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1.
Mol Cell ; 81(16): 3339-3355.e8, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34352206

RESUMO

Cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, but the underlying mechanisms are poorly understood. Here, we find that N7-methylguanosine (m7G) tRNA modification and its methyltransferase complex components, METTL1 and WDR4, are significantly upregulated in intrahepatic cholangiocarcinoma (ICC) and associated with poor prognosis. We further reveal the critical role of METTL1/WDR4 in promoting ICC cell survival and progression using loss- and gain-of-function assays in vitro and in vivo. Mechanistically, m7G tRNA modification selectively regulates the translation of oncogenic transcripts, including cell-cycle and epidermal growth factor receptor (EGFR) pathway genes, in m7G-tRNA-decoded codon-frequency-dependent mechanisms. Moreover, using overexpression and knockout mouse models, we demonstrate the crucial oncogenic function of Mettl1-mediated m7G tRNA modification in promoting ICC tumorigenesis and progression in vivo. Our study uncovers the important physiological function and mechanism of METTL1-mediated m7G tRNA modification in the regulation of oncogenic mRNA translation and cancer progression.


Assuntos
Colangiocarcinoma/genética , Proteínas de Ligação ao GTP/genética , Metiltransferases/genética , Biossíntese de Proteínas , Animais , Carcinogênese/genética , Colangiocarcinoma/patologia , Progressão da Doença , Receptores ErbB/genética , Guanosina/análogos & derivados , Guanosina/genética , Humanos , Camundongos , Processamento Pós-Transcricional do RNA/genética , RNA Mensageiro/genética , RNA de Transferência/genética
2.
Sci Rep ; 11(1): 6585, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33753780

RESUMO

The organogenesis and development of reproductive organs, i.e., stamen and gynoecium, are important floral characteristics that are closely related to pollinators and reproductive fitness. As a genus from Magnoliaceae, Liriodendron has only two relict species: L. chinense and L. tulipifera. Despite the similar flower shapes of these species, their natural seed-setting rates differ significantly, implying interspecies difference in floral organogenesis and development. MADS-box genes, which participate in floral organogenesis and development, remain unexplored in Liriodendron. Here, to explore the interspecies difference in floral organogenesis and development and identify MADS-box genes in Liriodendron, we examined the stamen and gynoecium primordia of the two Liriodendron species by scanning electron microscopy combined with paraffin sectioning, and then collected two types of primordia for RNA-seq. A total of 12 libraries were constructed and 42,268 genes were identified, including 35,269 reference genes and 6,999 new genes. Monoterpenoid biosynthesis was enriched in L. tulipifera. Genome-wide analysis of 32 MADS-box genes was conducted, including phylogenetic trees, exon/intron structures, and conserved motif distributions. Twenty-six genes were anchored on 17 scaffolds, and six new genes had no location information. The expression profiles of MIKC-type genes via RT-qPCR acrossing six stamen and gynoecium developmental stages indicates that the PI-like, AG/STK-like, SEP-like, and SVP-like genes may contribute to the species-specific differentiation of the organogenesis and development of reproductive organs in Liriodendron. Our findings laid the groundwork for the future exploration of the mechanism underlying on the interspecific differences in reproductive organ development and fitness in Liriodendron.

