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1.
J Mol Med (Berl) ; 97(3): 281-289, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30675649

RESUMO

The accumulation of glutamate (Glu) in the synaptic cleft during cerebral ischemia triggers the death of neurons, causing mental or physical handicap. However, the mechanisms of the alteration in Glu homeostasis and the imbalance between the release and clearance of Glu in ischemia are not yet completely understood. Additionally, the role of Glu transporters in regulating Glu concentration in the synaptic cleft is controversial. This review aims to provide readers with an in-depth understanding of Glu transporters in the early or later stages of ischemic events, or in mild or severe cerebral ischemia via alteration of Glu transporter expression, reversal of Glu transporters function, and trafficking between membrane and cytoplasm, to further clarify whether the Glu transporters are neuroprotective or neurodegenerative during cerebral ischemia. We provide the insights for deeper understanding of the mechanism of Glu transporters regulation after different periods and severities of cerebral ischemia.

2.
Mol Med Rep ; 19(3): 1521-1528, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30592287

RESUMO

Glutamate excitotoxicity is responsible for neuronal death in acute neurological disorders, including stroke, trauma and neurodegenerative diseases. Astrocytes are the main cells for the removal of glutamate in the synaptic cleft and may affect the tolerance of neurons to the glutamate excitotoxicity. Therefore, the present study aimed to investigate the tolerance of rat cortical neurons to glutamate excitotoxicity in the presence and absence of astrocytes. Rat cortical neurons in the presence or absence of astrocytes were exposed to different concentrations of glutamate (10­2,000 µM) and 10 µM glycine for different incubation periods. After 24 h, the Cell Counting kit­8 (CCK­8) assay was used to measure the cytotoxicity to neurons in the presence or absence of astrocytes. According to the results, in the absence of astrocytes, glutamate induced a concentration­dependent decrease of neuronal survival rate compared with the control rat cortical neurons, and the neurotoxic half­maximal inhibitory concentration (IC50) at 15, 30 and 60 min was 364.5, 258.5 and 138.3 µM, respectively. Furthermore, in the presence of astrocytes, glutamate induced a concentration­dependent decrease of neuronal survival rate compared with the control rat cortical neurons, and the neurotoxic IC50 at 15, 30 and 60 min was 1,935, 932.8 and 789.3 µM, respectively. However, astrocytic toxicity was not observed when the rat cortical astrocytes alone were exposed to different concentrations of glutamate (500, 1,000 and 2,000 µM) for 6, 12 and 24 h. In conclusion, the glutamate­induced neurotoxic IC50 values at 15, 30 and 60 min were respectively higher in the presence of astrocytes as compared with those in the absence of astrocytes, suggesting that astrocytes can protect against rat cortical neuronal acute damage induced by glutamate.


Assuntos
Astrócitos/metabolismo , Córtex Cerebral/efeitos dos fármacos , Ácido Glutâmico/administração & dosagem , Neurônios/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Tolerância a Medicamentos/genética , Ácido Glutâmico/toxicidade , Glicina/administração & dosagem , Glicina/efeitos adversos , Neurônios/patologia , Ratos
3.
Neurochem Res ; 43(10): 2016, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30171421

RESUMO

The order of corresponding author was inadvertently published. Hence, the first and the second corresponding authors should be Min Zhang (hebmuzhangmin@163.com) and Jing-Ge Zhang (zhangjg001@163.com).

