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1.
Brain Imaging Behav ; 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34478055

RESUMO

Unilateral temporal lobe epilepsy (TLE) is the most common type of focal epilepsy characterized by foci in the unilateral temporal lobe grey matters of regions such as the hippocampus. However, it remains unclear how the functional features of white matter are altered in TLE. In the current study, resting-state functional magnetic resonance imaging (fMRI) was performed on 71 left TLE (LTLE) patients, 79 right TLE (RTLE) patients and 47 healthy controls (HC). Clustering analysis was used to identify fourteen white matter networks (WMN). The functional connectivity (FC) was calculated among WMNs and between WMNs and grey matter. Furthermore, the FC laterality of hemispheric WMNs was assessed. First, both patient groups showed decreased FCs among WMNs. Specifically, cerebellar white matter illustrated decreased FCs with the cerebral superficial WMNs, implying a dysfunctional interaction between the cerebellum and the cerebral cortex in TLE. Second, the FCs between WMNs and the ipsilateral hippocampus (grey matter foci) were also reduced in patient groups, which may suggest insufficient functional integration in unilateral TLE. Interestingly, RTLE showed more severe abnormalities of white matter FCs, including links to the bilateral hippocampi and temporal white matter, than LTLE. Taken together, these findings provide functional evidence of white matter abnormalities, extending the understanding of the pathological mechanism of white matter impairments in unilateral TLE.

2.
Neuroimage Clin ; 31: 102714, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34102537

RESUMO

OBJECTIVE: To explore the structural and functional reorganization of contralateral hippocampus in patients with unilateral mesial temporal lobe epilepsy (mTLE) who achieved seizure-freedom after anterior temporal lobectomy (ATL). METHODS: We obtained high-resolution structural MRI and resting-state functional MRI data in 28 unilateral mTLE patients and 29 healthy controls. Patients were scanned before and three and 24 months after surgery while controls were scanned only once. Hippocampal gray matter volume (GMV) and functional connectivity (FC) were assessed. RESULTS: No obvious GMV changes were observed in contralateral hippocampus before and after successful surgery. Before surgery, ipsilateral hippocampus showed increased FC with ipsilateral insula (INS) and temporoparietal junction (TPJ), but decreased FC with widespread bilateral regions, as well as contralateral hippocampus. After successful ATL, contralateral hippocampus showed: (1) decreased FC with ipsilateral INS at three months follow-up, without further changes; (2) decreased FC with ipsilateral TPJ, postcentral gyrus and rolandic operculum at three months, with an obvious increase at 24 months follow-up; (3) increased FC with bilateral medial prefrontal cortex (MPFC) and superior frontal gyrus (SFG) at three months follow-up, without further changes. CONCLUSIONS: Successful ATL may not lead to an obvious structural reorganization in contralateral hippocampus. Surgical manipulation may lead to a transient FC reduction of contralateral hippocampus. Increased FC between contralateral hippocampus and bilateral MPFC and SFG may be related to postoperative functional remodeling.


Assuntos
Epilepsia do Lobo Temporal , Lobectomia Temporal Anterior , Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/cirurgia , Substância Cinzenta , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética
3.
Epilepsy Behav ; 121(Pt A): 108046, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34111767

RESUMO

The objective of the study was to design a clinically useful tool to predict the risk of seizure-related motor vehicle accidents (MVAs) for people with epilepsy (PWE). Participants were patients who visited our epilepsy center in West China Hospital from October 2012 to October 2019 and were divided into a primary cohort and a validation cohort. Ultimately, we included 525 patients in the primary cohort and 86 patients in the validation cohort. Proportional hazard regression was performed to measure the prognostic factors of car accidents. The outcome was used to create a nomogram model. The final model had 7 factors, with a C-index of 0.85 (95% CI, 0.80-0.91), to predict the possibility of non-MVA for PWE. For the validation cohort, the C-index was 0.83 (95% CI, 0.72-0.95). This nomogram model can offer more individualized advice to PWE who are still driving by estimating the risk of car accidents.