3.
Hepatology ; 74(3): 1339-1356, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33638162

RESUMO

BACKGROUND AND AIMS: The dynamic N6-methyladenosine (m6 A) mRNA modification is essential for acute stress response and cancer progression. Sublethal heat stress from insufficient radiofrequency ablation (IRFA) has been confirmed to promote HCC progression; however, whether m6 A machinery is involved in IRFA-induced HCC recurrence remains open for study. APPROACH AND RESULTS: Using an IRFA HCC orthotopic mouse model, we detected a higher level of m6 A reader YTH N6-methyladenosine RNA binding protein 1-3 (YTHDF1) in the sublethal-heat-exposed transitional zone close to the ablation center than that in the farther area. In addition, we validated the increased m6 A modification and elevated YTHDF1 protein level in sublethal-heat-treated HCC cell lines, HCC patient-derived xenograft (PDX) mouse model, and patients' HCC tissues. Functionally, gain-of-function/loss-of-function assays showed that YTHDF1 promotes HCC cell viability and metastasis. Knockdown of YTHDF1 drastically restrains the tumor metastasis evoked by sublethal heat treatment in tail vein injection lung metastasis and orthotopic HCC mouse models. Mechanistically, we found that sublethal heat treatment increases epidermal factor growth receptor (EGFR) m6 A modification in the vicinity of the 5' untranslated region and promotes its binding with YTHDF1, which enhances the translation of EGFR mRNA. The sublethal-heat-induced up-regulation of EGFR level was further confirmed in the IRFA HCC PDX mouse model and patients' tissues. Combination of YTHDF1 silencing and EGFR inhibition suppressed the malignancies of HCC cells synergically. CONCLUSIONS: The m6 A-YTHDF1-EGFR axis promotes HCC progression after IRFA, supporting the rationale for targeting m6 A machinery combined with EGFR inhibitors to suppress HCC metastasis after RFA.

4.
Cell Death Dis ; 11(3): 199, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32251270

RESUMO

Hepatocytes undergo the metaplasia into ductal biliary epithelial cells (BECs) in response to chronic injury, and subsequently contribute to liver regeneration. The mechanism underlying hepatocyte-to-ductal metaplasia has not been explored until now. In mouse models of liver fibrosis, a florid BEC response was observed in fibrotic liver, and the depletion of myofibroblasts attenuated BEC expansion remarkably. Then, in hepatocyte fate-tracing mouse model, we demonstrated the conversion of mature hepatocytes into ductal BECs in fibrotic liver, and the depletion of myofibroblasts diminished the hepatocyte-to-ductal metaplasia. Finally, the mechanism underlying the metaplasia was investigated. Myofibroblasts secreted laminin-rich extracellular matrix, and then laminin induced hepatocyte-to-ductal metaplasia through ɑvß6 integrin. Therefore, our results demonstrated myofibroblasts induce the conversion of mature hepatocytes into ductal BECs through laminin-ɑvß6 integrin, which reveals that the strategy improve regeneration in fibrotic liver through the modification of specific microenvironment.


Assuntos
Antígenos de Neoplasias/metabolismo , Integrinas/metabolismo , Laminina/metabolismo , Cirrose Hepática/fisiopatologia , Miofibroblastos/metabolismo , Animais , Proliferação de Células , Modelos Animais de Doenças , Humanos , Camundongos , Transfecção
5.
J Gastroenterol Hepatol ; 35(2): 271-277, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31247673

RESUMO

BACKGROUND AND AIMS: Diagnostic performance of ascitic fluid total protein (AFTP) concentration remained unsettled. Our aim was to determine diagnostic value of AFTP in differential diagnosis of causes of ascites. METHODS: Seven hundred four consecutive patients with new-onset ascites were prospectively enrolled in this study. RESULTS: In the training cohort, diagnostic performance of quantitative AFTP assay was superior to that of Rivalta test in differential diagnosis of ascites. At the predetermined cut-off value of 25 g/L, quantitative AFTP assay was more useful in the differentiation of non-portal hypertensive ascites from portal hypertensive ascites compared with the exudate-transudate classification, area under curve of receiver operating characteristic curve was 0.958. Quantitative AFTP assay was superior to serum-ascites albumin gradient in the detection of non-portal hypertensive ascites, especially malignant ascites and tuberculous peritonitis. In mixed ascites, AFTP was useful in identifying peritoneal lesions. CONCLUSIONS: Ascitic fluid total protein is a useful marker in non-portal hypertensive ascites; thus, it should be determined in diagnostic work-up of the patients with ascites.