4.
Neurochem Res ; 43(9): 1779-1790, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29995175

RESUMO

Previous studies have shown that intermittent hypobaric hypoxia (IH) preconditioning protected neurons survival from brain ischemia. However, the mechanism remains to be elucidated. The present study explored the role of nitric oxide (NO) in the process by measuring the expression of NO synthase (NOS) and NO levels. Male Wistar rats (100) were randomly assigned into four groups: sham group, IH + sham group, ischemia group and IH + ischemia group. Rats for IH preconditioning were exposed to hypobaric hypoxia mimicking 5000 m high-altitude (PB = 404 mmHg, PO2 = 84 mmHg) 6 h/day, once daily for 28 days. Global brain ischemia was established by four-vessel occlusion that has been created by Pulsinelli. Rats were sacrificed at 7th day after the ischemia for neuropathological evaluation by thionin stain. In addition, the expression of neuronal NOS (nNOS), inducible NOS (iNOS), and NO content in the hippocampal CA1 subfield were measured at 2nd day and 7th day after the ischemia. Results revealed that global brain ischemia engendered delayed neuronal death (DND), both nNOS and iNOS expression up-regulated, and NO content increased in the hippocampal CA1 subfield. IH preconditioning reduced neuronal injury induced by the ischemia, and prevented the up-regulation of NOS expression and NO production. In addition, L-NAME + ischemia group was designed to detect whether depressing NO production could alleviate the DND. Pre-administration of L-NAME alleviated DND induced by the ischemia. These results suggest that IH preconditioning plays a protective role by inhibiting the over expression of NOS and NO content after brain ischemia.

5.
Life Sci ; 193: 124-131, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29158051

RESUMO

Cell proliferation, apoptosis, autophagy, oxidative stress and metabolic dysregulation are the basis of many diseases. Forkhead box transcription factor O1 (FOXO1) changes in response to cellular stimulation and maintains tissue homeostasis during the above-mentioned physiological and pathological processes. Substantial evidences indicate that FOXO1's function depends on the modulation of downstream targets such as apoptosis- and autophagy-associated genes, anti-oxidative stress enzymes, cell cycle arrest genes, and metabolic and immune regulators. In addition, oxidative stress, high glucose and other stimulations induce the regulation of FOXO1 activity via PI3k-Akt, JNK, CBP, Sirtuins, ubiquitin E3 ligases, etc., which mediate multiple signalling pathways. Subsequent post-transcriptional modifications, including phosphorylation, ubiquitination, acetylation, deacetylation, arginine methylation and O-GlcNAcylation, activate or inhibit FOXO1. The regulation of FOXO1 and its role might provide a significant avenue for the prevention and treatment of diseases. However, the subtle mechanisms of the post-transcriptional modifications and the effect of FOXO1 remain elusive and even conflicting in the development of many diseases. The determination of these questions potentially has implications for further research regarding FOXO1 signalling and the identification of targeted drugs.


Assuntos
Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Acetilação , Apoptose/genética , Autofagia/genética , Proliferação de Células/genética , Progressão da Doença , Fatores de Transcrição Forkhead/metabolismo , Humanos , Estresse Oxidativo/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Ubiquitinação
6.
Gene ; 585(1): 44-50, 2016 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26992639

RESUMO

Transcription factor nuclear factor of activated T cells c4 (NFATc4) is the best-characterized target for the development of cardiac hypertrophy. Aberrant microRNA-29 (miR-29) expression is involved in the development of cardiac fibrosis and congestive heart failure. However, whether miR-29 regulates hypertrophic processes is still not clear. In this study, we investigated the potential functions of miR-29a-3p in endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy. We showed that miR-29a-3p was down-regulated in ET-1-treated H9c2 cardiomyocytes. Overexpression of miR-29a-3p significantly reduced ET-1-induced hypertrophic responses in H9c2 cardiomyocytes, which was accompanied by a decrease in NFATc4 expression. miR-29a-3p targeted directly to the 3'-UTR of NFATc4 mRNA and silenced NFATc4 expression. Our results indicate that miR-29a-3p inhibits ET-1-induced cardiomyocyte hypertrophy via inhibiting NFATc4 expression.


Assuntos
Cardiomegalia/genética , Endotelina-1/metabolismo , Insuficiência Cardíaca/genética , MicroRNAs/genética , Miócitos Cardíacos/patologia , Fatores de Transcrição NFATC/genética , Proteínas do Tecido Nervoso/genética , Regiões 3' não Traduzidas/genética , Animais , Linhagem Celular , Regulação para Baixo/genética , Fibrose/genética , MicroRNAs/biossíntese , Fatores de Transcrição NFATC/biossíntese , Proteínas do Tecido Nervoso/biossíntese , RNA Mensageiro/genética , Ratos
7.
Stem Cells ; 34(5): 1273-83, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26850336