Assuntos
Condução de Veículo , Epilepsia , Acidentes de Trânsito , China/epidemiologia , Epilepsia/epidemiologia , Humanos , Veículos Automotores
4.
Brain Topogr ; 34(4): 525-536, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33973138

RESUMO

Epilepsy and depression were proposed to facilitate each other reciprocally through common neurobiological anomalies, especially the prefrontal-limbic-subcortical abnormalities. Yet neuroimaging patterns of higher-order cognitive networks and neuroanatomical correlates were rarely compared in temporal lobe epilepsy patients with (TLE-D) and without depression (TLE-N). We collected T1-weighted structural and resting-state functional MRI data from 20 TLE-D, 31 TLE-N and 20 healthy controls (HCs) and performed analyses including hippocampal volume (HCV), cortical thickness, gray matter volume (GMV) and whole-brain functional network connectivity (FNC) across three groups. Imaging differences were related to clinical and psychological measurements. TLE-D demonstrated disrupted functional role of subcortical (SUB) and higher-order cognitive networks compared to TLE-N and HCs. In TLE-D, GMV in the right supplementary motor area (SMA) and FNC between the dorsal attention (DAN) and SUB were attenuated compared to TLE-N and HCs, FNC between SUB and the visual network (VIS) decreased compared to HCs. GMV in the right SMA was negatively correlated with depression severity and some symptoms. Combined, explicit emotion regulation may be impaired in TLE-D. Meanwhile, compared to HCs, TLE-N showed smaller HCVs, TLE-D and TLE-N showed smaller GMV in the medial orbital frontal gyrus and right hippocampus and hippocampal gyrus, possibly implying predisposition of epileptic activities to co-morbid depression. Our findings suggest distinct anatomical and FNC patterns in TLE-D and TLE-N. More than prefrontal-limbic-subcortical anomalies, disrupted higher-order cognitive network may contribute to depression in TLE, providing new potential treatment targets for depression and calling attention to relation between cognitive dysfunction and co-morbid depression.


Assuntos
Epilepsia do Lobo Temporal , Depressão/diagnóstico por imagem , Epilepsia do Lobo Temporal/diagnóstico por imagem , Hipocampo , Humanos , Imageamento por Ressonância Magnética , Lobo Temporal
5.
Sci Rep ; 11(1): 2742, 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33531579

RESUMO

People with epilepsy (PWE) have an increased suicide prevalence. This study aimed to identify the risk factors for suicidal tendency among PWE in West China. A nested case-control study was designed in a cohort of patients with epilepsy (n = 2087). In total, 28 variates were calculated. In the univariate analysis, unemployment, low income, seizure frequency, seizure-free time, infectious or structural etiology, levetiracetam or phenobarbital use, anxiety, depression, and stigma were associated with suicidal tendency. A multivariate analysis indicated that unemployment (odds ratio [OR] 5.74, 95% confidence interval [CI] 2.13-15.48), levetiracetam use (OR 2.80, 95%CI 1.11-7.05), depression (C-NDDI-E score ≥ 13; OR 3.21, 95%CI 1.26-8.21), and stigma (SSCI score ≥ 16; OR 6.67, 95%CI 1.80-24.69) were independently associated with suicidal tendency. Conditional inference tree analysis indicated that SSCI and C-NDDI-E scores could effectively identify patients with suicidal tendency. Thus, this study suggests that unemployment, levetiracetam use, depression, and stigma are independent risk factors for suicidal tendency in PWE in China.