Assuntos
Ascite/diagnóstico , Ascite/etiologia , Líquido Ascítico/química , Proteínas/análise , Biomarcadores/análise , Diagnóstico Diferencial , Humanos , Hipertensão/complicações
7.
Aliment Pharmacol Ther ; 49(1): 91-98, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30443960

RESUMO

BACKGROUND: The diagnostic value of ascitic cholesterol in the differential diagnosis of ascites is controversial. AIM: To investigate the diagnostic performance of ascitic cholesterol in the differential diagnosis of ascites. METHODS: Consecutive patients with new-onset ascites were enrolled prospectively. The pertinent data were collected from 629 patients with all forms of ascites. RESULTS: In the training cohort, determination of the ascitic cholesterol level was a highly effective method of distinguishing non-portal hypertension (NPH) from portal hypertension (PH). At the pre-determined cut-off value of 45 mg/dL, the sensitivity of ascitic cholesterol was superior to the serum-ascites albumin gradient (SAAG) in identifying NPH-related ascites; the area under the receiver operating characteristic curve was 0.945. In the patients misdiagnosed based on SAAG classification, the diagnostic accuracy of ascitic cholesterol was 69%. The ascitic cholesterol level showed excellent performance in identifying peritoneal lesions in patients with mixed ascites. CONCLUSION: Ascitic cholesterol is an excellent measure for detecting NPH ascites and for identifying peritoneal lesions in mixed ascites. Thus, this simple and cost-effective measure should be determined in patients with new-onset ascites (www.chictr.org.cn; ChiCTR-DCD-15006907).


Assuntos
Ascite/diagnóstico , Colesterol/sangue , Hipertensão Portal/diagnóstico , Albumina Sérica/análise , Estudos de Coortes , Diagnóstico Diferencial , Humanos , Estudos Prospectivos , Curva ROC
8.
Magn Reson Imaging ; 50: 26-37, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29545212

RESUMO

Alzheimer's disease (AD) pathology causes microstructural changes in the brain. These changes, if quantified with magnetic resonance imaging (MRI), could be studied for use as an early biomarker for AD. The aim of our study was to determine if T1 relaxation, diffusion tensor imaging (DTI), and quantitative magnetization transfer imaging (qMTI) metrics could reveal changes within the hippocampus and surrounding white matter structures in ex vivo transgenic mouse brains overexpressing human amyloid precursor protein with the Swedish mutation. Delineation of hippocampal cell layers using DTI color maps allows more detailed analysis of T1-weighted imaging, DTI, and qMTI metrics, compared with segmentation of gross anatomy based on relaxation images, and with analysis of DTI or qMTI metrics alone. These alterations are observed in the absence of robust intracellular Aß accumulation or plaque deposition as revealed by histology. This work demonstrates that multiparametric quantitative MRI methods are useful for characterizing changes within the hippocampal substructures and surrounding white matter tracts of mouse models of AD.


Assuntos
Doença de Alzheimer/patologia , Imagem de Tensor de Difusão/métodos , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Processamento de Imagem Assistida por Computador/métodos , Doença de Alzheimer/diagnóstico por imagem , Animais , Imagem de Difusão por Ressonância Magnética/métodos , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Transgênicos
9.
CNS Neurosci Ther ; 23(4): 310-320, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28191738

RESUMO

AIMS: Both amyloid deposition and neuroinflammation appear in the early course of Alzheimer's disease (AD). However, the progression of neuroinflammation and its relationship with amyloid deposition and behavioral changes have not been fully elucidated. A better understanding the role of neuroinflammation in AD might extend our current knowledge to therapeutic intervention possibilities. METHODS: This study systematically characterized changes in behavioral abnormalities in APP/PS1 transgenic mice. Brain pathology measures were performed in post-mortem brain tissues of mice from 2 to 22 months. RESULTS: APP/PS1 mice exhibited significant memory deficits from 5 months old, which were aggravated at the later stage of life. However, the degree of memory impairments reached a plateau at 12 months. An early appearance of amyloid plaques was at 3 months with a linear increase throughout the disease course. CD11b-positive microglia and glial fibrillary acidic protein-(GFAP) positive astrocytes were first detected at 3 months with a close association with amyloid plaques. Yet, the rate of changes in glial activation slowed down from 12 months despite the steady increase in Aß. CONCLUSION: These findings provided evidence that neuroinflammation might be involved in the development and progression of cognitive deficits in APP/PS1 mice, suggesting novel intervention and prevention strategies for AD.