RESUMO

Human mesenchymal stem cells (hMSCs) possess the potential to differentiate into endothelial cells (EC). DNA methylation plays an important role in cell differentiation during development. However, the role of the DNA methyltransferases Dnmt1 and Dnmt3a in specific arterial differentiation of hMSCs is not clear. Here, we show that the CpG islands in the promoter regions of the EC specification and arterial marker genes were highly methylated in hMSCs based on bisulfite genomic sequencing. Treatment with the DNMT inhibitor 5-aza-dc induced the reactivation of EC specification and arterial marker genes by promoting demethylation of these genes as well as stimulating tube-like structure formation. The hMSCs with stable knockdown of Dnmt1/Dnmt3a were highly angiogenic and expressed several arterial specific transcription factors and marker genes. A Matrigel plug assay confirmed that Dnmt1/Dnmt3a stable knockdown hMSCs enhanced blood vessel formation compared with WT MSCs. We also identified that the transcription factor E2F1 could upregulate the transcription of arterial marker genes by binding to the promoters of arterial genes, suggesting its critical role for arterial specification. Moreover, miRNA gain/loss-of-function analyses revealed that miR152 and miR30a were involved in endothelial differentiation of hMSCs by targeting Dnmt1 and Dnmt3a, respectively. Taken together, these data suggest that Dnmt1 and Dnmt3a are critical regulators for epigenetic silencing of EC marker genes and that E2F1 plays an important role in promoting arterial cell determination. Stem Cells 2016;34:1273-1283.


Assuntos
Artérias/citologia , Diferenciação Celular , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Técnicas de Silenciamento de Genes , Células-Tronco Mesenquimais/citologia , Neovascularização Fisiológica/genética , Especificidade de Órgãos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/enzimologia , MicroRNAs/genética , MicroRNAs/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/genética
8.
Mol Neurobiol ; 53(2): 1124-31, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25586061

RESUMO

The glutamate (Glu) transporters GLAST and GLT-1, as the two most important transporters in brain tissue, transport Glu from the extracellular space into the cell protecting against Glu toxicity. Furthermore, GLAST and GLT-1 are sodium-dependent Glu transporters (GluTs) that rely on sodium and potassium gradients generated principally by Na(+), K(+)-ATPase to generate ion gradients that drive Glu uptake. There is an interaction between Na(+), K(+)-ATPase and GluTs to modulate Glu uptake, and Na(+), K(+)-ATPase α, ß or γ subunit can be directly coupled to GluTs, co-localizing with GLAST or GLT-1 in vivo to form a macromolecular complex and operate as a functional unit to regulate glutamatergic neurotransmission. Therefore, GluTs/Na(+), K(+)-ATPase may be involved in the neuroprotective effect as a potential regulatory target of Glu uptake in neurodegenerative diseases induced by Glu-mediated neurotoxicity as the final common pathway.


Assuntos
Sistema X-AG de Transporte de Aminoácidos/metabolismo , Ácido Glutâmico/metabolismo , Fármacos Neuroprotetores/farmacologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Glutamina/metabolismo , Humanos , Modelos Biológicos
9.
Stem Cells Int ; 2015: 534758, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25949242

RESUMO

Mesenchymal stem cells (MSCs) are known to undergo endothelial differentiation in response to treatment with vascular endothelial growth factor (VEGF), but their angiogenic ability is poorly characterized. In the present study, we aimed to further investigate the role of Rho/MRTF-A in angiogenesis by MSCs and the effect of the Rho/MRTF-A pathway on the expression of integrins α1ß1 and α5ß1, which are known to mediate physiological and pathological angiogenesis. Our results showed that increased expression of α1, α5, and ß1 was observed during angiogenesis of differentiated MSCs, and the Rho/MRTF-A signaling pathway was demonstrated to be involved in regulating the expression of integrins α1, α5, and ß1. Luciferase reporter assay and ChIP assay determined that MRTF-A could bind to and transactivate the integrin α1 and α5 promoters. Treatment with the Rho inhibitor C3 transferase, the Rho-associated protein kinase (ROCK) inhibitor Y27632 or with shMRTF-A inhibited both the upregulation of α1, α5, and ß1 as well as angiogenesis. Furthermore, in human umbilical vein endothelial cells (HUVECs), MRTF-A deletion led to marked reductions in cell migration and vessel network formation compared with the control. These data demonstrate that Rho/MRTF-A signaling is an important mediator that controls integrin gene expression during MSC-mediated angiogenic processes.