6.
Acta Neurol Scand ; 143(3): 261-270, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33058145

RESUMO

OBJECTIVES: To explore the dynamic changes of gray matter volume and intrinsic brain activity following anterior temporal lobectomy (ATL) in patients with unilateral mesial temporal lobe epilepsy (mTLE) who achieved seizure-free for 2 years. MATERIALS AND METHODS: High-resolution T1-weighted MRI and resting-state functional MRI data were obtained in ten mTLE patients at five serial timepoints: before surgery, 3, 6, 12, and 24 months after surgery. The gray matter volume (GMV) and amplitude of low-frequency fluctuations (ALFF) were compared among the five scans to depict the dynamic changes after ATL. RESULTS: After successful ATL, GMV decreased in several ipsilateral brain regions: ipsilateral insula, thalamus, and putamen showed gradual gray matter atrophy from 3 to 24 months, while ipsilateral superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus, middle occipital gyrus, inferior occipital gyrus, caudate nucleus, lingual gyrus, and fusiform gyrus showed significant GMV decrease at 3 months follow-up, without further changes. Ipsilateral insula showed gradual ALFF decrease from 3 to 24 months after surgery. Ipsilateral superior temporal gyrus showed ALFF decrease at 3 months follow-up, without further changes. Ipsilateral thalamus and cerebellar vermis showed obvious ALFF increase after surgery. CONCLUSIONS: Surgical resection may lead to a short-term reduction of gray matter volume and intrinsic brain activity in neighboring regions, while the progressive gray matter atrophy may be due to possible intrinsic mechanism of mTLE. Dynamic ALFF changes provide evidence that disrupted focal spontaneous activities were reorganized after successful surgery.


Assuntos
Lobectomia Temporal Anterior/métodos , Epilepsia do Lobo Temporal/patologia , Epilepsia do Lobo Temporal/fisiopatologia , Epilepsia do Lobo Temporal/cirurgia , Substância Cinzenta/patologia , Adulto , Atrofia/patologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Encéfalo/cirurgia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Adulto Jovem
7.
J Neurol Sci ; 411: 116702, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32058179

RESUMO

BACKGROUND: Previous neuroimaging studies have revealed aberrant basal ganglia-thalamocortical circuit in patients with paroxysmal kinesigenic dyskinesia (PKD) with drug treatment. This study aims to investigate the topological organization of functional networks in drug-naive PKD. METHODS: Resting-state functional magnetic resonance imaging (rs-fMRI) was performed in 24 drug-naive PKD patients and 24 age, gender and mean framewise displacement (FD)-matched healthy controls (HCs). The network topological properties (including global and nodal measures) were analyzed between two groups by using graph-based theoretical approaches. Pearson's correlation analysis was performed between significant metrics and duration of disease and the age of onset of patients with PKD. RESULTS: Compare to HCs, the drug-naïve PKD patients showed increased nodal centralities mainly in left precentral gyrus, basal ganglia and limbic regions and decreased nodal centralities in the temporal pole. Our results showed that drug-naïve PKD patients presented the small-world topology and at the global level no significant differences were found between PKD and HCs. In the correlation analysis, the increased nodal efficiency in the left pallidum was positively correlated with the onset of age. CONCLUSIONS: Our findings supported the previous observation of the disruptive cortical-basal ganglia circuitry in PKD patients, but difference in that the prominent change of precentral area and temporal pole were also observed in our study when the potential impact of drug was excluded. These findings may provide a novel insight into further delineation of the pathophysiological genesis and possible target for PKD.


Assuntos
Distonia , Preparações Farmacêuticas , Encéfalo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética
8.
Seizure ; 71: 179-184, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31382137

RESUMO

PURPOSE: To investigate the current status of marriage and fertility of patients with epilepsy (PWE) and characterize its influencing factors. METHODS: A total of 1,823 adult patients (males age 22 years or older, females age 20 years or older) were included in this study. Data concerning sociodemographic and clinical characteristics were collected. Descriptive analyses, followed by univariate and multivariate logistic regression analyses were utilized to examine factors associated with marriage and fertility of PWE. Marital status of PWE was compared with Chinese population. Standardized marriage rate (SMR) for age and sex was estimated based on the 2010 sixth national population census. RESULTS: 1,132 patients (62.1%) were married and 823 (45.1%) had a history of fertility. Patients had lower marriage rates than Chinese population (62.1% vs 78.4%). Patients with adult-onset epilepsy (>18 years) had a significantly higher rate of marriage and fertility (p < 0.001) compared to those with childhood-onset epilepsy (≤18 years). Employed patients had higher marriage rates than unemployed patients (64.9% vs 58.6%, p = 0.006), with only male patients being significantly affected by employment status (p < 0.001). Multiple logistic regression revealed that age, age at first seizure onset, and employment status were related to both marriage and fertility. CONCLUSION: Epilepsy had negative effects on marriage and fertility status. Marriage and fertility rates were lower in patients with Childhood-onset epilepsy (≤18 years). Furthermore, employment status mainly affected the marriage rate of male patients.