Assuntos
Doença de Alzheimer/complicações , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Transtornos Cognitivos/etiologia , Fatores Etários , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/patologia , Antígeno CD11b/metabolismo , Transtornos Cognitivos/patologia , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/metabolismo , Mutação/genética , Neurônios/patologia , Presenilina-1/genética
10.
J Alzheimers Dis ; 55(4): 1683-1692, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27911305

RESUMO

Nitric oxide can attack thiol groups of cysteine residues in proteins and induce protein cysteine S-nitrosylation. Cholinergic and glutamatergic systems are dysregulated in Alzheimer's disease. Vesicular acetylcholine transporter (VAChT) and vesicular glutamate transporter 1 (VGLUT1) are important in packaging acetylcholine and glutamate into vesicles, which is an important step for neurotransmission. Previously we found that VAChT and VGLUT1 can be nitrosylated and that S-nitrosylation of these transporters inhibits vesicular uptake of acetylcholine and glutamate. To understand the role of VAChT and VGLUT1 nitrosylation in the pathophysiological development of Alzheimer's disease, we analyzed nitrosylation of VAChT and VGLUT1 in brain of amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice, an animal model for Alzheimer's disease. Using a Morris water maze test, we found that 9- and 12-month-old APP/PS1 mice showed memory deficit, compared to wild type mice. We further found that total protein nitrosylation was increased in frontal cortex and hippocampus of 9- and 12-month-old APP/PS1 mice. Although nitrosylation of VAChT and VGLUT1 was not changed in hippocampus of 9- and 12-month-old APP/PS1 mice, nitrosylation of VAChT and VGLUT1 was significantly increased in frontal cortex of APP/PS1 mice at these ages. We also found that nitrosylation of VAChT and VGLUT1 was increased in hippocampus (but not frontal cortex) of 3-month-old APP/PS1 mice. These findings suggest that nitrosylation of VAChT and VGLUT1 may be associated with dysfunctional acetylcholinergic and glutamatergic neurotransmission in Alzheimer's disease.


Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide/genética , Encéfalo/metabolismo , Presenilina-1/genética , Proteínas de Transporte Vesicular/metabolismo , Fatores Etários , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/farmacologia , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Linhagem Celular Transformada , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Aprendizagem em Labirinto , Camundongos , Camundongos Transgênicos , Óxido Nítrico/metabolismo , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Presenilina-1/metabolismo , Transfecção , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismo , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo
11.
Glia ; 64(2): 240-54, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26446044

RESUMO

Studies have implicated astrocytic dysfunction in Alzheimer's disease (AD). However, the role of astrocytes in the pathophysiology and treatment of the disease is poorly characterized. Here, we identified astrocytes as independent key factors involved in several Alzheimer-like phenotypes in an APP/PS1 mouse model, including amyloid pathology, altered neuronal and synaptic properties, and impaired cognition. In vitro astrocytes from APP/PS1 mice induced synaptotoxicity as well as reduced dendritic complexity and axonal branching of hippocampal neurons. These astrocytes produced high levels of soluble ß-amyloid (Aß) which could be significantly inhibited by fluoxetine (FLX) via activating serotonin 5-HT2 receptors. FLX could also protect hippocampal neurons against astrocyte-induced neuronal damage in vitro. In the same APP/PS1 mice, FLX inhibited activation of astrocytes, lowered Aß products, ameliorated neurotoxicity, and improved behavioral performance. These findings may provide a basis for the clinical application of FLX in patients, and may also lay the groundwork for exploration of other novel astrocyte-based therapies of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Astrócitos/efeitos dos fármacos , Fluoxetina/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Astrócitos/patologia , Astrócitos/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Humanos , Aprendizagem em Labirinto , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/tratamento farmacológico , Placa Amiloide/patologia , Placa Amiloide/fisiopatologia , Presenilina-1/genética , Presenilina-1/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo
12.
Neurochem Res ; 39(12): 2385-93, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25270429

