. Of note, 11,12-EET ligand dependently activated PPAR-α. Thus increased sEH activity is a key determinant in the pathogenesis of HHcy-induced hepatic steatosis, and sEH inhibition could be an effective treatment for HHcy-induced hepatic steatosis. NEW & NOTEWORTHY In the current study, we demonstrated that upregulation of soluble epoxide hydrolase (sEH) is involved in the hyperhomocysteinemia (HHcy)-caused hepatic steatosis in an HHcy mouse model and in murine primary hepatocytes. Improving hepatic steatosis in HHcy mice by pharmacological inhibition of sEH to activate peroxisome proliferator-activated receptor-α was ligand dependent, and sEH could be a potential therapeutic target for the treatment of nonalcoholic fatty liver disease.


Assuntos
Inibidores Enzimáticos/farmacocinética , Epóxido Hidrolases , Ácidos Graxos/metabolismo , Fígado Gorduroso , Hiper-Homocisteinemia , PPAR alfa/metabolismo , Animais , Modelos Animais de Doenças , Descoberta de Drogas , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/metabolismo , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/enzimologia , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/metabolismo , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Regulação para Cima
16.
Am J Physiol Heart Circ Physiol ; 316(5): H1039-H1046, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30767669

RESUMO

Endothelial inflammation plays an important role in hyperhomocysteinemia (HHcy)-associated vascular diseases. High mobility group box 1 (HMGB1) is a pro-inflammatory danger molecule produced by endothelial cells. However, whether HMGB1 is involved in vascular endothelial inflammation of HHcy is poorly understood. Neuropilin-1 (NRP1) mediates inflammatory response and activates mitogen-activated protein kinases (MAPKs) pathway that has been reported to be involved in regulation of HMGB1. The aim of this study was to determine the alteration of HMGB1 in HHcy, and the role of NRP1 in regulation of endothelial HMGB1 under high homocysteine (Hcy) condition. In the present study, we first observed that the plasma level of HMGB1 was elevated in HHcy patients and an experimental rat model, and increased HMGB1 was also observed in the thoracic aorta of an HHcy rat model. HMGB1 was induced by Hcy accompanied with upregulated NRP1 in vascular endothelial cells. Overexpression of NRP1 promoted expression and secretion of HMGB1 and endothelial inflammation; knockdown of NRP1 inhibited HMGB1 and endothelial inflammation induced by Hcy, which partially regulated through p38 MAPK pathway. Furthermore, NRP1 inhibitor ATWLPPR reduced plasma HMGB1 level and expression of HMGB1 in the thoracic aorta of HHcy rats. In conclusion, our data suggested that Hcy requires NRP1 to regulate expression and secretion of HMGB1. The present study provides the evidence for inhibition of NRP1 and HMGB1 to be the novel therapeutic targets of vascular endothelial inflammation in HHcy in the future. NEW & NOTEWORTHY This study shows for the first time to our knowledge that the plasma level of high mobility group box 1 (HMGB1) is elevated in hyperhomocysteinemia (HHcy) patients, and homocysteine promotes expression and secretion of HMGB1 partially regulated by neuropilin-1 in endothelial cells, which is involved in endothelial inflammation. Most importantly, these new findings will provide a potential therapeutic strategy for vascular endothelial inflammation in HHcy.


Assuntos
Proteína HMGB1/metabolismo , Homocisteína/sangue , Células Endoteliais da Veia Umbilical Humana/metabolismo , Hiper-Homocisteinemia/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Neuropilina-1/metabolismo , Adulto , Animais , Biomarcadores/sangue , Estudos de Casos e Controles , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/genética , Inflamação/sangue , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Neuropilina-1/genética , Ratos Sprague-Dawley , Transdução de Sinais , Células THP-1 , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Int J Mol Sci ; 20(4)2019 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-30781581

RESUMO

Homocysteine (Hcy) is a sulfur-containing non-proteinogenic amino acid formed during the metabolism of the essential amino acid methionine. Hcy is considered a risk factor for atherosclerosis and cardiovascular disease (CVD), but the molecular basis of these associations remains elusive. The impairment of endothelial function, a key initial event in the setting of atherosclerosis and CVD, is recurrently observed in hyperhomocysteinemia (HHcy). Various observations may explain the vascular toxicity associated with HHcy. For instance, Hcy interferes with the production of nitric oxide (NO), a gaseous master regulator of endothelial homeostasis. Moreover, Hcy deregulates the signaling pathways associated with another essential endothelial gasotransmitter: hydrogen sulfide. Hcy also mediates the loss of critical endothelial antioxidant systems and increases the intracellular concentration of reactive oxygen species (ROS) yielding oxidative stress. ROS disturb lipoprotein metabolism, contributing to the growth of atherosclerotic vascular lesions. Moreover, excess Hcy maybe be indirectly incorporated into proteins, a process referred to as protein N-homocysteinylation, inducing vascular damage. Lastly, cellular hypomethylation caused by build-up of S-adenosylhomocysteine (AdoHcy) also contributes to the molecular basis of Hcy-induced vascular toxicity, a mechanism that has merited our attention in particular. AdoHcy is the metabolic precursor of Hcy, which accumulates in the setting of HHcy and is a negative regulator of most cell methyltransferases. In this review, we examine the biosynthesis and catabolism of Hcy and critically revise recent findings linking disruption of this metabolism and endothelial dysfunction, emphasizing the impact of HHcy on endothelial cell methylation status.