Assuntos
Emprego/estatística & dados numéricos , Epilepsia/epidemiologia , Fertilidade , Estado Civil/estatística & dados numéricos , Paridade , Adulto , Idade de Início , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
J Am Heart Assoc ; 3(5): e000779, 2014 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-25237043

RESUMO

BACKGROUND: Increasing evidence suggests a critical role for mitochondrial aldehyde dehydrogenase 2 (ALDH2) in protection against cardiac injuries; however, the downstream cytosolic actions of this enzyme are largely undefined. METHODS AND RESULTS: Proteomic analysis identified a significant downregulation of mitochondrial ALDH2 in the heart of a rat heart failure model after myocardial infarction. The mechanistic insights underlying ALDH2 action were elucidated using murine models overexpressing ALDH2 or its mutant or with the ablation of the ALDH2 gene (ALDH2 knockout) and neonatal cardiomyocytes undergoing altered expression and activity of ALDH2. Left ventricle dilation and dysfunction and cardiomyocyte death after myocardial infarction were exacerbated in ALDH2-knockout or ALDH2 mutant-overexpressing mice but were significantly attenuated in ALDH2-overexpressing mice. Using an anoxia model of cardiomyocytes with deficiency in ALDH2 activities, we observed prominent cardiomyocyte apoptosis and increased accumulation of the reactive aldehyde 4-hydroxy-2-nonenal (4-HNE). We subsequently examined the impacts of mitochondrial ALDH2 and 4-HNE on the relevant cytosolic protective pathways. Our data documented 4-HNE-stimulated p53 upregulation via the phosphorylation of JNK, accompanying increased cardiomyocyte apoptosis that was attenuated by inhibition of p53. Importantly, elevation of 4-HNE also triggered a reduction of the cytosolic HSP70, further corroborating cytosolic action of the 4-HNE instigated by downregulation of mitochondrial ALDH2. CONCLUSIONS: Downregulation of ALDH2 in the mitochondria induced an elevation of 4-HNE, leading to cardiomyocyte apoptosis by subsequent inhibition of HSP70, phosphorylation of JNK, and activation of p53. This chain of molecular events took place in both the mitochondria and the cytosol, contributing to the mechanism underlying heart failure.


Assuntos
Aldeído Desidrogenase/metabolismo , Insuficiência Cardíaca/prevenção & controle , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Mitocôndrias Cardíacas/enzimologia , Infarto do Miocárdio/enzimologia , Miocárdio/enzimologia , Proteína Supressora de Tumor p53/metabolismo , Aldeído Desidrogenase/deficiência , Aldeído Desidrogenase/genética , Aldeído-Desidrogenase Mitocondrial , Aldeídos/metabolismo , Animais , Animais Recém-Nascidos , Apoptose , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo , Proteínas de Choque Térmico HSP70/metabolismo , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais/metabolismo , Mutação , Infarto do Miocárdio/complicações , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Fosforilação , Interferência de RNA , Ratos Sprague-Dawley , Transdução de Sinais , Fatores de Tempo , Transfecção , Disfunção Ventricular Esquerda/enzimologia , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda
10.
Yao Xue Xue Bao ; 49(5): 666-71, 2014 May.
Artigo em Chinês | MEDLINE | ID: mdl-25151739