RESUMO

Use of phencyclidine (PCP) in rodents can mimic some aspects of schizophrenia. However, the underlying mechanism is still unclear. Growing evidence indicates that neuroinflammation plays a significant role in the pathophysiology of schizophrenia. In this study, we focused on inflammatory responses as target of PCP for inducing schizophrenia-like symptoms. 3-month-old C57BL/6J mice received daily injections of PCP (20 mg/kg, i.p.) or saline for one week. PCP-injected mice produced schizophrenia-like behaviours including impaired spatial short-term memory assessed by the Y-maze task and sensorimotor gating deficits in a prepulse inhibition task. Simultaneously, chronic PCP administration induced astrocyte and microglial activation in both the cortex and hippocampus. Additionally, the proinflammatory cytokine interleukin-1ß was significantly up-regulated in PCP administrated mice. Furthermore, PCP treatment decreased ratio of the phospho-Ser9 epitope of glycogen synthase kinase-3ß (GSK3ß) over total GSK3ß, which is indicative of increased GSK3ß activity. These data demonstrate that chronic PCP in mouse produces inflammatory responses and GSK3ß activation.


Assuntos
Quinase 3 da Glicogênio Sintase/metabolismo , Inflamação/induzido quimicamente , Fenciclidina/toxicidade , Animais , Ativação Enzimática , Glicogênio Sintase Quinase 3 beta , Camundongos
13.
CNS Neurosci Ther ; 20(12): 1045-55, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25230377

RESUMO

INTRODUCTION: A basal level of mitophagy is essential in mitochondrial quality control in physiological conditions, while excessive mitophagy contributes to cell death in a number of diseases including ischemic stroke. Signals regulating this process remain unknown. BNIP3, a pro-apoptotic BH3-only protein, has been implicated as a regulator of mitophagy. AIMS: Both in vivo and in vitro models of stroke, as well as BNIP3 wild-type and knock out mice were used in this study. RESULTS: We show that BNIP3 and its homologue BNIP3L (NIX) are highly expressed in a "delayed" manner and contribute to delayed neuronal loss following stroke. Deficiency in BNIP3 significantly decreases both neuronal mitophagy and apoptosis but increases nonselective autophagy following ischemic/hypoxic insults. The mitochondria-localized BNIP3 interacts with the autophagosome-localized LC3, suggesting that BNIP3, similar to NIX, functions as a LC3-binding receptor on mitochondria. Although NIX expression is upregulated when BNIP3 is silenced, up-regulation of NIX cannot functionally compensate for the loss of BNIP3 in activating excessive mitophagy. CONCLUSIONS: NIX primarily regulates basal level of mitophagy in physiological conditions, whereas BNIP3 exclusively activates excessive mitophagy leading to cell death.


Assuntos
Regulação da Expressão Gênica/genética , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Mitocondriais/metabolismo , Mitofagia/fisiologia , Neurônios/patologia , Animais , Animais Recém-Nascidos , Infarto Encefálico/etiologia , Morte Celular/fisiologia , Células Cultivadas , Córtex Cerebral/citologia , Citocromos c/metabolismo , Modelos Animais de Doenças , Embrião de Mamíferos , Glucose/deficiência , Hipóxia/metabolismo , L-Lactato Desidrogenase/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais/genética , Mitofagia/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/ultraestrutura , Acidente Vascular Cerebral/complicações , Fatores de Tempo
14.
Neuroreport ; 25(14): 1151-5, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25089805