10.
Adv Clin Exp Med ; 24(1): 161-5, 2015 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25923101

RESUMO

As the major neurotransmitter in the mammalian central nervous system (CNS), excessive extracellular glutamate (Glu) can activate the Glu receptors and neuronal calcium (Ca2+) overload, then produce neurotoxicity, which is a common pathway for neuronal injury or death, and is associated with acute and chronic neurodegenerative diseases. Therefore, it has been a therapeutic strategy to investigate neuroprotective effects against Glu-induced neurotoxicity for treating both acute and chronic forms of neurodegeneration. Resveratrol (Res), as a naturally occurring polyphenol mainly found in grapes and red wine, has shown a neuroprotective effect in a variety of experimental models for neurodegenerative diseases in vitro and in vivo. This review will focus on the neuroprotective effect of Res against Glu-induced excitotoxicity in neurodegenerative diseases by blocking different Glu receptors and Ca2+ ion channels.


Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/toxicidade , Doenças Neurodegenerativas/prevenção & controle , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estilbenos/farmacologia , Animais , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurônios/metabolismo , Neurônios/patologia , Receptores de AMPA/metabolismo , Receptores de Ácido Caínico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Resveratrol
11.
Gene ; 563(1): 17-23, 2015 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-25746323

RESUMO

Vascular endothelial cadherin (VE-cadherin) is the major determinant of endothelial cell contact integrity and is required in vascular development and angiogenesis. Serum response factor (SRF) plays essential roles in postnatal retinal angiogenesis and adult neovascularization. It is unclear whether transcription of VE-cadherin is mediated by a SRF co-activator, myocardin-related transcription factor-A (MRTF-A). Here we have demonstrated that MRTF-A is a key regulatory factor to activate the transcription of VE-cadherin in human umbilical vein endothelial cells (HUVECs). siRNA-mediated knockdown of MRTF-A decreased the level of VE-cadherin in HUVECs. Vascular endothelial growth factor (VEGF) induced MRTF-A binding to the SRF-binding site (CArG box) within VE-cadherin promoter. Histone acetyltransferase p300 and MRTF-A could synergistically augment the expression of VE-cadherin by enhancing acetylation of histone3K9 (H3K9Ac), histone3K14 (H3K14Ac) and histone4 at the SRF-binding site within VE-cadherin promoter. Taken together, these data identified a detailed regulatory mechanism of VE-cadherin gene expression.


Assuntos
Antígenos CD/genética , Caderinas/genética , Transativadores/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo , Acetilação , Antígenos CD/metabolismo , Sítios de Ligação , Caderinas/metabolismo , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Histonas/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Regiões Promotoras Genéticas , Fator de Resposta Sérica/metabolismo , Transativadores/genética , Ativação Transcricional , Fator A de Crescimento do Endotélio Vascular/farmacologia , Fatores de Transcrição de p300-CBP/genética
12.
Mol Med Rep ; 8(5): 1291-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24065247

RESUMO

Dopamine (DA) receptors, which belong to the G protein-coupled receptor family, are the target of ~50% of all modern medicinal drugs and constitute a large and diverse class of proteins whose primary function is to transduce extracellular stimuli into intracellular signals. Na+/K+-ATPase (NKA) is ubiquitous and crucial for the maintenance of intracellular ion homeostasis and excitability. Furthermore, it plays a critical role in diverse effects, including clinical cardiotonic and cardioprotective effects, ischemic preconditioning in the brain, natriuresis, lung edema clearance and other processes. NKA regulation is of physiological and pharmacological importance and has species- and tissue-specific variations. The activation of DA receptors regulates NKA expression/activity and trafficking in various tissues and cells, for example in the kidney, lung, intestine, brain, non-pigmented ciliary epithelium and the vascular bed. DA receptor-mediated regulation of NKA mediates a diverse range of cellular responses and includes endocytosis/exocytosis, phosphorylation/dephosphorylation of the α subunit of NKA and multiple signaling pathways, including phosphatidylinositol (PI)-phospholipase C/protein kinase (PK) C, cAMP/PKA, PI3K, adaptor protein 2, tyrosine phosphatase and mitogen-activated protein kinase/extracellular signal-regulated protein kinase. Furthermore, in brain and HEK293T cells, D1 and D2 receptors exist in a complex with NKA. Among D1 and D2 receptors and NKA, regulations are reciprocal, which leads to crosstalk between DA receptors and NKA. In the present study, the current understanding of signaling mechanisms responsible for the crosstalk between DA receptors and NKA, as well as with specific consequent functions, is reviewed.