RESUMO

In our previous work, we found that trivalent dimethylarsinous acid (DMA(III)) have high affinity binding to cysteine residue 13 of rat hemoglobin. However, it is still unknown why arsenic intermediate metabolite DMA(III) has high binding affinity for Cysl3 but not for other cysteine residues 93, 140, 111 and 125. In order to better understand the molecular mechanism of DMA(III) with rat hemoglobin, we have done current study. So, SD rats were divided into control and arsenic-treated groups randomly. Arsenic species in lysate of red blood cells were analyzed by HPLC-ICP-MS, and then determined by a hybrid quadrupole TOF MS. In addition, trivalent DMA(III) binds to different cysteine residues in rat hemoglobin alpha and beta chains were also simulated by Molecular Docking. Only Cys13 in alpha chain is able to bind to DMA(III) from the experiment results. Cys13 of alpha chain in rat hemoglobin is a specific binding site for DMA(III), and we found that amino acids compose pockets structure and surround Cys13 (but not other cysteine residues), make DMA(III) much easy to bind cysteine 13. Taken together, the DMA(III) specific binding to Cys13 is related to spatial structure of Cys13.


Assuntos
Ácido Cacodílico/análogos & derivados , Hemoglobinas/metabolismo , Fragmentos de Peptídeos/metabolismo , Animais , Arsênio/metabolismo , Sítios de Ligação , Ácido Cacodílico/química , Cromatografia Líquida de Alta Pressão , Cisteína/metabolismo , Espectrometria de Massas , Ratos
11.
Hypertens Res ; 36(10): 859-65, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23719127

RESUMO

Notch signaling is involved in an intercellular communication mechanism that is essential for coordinated cell fate determination and tissue morphogenesis. The biological effects of Notch signaling are context-dependent. We investigated the functional and hierarchical relationship between angiotensin (Ang) II receptor signaling and Notch signaling in vascular smooth muscle cells (VSMCs). A fluorogenic substrate assay revealed directly that the enzymatic activity of γ-secretase was enhanced after 10 min of Ang II stimulation in HEK293 cells expressing Ang II type 1 receptor. Notch cleavage by γ-secretase was consistently induced and peaked at 10 min after Ang II stimulation, and the Ang II-stimulated increase in Notch intracellular domain production was significantly suppressed by treatment with the γ-secretase inhibitor DAPT. Treatment with DAPT also significantly reduced the Ang II-stimulated proliferation and migration of human aortic VSMCs, as revealed by BrdU incorporation and the Boyden chamber assay, respectively. Systemic administration of the γ-secretase inhibitor dibenzazepine reduced Ang II-induced medial thickening and perivascular fibrosis in the aortas of wild-type mice. These findings suggest that the hierarchical Ang II receptor-Notch signaling pathway promotes the proliferation and migration of VSMCs, and thereby contributes to the progression of vascular remodeling.


Assuntos
Angiotensina II/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Receptores Notch/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/efeitos dos fármacos , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Aorta/citologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/fisiologia , Movimento Celular/fisiologia , Células Cultivadas , Dibenzazepinas/farmacologia , Dipeptídeos/farmacologia , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Músculo Liso Vascular/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Notch/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
12.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 42(1): 32-7, 2013 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-23505105

RESUMO

OBJECTIVE: To purify the arsenic-binding proteins (As-BP) in hamster plasma after a single oral administration of arsenite (iAs(III)). METHODS: Arsenite was given to hamsters in a single dose. Three types of HPLC columns, size exclusion, gel filtration and anion exchange columns, combined with an inductively coupled argon plasma mass spectrometer (ICP MS) were used to purify the As-BP in hamster plasma. SDS-PAGE was used to confirm the arsenic-binding proteins at each purification step. RESULTS: The three-step purification process successfully separated As-BP from other proteins (ie, arsenic unbound proteins) in hamster plasma. The molecular mass of purified As-BP in plasma was approximately 40-50 kD on SDS-PAGE. CONCLUSION: The three-step purification method is a simple and fast approach to purify the As-BP in plasma samples.