RESUMO

The chronic stress model was developed on the basis of the stress-diathesis hypothesis of depression. However, these behavioural responses associated with different stress paradigms are quite complex. This study examined the effects of two chronic stress regimens on anxiety-like and depressive behaviours. C57BL/6 mice were subjected to unpredictable chronic mild stress or to chronic restraint stress for 4 weeks. Subsequently, both anxiety-like behaviours (open field, elevated plus maze and novelty suppressed feeding) and depression-like behaviours (tail suspension, forced swim and sucrose preference) were evaluated. Both chronic stress models generated anxiety-like behaviours, whereas only unpredictable chronic mild stress could induce depressive behaviours such as increased immobility and decreased sucrose consumption. These results of the present study provide additional evidence on how chronic stress affects behavioural responses and point to the importance of the validity of animal models of chronic stress in studying depression.


Assuntos
Transtorno Depressivo/etiologia , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Estresse Psicológico/complicações , Estresse Psicológico/fisiopatologia , Animais , Ansiedade/etiologia , Ansiedade/fisiopatologia , Doença Crônica , Sacarose na Dieta/administração & dosagem , Comportamento de Ingestão de Líquido/fisiologia , Feminino , Camundongos Endogâmicos C57BL , Atividade Motora/fisiologia , Testes Psicológicos , Restrição Física , Incerteza
15.
Curr Alzheimer Res ; 11(7): 672-80, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25115542

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disorder of the central nervous system. Current approaches for AD treatment only ameliorate symptoms. Therapeutic strategies that target the pathological processes of the disease remain elusive. Fluoxetine (FLX) is one of the most widely used antidepressants for the treatment of depression and anxiety associated with AD, however, it is unknown if the drug affects the pathogenesis of the disease. We showed that FLX improved spatial memory, learning and emotional behaviors of APP/PS1 mice, a well characterized model of AD. In the same mice, FLX effectively prevented the protein loss of synaptophysin (SYP) and microtubuleassociated protein 2 (MAP2). FLX was unable to prevent plaque formation, but significantly lowered high levels of soluble ß-amyloid (Aß) in brain tissue, cerebrospinal fluid (CSF) and blood sera. FLX also effectively inhibited the phosphorylation of amyloid precursor protein (APP) at T668, which may be a possible mechanism of the reduced Aß production in APP/PS1 mouse after treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/metabolismo , Fluoxetina/farmacologia , Nootrópicos/farmacologia , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Emoções/efeitos dos fármacos , Emoções/fisiologia , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Fosforilação/efeitos dos fármacos , Placa Amiloide/tratamento farmacológico , Placa Amiloide/patologia , Placa Amiloide/fisiopatologia , Aprendizagem Espacial/efeitos dos fármacos , Aprendizagem Espacial/fisiologia , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia , Sinaptofisina/metabolismo
16.
J Neurochem ; 131(2): 229-38, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24934403

RESUMO

Serotonin/norepinephrine reuptake inhibitors antidepressants exert their effects by increasing serotonin and norepinephrine in the synaptic cleft. Studies show it takes 2-3 weeks for the mood-enhancing effects, which indicate other mechanisms may underlie their treatment effects. Here, we investigated the role of white matter in treatment and pathogenesis of depression using an unpredictable chronic mild stress (UCMS) mouse model. Desvenlafaxine (DVS) was orally administrated to UCMS mice at the dose of 10 mg/kg/day 1 week before they went through a 7-week stress procedure and lasted for over 8 weeks before the mice were killed. No significant changes were found for protein markers of neurons and astrocytes in UCMS mice. However, myelin and oligodendrocyte-related proteins were significantly reduced in UCMS mice. DVS prevented the stress-induced injury to white matter and the decrease of phosphorylated 5'-AMP-activated protein kinase and 3-hydroxy-3-methyl-glutaryl-CoA reductase protein expression. DVS increased open arm entries in an elevated plus-maze test, sucrose consumption in the sucrose preference test and decreased immobility in tail suspension and forced swimming tests. These findings suggest that stress induces depression-like behaviors and white matter deficits in UCMS mice. DVS may ameliorate the oligodendrocyte dysfunction by affecting cholesterol synthesis, alleviating the depression-like phenotypes in these mice. We examined the possible role of oligodendrocyte and myelin in the pathological changes of depression with an unpredictable chronic mild stress (UCMS) mouse model. Oligodendrocyte-related proteins in the mouse brain were specifically changed during the stress period. The depressive-like behaviors and oligodendrocyte deficits could be prevented by the administration of desvenlafaxine. Oligodendrocyte and myelin may be an essential target of desvenlafaxine for the treatment of depression.