Assuntos
Receptor Cross-Talk/fisiologia , Receptores Dopaminérgicos/metabolismo , Transdução de Sinais , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Humanos
13.
Fundam Clin Pharmacol ; 27(1): 96-103, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23033963

RESUMO

Alzheimer disease (AD) is a neurodegenerative disorder clinically characterized by progressive cognitive and memory dysfunction, which is the most common form of dementia. Although the pathogenesis of neuronal injury in AD is not clear, recent evidences suggest that Na⁺-K⁺-ATPase plays an important role in AD, and may be a potent neuroprotective modulator against AD. This review aims to provide readers with an in-depth understanding of Na⁺-K⁺-ATPase in AD through these modulations of some factors that are as follows, which leads to the change of learning and memory in the process of AD. 1. The deficiency in Na⁺, K⁺-ATPase α1, α2 and α3 isoform genes induced learning and memory deficits, and α isoform was evidently changed in AD, revealing that Na⁺, K⁺-ATPase α isoform genes may play an important role in AD. 2. Some factors, such as ß-amyloid, cholinergic and oxidative stress, can modulate learning and memory in AD through the mondulation of Na⁺-K⁺-ATPase activity. 3. Some substances, such as Zn, s-Ethyl cysteine, s-propyl cysteine, citicoline, rivastigmine, Vit E, memantine, tea polyphenol, curcumin, caffeine, Alpinia galanga (L.) fractions, and Bacopa monnieri could play a role in improving memory performance and exert protective effects against AD by increasing expression or activity of Na⁺, K⁺-ATPase.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/enzimologia , Neurônios/enzimologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Doença de Alzheimer/etiologia , Doença de Alzheimer/prevenção & controle , Doença de Alzheimer/terapia , Animais , Encéfalo/metabolismo , Suplementos Nutricionais , Ativação Enzimática/efeitos dos fármacos , Indução Enzimática/efeitos dos fármacos , Humanos , Isoenzimas/química , Isoenzimas/deficiência , Isoenzimas/metabolismo , Neurônios/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Nootrópicos/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Subunidades Proteicas/agonistas , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/deficiência , Subunidades Proteicas/metabolismo , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/química , ATPase Trocadora de Sódio-Potássio/deficiência
14.
Toxicol Appl Pharmacol ; 262(1): 32-42, 2012 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-22546087

RESUMO

The composition of different isoforms of Na+-K+-ATPase (NKA, Na/K pump) in ventricular myocytes is an important factor in determining the therapeutic effect and toxicity of cardiac glycosides (CGs) on heart failure. The mechanism whereby CGs cause these effects is still not completely clear. In the present study, we prepared two site-specific antibodies (SSA78 and WJS) against the H1-H2 domain of α1 and α2 isoforms of NKA in rat heart, respectively, and compared their influences on the effect of ouabain (OUA) in isolated rat ventricular myocytes. SSA78 or WJS, which can specifically bind with the α1 or α2 isoform, were assessed with enzyme linked immunosorbent assay (ELISA), Western blot and immunofluorescent staining methods. Preincubation of myocytes with SSA78 inhibited low OUA affinity pump current but not high OUA affinity pump current, reduced the rise in cytosolic calcium concentration ([Ca²âº](i)), attenuated mitochondrial Ca²âº overload, restored mitochondrial membrane potential reduction, and delayed the decrease of the myocardial contractile force as well as the occurrence of arrhythmic contraction induced by high concentrations (1 mM) but not low concentrations (1 µM) of OUA. Similarly, preincubation of myocytes with WJS inhibited high OUA affinity pump current, reduced the increase of [Ca²âº](i) and the contractility induced by 1 µM but not that induced by 1 mM OUA. These results indicate that the H1-H2 domain of the NKA α1 isoform mediates OUA-induced cardiac toxicity in rat ventricular myocytes, and inhibitors for this binding site may be used as an adjunct to CGs treatment for cardiovascular disease.