Assuntos
Arsênio/sangue , Arsenitos/administração & dosagem , Cromatografia Líquida de Alta Pressão/métodos , Administração Oral , Animais , Arsenitos/farmacocinética , Proteínas de Transporte/sangue , Cricetinae
13.
Am J Cardiol ; 110(9): 1296-301, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-22840347

RESUMO

Addition of fenofibrate to statin therapy might represent a viable treatment option for patients whose high risk for coronary heart disease is not controlled by a statin alone. However, safety of coadministration of statin with fenofibrate has been a great concern. The present study tested the safety of coadministration of statin with fenofibrate. We systematically searched the literature to identify randomized controlled trials examining safety of coadministration of statin with fenofibrate. A meta-analysis was performed to estimate safety of coadministration of statin with fenofibrate using fixed-effects models. There were 1,628 subjects in the identified 6 studies. Discontinuation attributed to any adverse events (4.5% vs 3.1%, p = 0.20), any adverse events (42% vs 41%, p = 0.82), adverse events related to study drug (10.9% vs 11.0%, p = 0.95), and serious adverse events (2.0% vs 1.5%, p = 0.71) were not significantly different in the 2 arms. Incidence of alanine aminotransferase and/or aspartate aminotransferase ≥3 times upper limit of normal in the combination therapy arm was significantly higher than in the statin monotherapy arm (3.1% vs 0.2%, p = 0.0009). In the 6 trials with 1,628 subjects no case of myopathy or rhabdomyolysis was reported. In conclusion, statin-fenofibrate combination therapy was tolerated as well as statin monotherapy. Physicians should consider statin-fenofibrate combination therapy to treat patients with mixed dyslipidemia.


Assuntos
Fenofibrato/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Fatores Etários , Idoso , Estudos Cross-Over , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Feminino , Fenofibrato/efeitos adversos , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hiperlipidemia Familiar Combinada/diagnóstico , Hiperlipidemia Familiar Combinada/mortalidade , Hipolipemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Gestão da Segurança , Índice de Gravidade de Doença , Fatores Sexuais , Taxa de Sobrevida , Resultado do Tratamento
14.
J Biol Chem ; 286(24): 21458-65, 2011 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-21525005

RESUMO

The activation of renin-angiotensin system contributes to the development of metabolic syndrome and diabetes as well as hypertension. However, it remains undetermined how renin-angiotensin system is implicated in feeding behavior. Here, we show that angiotensin II type 1 (AT(1)) receptor signaling regulates the hypothalamic neurocircuit that is involved in the control of food intake. Compared with wild-type Agtr1a(+/+) mice, AT(1) receptor knock-out (Agtr1a(-/-)) mice were hyperphagic and obese with increased adiposity on an ad libitum diet, whereas Agtr1a(-/-) mice were lean with decreased adiposity on a pair-fed diet. In the hypothalamus, mRNA levels of anorexigenic neuropeptide corticotropin-releasing hormone (Crh) were lower in Agtr1a(-/-) mice than in Agtr1a(+/+) mice both on an ad libitum and pair-fed diet. Furthermore, intracerebroventricular administration of CRH suppressed food intake both in Agtr1a(+/+) and Agtr1a(-/-) mice. In addition, the Crh gene promoter was significantly transactivated via the cAMP-responsive element by angiotensin II stimulation. These results thus demonstrate that central AT(1) receptor signaling plays a homeostatic role in the regulation of food intake by maintaining gene expression of Crh in hypothalamus and suggest a therapeutic potential of central AT(1) receptor blockade in feeding disorders.


Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Comportamento Alimentar , Regulação da Expressão Gênica , Hipotálamo/fisiologia , Receptor Tipo 1 de Angiotensina/metabolismo , Tecido Adiposo/metabolismo , Animais , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Knockout , Neuropeptídeos/química , Obesidade/metabolismo , Oligopeptídeos/química , Ácido Pirrolidonocarboxílico/análogos & derivados , Ácido Pirrolidonocarboxílico/química
15.
Hypertens Res ; 32(10): 875-83, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19662020