Assuntos
Aterosclerose/metabolismo , Doenças Cardiovasculares/metabolismo , Homocisteína/metabolismo , Hiper-Homocisteinemia/metabolismo , Aterosclerose/patologia , Doenças Cardiovasculares/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Homocisteína/toxicidade , Humanos , Sulfeto de Hidrogênio/metabolismo , Hiper-Homocisteinemia/patologia , Metionina/metabolismo , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , S-Adenosil-Homocisteína/metabolismo
18.
Nutrients ; 11(2)2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30781775

RESUMO

Patients affected by chronic kidney disease (CKD) or end-stage renal disease (ESRD) experience a huge cardiovascular risk and cardiovascular events represent the leading causes of death. Since traditional risk factors cannot fully explain such increased cardiovascular risk, interest in non-traditional risk factors, such as hyperhomocysteinemia and folic acid and vitamin B12 metabolism impairment, is growing. Although elevated homocysteine blood levels are often seen in patients with CKD and ESRD, whether hyperhomocysteinemia represents a reliable cardiovascular and mortality risk marker or a therapeutic target in this population is still unclear. In addition, folic acid and vitamin B12 could not only be mere cofactors in the homocysteine metabolism; they may have a direct action in determining tissue damage and cardiovascular risk. The purpose of this review was to highlight homocysteine, folic acid and vitamin B12 metabolism impairment in CKD and ESRD and to summarize available evidences on hyperhomocysteinemia, folic acid and vitamin B12 as cardiovascular risk markers, therapeutic target and risk factors for CKD progression.


Assuntos
Ácido Fólico/administração & dosagem , Falência Renal Crônica/complicações , Vitamina B 12/administração & dosagem , Biomarcadores , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/metabolismo , Ácido Fólico/metabolismo , Homocisteína/metabolismo , Humanos , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/metabolismo , Falência Renal Crônica/genética , Fatores de Risco , Vitamina B 12/metabolismo
19.
Exp Mol Med ; 51(2): 1-13, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30804341

RESUMO

Hyperhomocysteinemia/Homocysteinuria is characterized by an increased level of toxic homocysteine in the plasma. The plasma concentration of homocysteine is 5-15 µmol/L in healthy individuals, while in hyperhomocysteinemic patients, it can be as high as 500 µmol/L. While increased homocysteine levels can cause symptoms such as osteoporosis and eye lens dislocation, high homocysteine levels are most closely associated with cardiovascular complications. Recent advances have shown that increased plasma Hcy is also a fundamental cause of neurodegenerative diseases (including Alzheimer's disease, Parkinson's disease, and dementia), diabetes, Down syndrome, and megaloblastic anemia, among others. In recent years, increased plasma homocysteine has also been shown to be closely related to cancer. In this review, we discuss the relation between elevated plasma Hcy levels and cancer, and we conclude that disturbed homocysteine metabolism is associated with cancer. Future clinical perspectives are also discussed.


Assuntos
Suscetibilidade a Doenças , Homocisteína/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Alelos , Animais , Cistationina beta-Sintase/genética , Cistationina beta-Sintase/metabolismo , Ácido Fólico/sangue , Ácido Fólico/metabolismo , Predisposição Genética para Doença , Homocisteína/sangue , Humanos , Sulfeto de Hidrogênio/metabolismo , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/metabolismo , Redes e Vias Metabólicas , Neoplasias/patologia , Polimorfismo Genético , Fatores de Risco , Enxofre/metabolismo , Tromboembolia/etiologia , Tromboembolia/metabolismo
20.
Neurosci Bull ; 35(4): 724-734, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30632006

RESUMO

Hyperhomocysteinemia (Hhcy) is an independent risk factor for Alzheimer's disease (AD), and insulin-resistance is commonly seen in patients with Hhcy. Liraglutide (Lir), a glucagon-like peptide that increases the secretion and sensitivity of insulin, has a neurotrophic or neuroprotective effect. However, it is not known whether Lir ameliorates the AD-like pathology and memory deficit induced by Hhcy. By vena caudalis injection of homocysteine to produce the Hhcy model in rats, we found here that simultaneous administration of Lir for 2 weeks ameliorated the Hhcy-induced memory deficit, along with increased density of dendritic spines and up-regulation of synaptic proteins. Lir also attenuated the Hhcy-induced tau hyperphosphorylation and Aß overproduction, and the molecular mechanisms involved the restoration of protein phosphatase-2A activity and inhibition of ß- and γ-secretases. Phosphorylated insulin receptor substrate-1 also decreased after treatment with Lir. Our data reveal that Lir improves the Hhcy-induced AD-like spatial memory deficit and the mechanisms involve the modulation of insulin-resistance and the pathways generating abnormal tau and Aß.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/etiologia , Hiper-Homocisteinemia/tratamento farmacológico , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Hiper-Homocisteinemia/induzido quimicamente , Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/patologia , Resistência à Insulina , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/tratamento farmacológico , Plasticidade Neuronal , Fármacos Neuroprotetores/farmacologia , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Neurotransmissores , Proteínas tau/metabolismo
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