Assuntos
Glicosídeos Cardíacos/toxicidade , Ventrículos do Coração/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Ouabaína/toxicidade , ATPase Trocadora de Sódio-Potássio/efeitos dos fármacos , Animais , Anticorpos/imunologia , Especificidade de Anticorpos , Sítios de Ligação , Western Blotting , Cálcio/metabolismo , Glicosídeos Cardíacos/administração & dosagem , Cardiotônicos/administração & dosagem , Cardiotônicos/toxicidade , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Ventrículos do Coração/citologia , Ventrículos do Coração/patologia , Isoenzimas , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/patologia , Ouabaína/administração & dosagem , Ratos , Ratos Sprague-Dawley , ATPase Trocadora de Sódio-Potássio/metabolismo
15.
BMC Neurosci ; 13: 10, 2012 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-22257758

RESUMO

BACKGROUND: The aim of this study was to investigate whether serotonin (5-hydroxytryptamine, 5-HT) can modulate Na+/K+ pump in rat hippocampal CA1 pyramidal neurons. RESULTS: 5-HT (0.1, 1 mM) showed Na+/K+ pump current (Ip) densities of 0.40 ± 0.04, 0.34 ± 0.03 pA/pF contrast to 0.63 ± 0.04 pA/pF of the control of 0.5 mM strophanthidin (Str), demonstrating 5-HT-induced inhibition of Ip in a dose-dependent manner in hippocampal CA1 pyramidal neurons. The effect was partly attenuated by ondasetron, a 5-HT3 receptor (5-HT3R) antagonist, not by WAY100635, a 5-HT1AR antagonist, while 1-(3-Chlorophenyl) biguanide hydrochloride (m-CPBG), a 5-HT3R specific agonist, mimicked the effect of 5-HT on Ip. CONCLUSION: 5-HT inhibits neuronal Na+/K+ pump activity via 5-HT3R in rat hippocampal CA1 pyramidal neurons. This discloses novel mechanisms for the function of 5-HT in learning and memory, which may be a useful target to benefit these patients with cognitive disorder.


Assuntos
Região CA1 Hipocampal/citologia , Células Piramidais/efeitos dos fármacos , Serotonina/farmacologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Animais Recém-Nascidos , Biguanidas/farmacologia , Biofísica , Relação Dose-Resposta a Droga , Estimulação Elétrica , Técnicas In Vitro , Inibição Neural/efeitos dos fármacos , Técnicas de Patch-Clamp , Piperazinas/farmacologia , Células Piramidais/fisiologia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Estrofantidina/farmacologia , Tetrodotoxina/farmacologia
16.
Am J Physiol Heart Circ Physiol ; 300(6): H2280-7, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21441313

RESUMO

Chronic intermittent hypobaric hypoxia (CIHH) has been shown to attenuate intracellular Na(+) accumulation and Ca(2+) overload during ischemia and reperfusion (I/R), both of which are closely related to the outcome of myocardial damage. Na/K pump plays an essential role in maintaining the equilibrium of intracellular Na(+) and Ca(2+) during I/R. It has been shown that enhancement of Na/K pump activity by ischemic preconditioning may be involved in the cardiac protection. Therefore, we tested whether Na/K pump was involved in the cardioprotection by CIHH. We found that Na/K pump current in cardiac myocytes of guinea pigs exposed to CIHH increased 1.45-fold. The K(1) and f(1), which reflect the portion of α(1)-isoform of Na/K pump, dramatically decreased or increased, respectively, in CIHH myocytes. Western blot analysis revealed that CIHH increased the protein expression of the α(1)-isoform by 76%, whereas the protein expression of the α(2)-isoform was not changed significantly. Na/K pump current was significantly suppressed in simulated I/R, and CIHH preserved the Na/K pump current. CIHH significantly improved the recovery of cell length and contraction during reperfusion. Furthermore, inhibition of Na/K pump by ouabain attenuated the protective effect afforded by CIHH. Collectively, these data suggest that the increase of Na/K pump activity following CIHH is due to the upregulating α(1)-isoform of Na/K pump, which may be one of the mechanisms of CIHH against I/R-induced injury.