RESUMO

Type 1 angiotensin II (AT(1)) receptor has a critical role in the development of load-induced cardiac hypertrophy. Recently, we showed that mechanical stretching of cells activates the AT(1) receptor without the involvement of angiotensin II (AngII) and that this AngII-independent activation is inhibited by the inverse agonistic activity of the AT(1) receptor blocker (ARB), candesartan. Although the inverse agonist activity of ARBs has been studied in terms of their action on constitutively active AT(1) receptors, the structure-function relationship of the inverse agonism they exert against stretch-induced AT(1) receptor activation has not been fully elucidated. Assays evaluating c-fos gene expression and phosphorylated extracellular signal-regulated protein kinases (ERKs) have shown that olmesartan has strong inverse agonist activities against the constitutively active AT(1) receptor and the stretch-induced activation of AT(1) receptor, respectively. Ternary drug-receptor interactions, which occur between the hydroxyl group of olmesartan and Tyr(113) and between the carboxyl group of olmesartan and Lys(199) and His(256), were essential for the potent inverse agonist action olmesartan exerts against stretch-induced ERK activation and the constitutive activity of the AT(1)-N111G mutant receptor. Furthermore, the inverse agonist activity olmesartan exerts against stretch-induced ERK activation requires an additional drug-receptor interaction involving the tetrazole group of olmesartan and Gln(257) of the AT(1) receptor. These results suggest that multivalent interactions between an inverse agonist and the AT(1) receptor are required to stabilize the receptor in an inactive conformation in response to the distinct processes that lead to an AngII-independent activation of the AT(1) receptor.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Animais , Northern Blotting , Western Blotting , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Imidazóis/química , Imidazóis/farmacologia , Técnicas In Vitro , Ligantes , Losartan , Mutação , Proteínas Proto-Oncogênicas c-fos/fisiologia , RNA/biossíntese , RNA/isolamento & purificação , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/genética , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacologia
16.
EMBO Rep ; 9(2): 179-86, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18202720

RESUMO

The angiotensin II type 1 (AT(1)) receptor is a G protein-coupled receptor that has a crucial role in the development of load-induced cardiac hypertrophy. Here, we show that cell stretch leads to activation of the AT(1) receptor, which undergoes an anticlockwise rotation and a shift of transmembrane (TM) 7 into the ligand-binding pocket. As an inverse agonist, candesartan suppressed the stretch-induced helical movement of TM7 through the bindings of the carboxyl group of candesartan to the specific residues of the receptor. A molecular model proposes that the tight binding of candesartan to the AT(1) receptor stabilizes the receptor in the inactive conformation, preventing its shift to the active conformation. Our results show that the AT(1) receptor undergoes a conformational switch that couples mechanical stress-induced activation and inverse agonist-induced inactivation.


Assuntos
Receptor Tipo 1 de Angiotensina/química , Receptor Tipo 1 de Angiotensina/metabolismo , Benzimidazóis/química , Benzimidazóis/farmacologia , Linhagem Celular , Humanos , Modelos Moleculares , Estrutura Secundária de Proteína , Receptor Tipo 1 de Angiotensina/agonistas , Rotação , Estresse Mecânico , Tetrazóis/química , Tetrazóis/farmacologia
17.
Naunyn Schmiedebergs Arch Pharmacol ; 377(4-6): 393-9, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18046542

RESUMO

The angiotensin II (AngII) type 1 (AT1) receptor is a seven transmembrane-spanning G-protein-coupled receptor, and the activation of AT1 receptor plays an important role in the development of load-induced cardiac hypertrophy. Locally generated AngII was believed to trigger cardiac hypertrophy by an autocrine or paracrine mechanism. However, we found that mechanical stress can activate AT1 receptor independently of AngII. Without the involvement of AngII, mechanical stress not only activates extracellular signal-regulated kinases in vitro, but also induces cardiac hypertrophy in vivo. All of these events are inhibited by candesartan as an inverse agonist for AT1 receptor. It is conceptually novel that AT1 receptor directly mediates mechanical stress-induced cellular responses, and inverse-agonist activity emerges as an important pharmacological parameter for AT1-receptor blockers that determines their efficacy in preventing organ damage in cardiovascular diseases.