Assuntos
Hipóxia/fisiopatologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/fisiopatologia , ATPase Trocadora de Sódio-Potássio/fisiologia , Animais , Cobaias , Masculino , Modelos Animais , Contração Miocárdica/fisiologia , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Ouabaína/farmacologia , Técnicas de Patch-Clamp , Isoformas de Proteínas/fisiologia , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/efeitos dos fármacos , Resultado do Tratamento
17.
Acta Pharmacol Sin ; 30(7): 947-55, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19543301

RESUMO

AIM: To investigate the protection and the anti-oxidative mechanism afforded by chronic intermittent hypobaric hypoxia (CIHH) against ischemia/reperfusion (I/R) injury in guinea pig hearts. METHODS: Adult male guinea pigs were exposed to CIHH by mimicking a 5000 m high altitude (p(B)=404 mmHg, p(O2)=84 mmHg) in a hypobaric chamber for 6 h/day for 28 days. Langendorff-perfused isolated guinea pig hearts were used to measure variables of left ventricular function during baseline perfusion, ischemia and the reperfusion period. The activity and protein expression of antioxidant enzymes in the left myocardium were evaluated using biochemical methods and Western blotting, respectively. Intracellular reactive oxygen species (ROS) were assessed using ROS-sensitive fluorescence. RESULTS: After 30 min of global no-flow ischemia followed by 60 min of reperfusion, myocardial function had better recovery rates in CIHH guinea pig hearts than in control hearts. The activity and protein expression of superoxide dismutase (SOD) and catalase (CAT) were significantly increased in the myocardium of CIHH guinea pigs. Pretreatment of control hearts with an antioxidant mixture containing SOD and CAT exerted cardioprotective effects similar to CIHH. The irreversible CAT inhibitor aminotriazole (ATZ) abolished the cardioprotection of CIHH. Cardiac contractile dysfunction and oxidative stress induced by exogenous hydrogen peroxide (H(2)O(2)) were attenuated by CIHH and CAT. CONCLUSIONS: These data suggest that CIHH protects the heart against I/R injury through upregulation of antioxidant enzymes in guinea pig.Acta Pharmacologica Sinica (2009) 30: 947-955; doi: 10.1038/aps.2009.57; published online 22 June 2009.


Assuntos
Antioxidantes/metabolismo , Hipóxia , Miocárdio/enzimologia , Miocárdio/patologia , Traumatismo por Reperfusão/prevenção & controle , Amitrol (Herbicida)/metabolismo , Animais , Peso Corporal , Catalase/metabolismo , Inibidores Enzimáticos/metabolismo , Cobaias , Peróxido de Hidrogênio/metabolismo , Masculino , Malondialdeído/metabolismo , Miocárdio/citologia , Tamanho do Órgão , Oxidantes/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo , Superóxido Dismutase/metabolismo
18.
Acta Pharmacol Sin ; 30(4): 404-12, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19305421

RESUMO

AIM: The present study investigated the effect of adenosine on Na(+)-K(+) pumps in acutely isolated guinea pig (Cavia sp.) ventricular myocytes. METHODS: The whole-cell, patch-clamp technique was used to record the Na(+)-K(+) pump current (I(p)) in acutely isolated guinea pig ventricular myocytes. RESULTS: Adenosine inhibited the high DHO-affinity pump current (I(h)) in a concentration-dependent manner, which was blocked by the selective adenosine A(1) receptor antagonist DPCPX and the general protein kinase C (PKC) antagonists staurosporine, GF 109203X or the specific delta isoform antagonist rottlerin. In addition, the inhibitory action of adenosine was mimicked by a selective A(1) receptor agonist CCPA and a specific activator peptide of PKC-delta, PP114. In contrast, the selective A(2A) receptor agonist CGS21680 and A(3) receptor agonist Cl-IB-MECA did not affect I(h). Application of the selective A(2A) receptor antagonist SCH58261 and A(3) receptor antagonist MRS1191 also failed to block the effect of adenosine. Furthermore, H89, a selective protein kinase A (PKA) antagonist, did not exert any effect on adenosine-induced I(h) inhibition. CONCLUSION: The present study provides the electrophysiological evidence that adenosine can induce significant inhibition of I(h) via adenosine A(1) receptors and the PKC-delta isoform.


Assuntos
Adenosina/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Animais , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Cobaias , Ventrículos do Coração/metabolismo , Miócitos Cardíacos/metabolismo , Isoformas de Proteínas/fisiologia , Proteína Quinase C-delta/fisiologia , Receptor A1 de Adenosina/fisiologia , Receptor A2A de Adenosina/fisiologia , Receptor A3 de Adenosina/fisiologia
19.
Zhongguo Zhong Yao Za Zhi ; 32(15): 1563-5, 2007 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-17972590

RESUMO

OBJECTIVE: To observe the protective effects of resveratrol (RES) on the heart function of the rats with adriamycin-induced heart failure. METHOD: Thirty adult male SD rats were randomly divided into 5 groups: normal control (NC) group, adriamycin (ADR) group, RESL + ADR group, RES(H) + ADR group and RES group. RES of 30, 120, 120 mg x kg(-1) x d(-1) was given intraperitoneally (ip) once a day for 3 days in RES(L) + ADR group, RES(H) + ADR group and RES group respectively. The other two groups were given the same amount of normal saline the same way. On the 4h day,ADR of 10 mg x kg(-1) was given intraperitoneally once to induce myocardium injury model. After twenty-four hours, the pathological and biochemical changes of the myocardium were examined. RESULT: As compared with NC group, the MDA, NO and NOS of the ADR group were significantly higher (P < 0.05), and the SOD of the ADR group were markedly lower (P < 0.05). As compared with ADR group, the indexes in RES(L) + ADR group, RES(H) + ADR group were exactly opposing, and took on dose dependance (P < 0.05). Light microscopic morphometry of the heart samples of the rats in ADR + RES(L, H) groups revealed typical diminishing of damage. CONCLUSION: RES can relieve the toxic effects of ADR on myocardium, and the cardioprotective effects may be correlated with its antioxidant activity and downregulation of NO.


Assuntos
Insuficiência Cardíaca , Coração/fisiopatologia , Miocárdio/patologia , Estilbenos/farmacologia , Animais , Doxorrubicina , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Masculino , Malondialdeído/sangue , Óxido Nítrico/sangue , Óxido Nítrico Sintase/sangue , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Resveratrol , Superóxido Dismutase/sangue
20.
Zhongguo Zhong Yao Za Zhi ; 32(13): 1317-9, 2007 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-17879735

RESUMO

OBJECTIVE: To study the effects of resvaratrol derivatives on spontaneous HR and CF of isolated guinea pig atrium. METHOD: The dose-effect curve of resvaratrol was observed. The possible mechanism of potassium channels responsible for changes of CF and HR after administering with resvaratrol was measured. RESULT: Resvaratrol reduced the spontaneous HR and weakened the CF in a dose-dependent manner ranging from 10(-6) to 3 x 10(-4) mol x L(-1) (P < 0.05). As compared with Res group, the effects were partly blocked by Gli (P < 0.05) and TEA (P < 0.01), but not blocked by 4-AP, BaCl2, Atropine. CONCLUSION: Resvaratrol can induce negative chronotropic action and negative (inotropic action. The mechanism(s) may relate to the opening of K(ATP) and Kc(Ca).


Assuntos
Cardiotônicos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Estilbenos/farmacologia , Animais , Compostos de Bário/farmacologia , Cardiotônicos/administração & dosagem , Cardiotônicos/isolamento & purificação , Cloretos/farmacologia , Relação Dose-Resposta a Droga , Feminino , Glibureto/farmacologia , Cobaias , Técnicas In Vitro , Canais KATP/antagonistas & inibidores , Masculino , Plantas Medicinais/química , Canais de Potássio Cálcio-Ativados/antagonistas & inibidores , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Resveratrol , Estilbenos/administração & dosagem , Estilbenos/isolamento & purificação , Tetraetilamônio/farmacologia
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