Assuntos
Angiotensina II/metabolismo , Cardiomegalia/fisiopatologia , Receptor Tipo 1 de Angiotensina/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Benzimidazóis/farmacologia , Cardiomegalia/metabolismo , Agonismo Inverso de Drogas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Estresse Mecânico , Tetrazóis/farmacologia
18.
Circ J ; 71(12): 1958-64, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18037754

RESUMO

BACKGROUND: Angiotensin II (AT) is implicated in the development of cardiac remodeling, which leads to heart failure, and pharmacological inhibition of the AT type 1 (AT1) receptor has improved mortality and morbidity in patients of heart failure. The aim of this study was to elucidate the role of the AT1 receptor in disease progression in muscle LIM protein (MLP)-deficient mice, which are susceptible to heart failure because of defective function of mechanosensors in cardiomyocytes. METHOD AND RESULTS: Hearts from MLP knockout (MLPKO) mice and MLP-AT1a receptor double knockout (DKO) mice were analyzed. MLPKO hearts showed marked chamber dilatation with cardiac fibrosis and reactivation of the fetal gene program. All of these changes were significantly milder in the DKO hearts. Impaired left ventricular (LV) contractility and filling were alleviated in DKO hearts. However, the impaired relaxation and downregulated expression of sarcoplasmic reticulum calcium-ATPase 2 were unchanged in DKO hearts. CONCLUSIONS: The AT1a receptor is involved in progression of LV remodeling and deterioration of cardiac function in the hearts of MLPKO mice. These results suggest that blockade of the receptor is effective in preventing progression of heart failure in dilated cardiomyopathy.


Assuntos
Insuficiência Cardíaca/fisiopatologia , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/fisiologia , Transdução de Sinais/fisiologia , Animais , Cardiomiopatia Dilatada , Modelos Animais de Doenças , Progressão da Doença , Feminino , Fibrose , Insuficiência Cardíaca/genética , Proteínas com Domínio LIM , Masculino , Camundongos , Camundongos Knockout , Proteínas Musculares/genética , Proteínas Musculares/fisiologia , Remodelação Ventricular
19.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 24(4): 794-7, 2007 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-17899747

RESUMO

This study was undertaken to elucidate the degradation regularity of calcium polyphosphate (CPP) scaffolds with different preparation parameters. CPP scaffolds with different main crystalline phases were prepared by controlling the particle size of the calcining stuff and the calcining heat. Specimens were soaked into Tris-buffer solution and simulated body fluid (SBF) for 60 days. Results show: alpha-CPP degrades faster than does beta-CPP, and beta-CPP degrades faster than does gamma-CPP; the lower the sinter temperature, the better the degradation of CPP morever, the degradation rate of CPP is inversely proportional to the original particle size. These data suggest that crystal type, sinter temperature and particle size influence the degradation rate of CPP markedly.


Assuntos
Implantes Absorvíveis , Substitutos Ósseos/química , Fosfatos de Cálcio/química , Polifosfatos/química , Tecidos Suporte/química , Materiais Biocompatíveis/química , Cálcio/química , Cerâmica/química , Polímeros/química
20.
Nature ; 446(7134): 444-8, 2007 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-17334357

RESUMO

Cardiac hypertrophy occurs as an adaptive response to increased workload to maintain cardiac function. However, prolonged cardiac hypertrophy causes heart failure, and its mechanisms are largely unknown. Here we show that cardiac angiogenesis is crucially involved in the adaptive mechanism of cardiac hypertrophy and that p53 accumulation is essential for the transition from cardiac hypertrophy to heart failure. Pressure overload initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenic factors, and inhibition of angiogenesis prevented the development of cardiac hypertrophy and induced systolic dysfunction. Sustained pressure overload induced an accumulation of p53 that inhibited Hif-1 activity and thereby impaired cardiac angiogenesis and systolic function. Conversely, promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation developed hypertrophy further and restored cardiac dysfunction under chronic pressure overload. These results indicate that the anti-angiogenic property of p53 may have a crucial function in the transition from cardiac hypertrophy to heart failure.


Assuntos
Baixo Débito Cardíaco/fisiopatologia , Cardiomegalia/fisiopatologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Animais , Aorta/patologia , Aorta/fisiopatologia , Pressão Sanguínea , Cardiomegalia/patologia , Circulação Coronária , Progressão da Doença , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Neovascularização Patológica , Proteína Supressora de Tumor p53/genética
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