Assuntos
Colesterol/biossíntese , Cicloexanóis/uso terapêutico , Depressão/tratamento farmacológico , Depressão/enzimologia , Modelos Animais de Doenças , Substância Branca/enzimologia , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Cicloexanóis/farmacologia , Depressão/patologia , Succinato de Desvenlafaxina , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Distribuição Aleatória , Substância Branca/efeitos dos fármacos , Substância Branca/patologia
17.
Brain Res ; 1576: 81-90, 2014 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-24971831

RESUMO

The unpredictable chronic mild stress (UCMS) model was developed based upon the stress-diathesis hypothesis of depression. Most effects of UCMS can be reversed by antidepressants, demonstrating a strong predictive validity of this model for depression. However, the mechanisms underlying the effects induced by UCMS remain incompletely understood. Increasing evidence has shown that AMP-activated protein kinase (AMPK) regulates intracellular energy metabolism and is especially important for neurons because neurons are known to have small energy reserves. Abnormalities in the AMPK pathway disturb normal brain functions and synaptic integrity. In the present study, we first investigated the effects of UCMS on a battery of different tests measuring anxiety and depression-like behaviors in female C57BL/6N mice after 4 weeks of UCMS exposure. Stressed mice showed suppressed body weight gain, heightened anxiety, and increased immobility in the forced swim and tail suspension tests. These results are representative of some of the core symptoms of depression. Simultaneously, we observed decrease of synaptic proteins in the cortex of mice subjected to UCMS, which is associated with decreased levels of phosphorylated AMP-activated protein kinase α (AMPKα) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase). Our findings suggest that AMPKα inactivation might be a mechanism by which UCMS causes anxiety/depression-like behaviors in mice.


Assuntos
Proteínas Quinases Ativadas por AMP/fisiologia , Ansiedade/etiologia , Córtex Cerebral/enzimologia , Depressão/etiologia , Desamparo Aprendido , Proteínas do Tecido Nervoso/fisiologia , Estresse Fisiológico/fisiologia , Estresse Psicológico/complicações , Animais , Ansiedade/enzimologia , Peso Corporal , Depressão/enzimologia , Ativação Enzimática , Comportamento Exploratório , Comportamento Alimentar , Feminino , Hidroximetilglutaril-CoA Redutases/metabolismo , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Processamento de Proteína Pós-Traducional , Restrição Física , Estresse Psicológico/enzimologia
18.
J Neurochem ; 130(6): 780-9, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24862291

RESUMO

Previous studies have demonstrated that quetiapine (QTP) may have neuroprotective properties; however, the underlying mechanisms have not been fully elucidated. In this study, we identified a novel mechanism by which QTP increased the synthesis of ATP in astrocytes and protected GABAergic neurons from aging-induced death. In 12-month-old mice, QTP significantly improved cell number of GABAegic neurons in the cortex and ameliorated anxiety-like behaviors compared to control group. Complimentary in vitro studies showed that QTP had no direct effect on the survival of aging GABAergic neurons in culture. Astrocyte-conditioned medium (ACM) pretreated with QTP (ACMQTP) for 24 h effectively protected GABAergic neurons against aging-induced spontaneous cell death. It was also found that QTP boosted the synthesis of ATP from cultured astrocytes after 24 h of treatment, which might be responsible for the protective effects on neurons. Consistent with the above findings, a Rhodamine 123 test showed that ACMQTP, not QTP itself, was able to prevent the decrease in mitochondrial membrane potential in the aging neurons. For the first time, our study has provided evidence that astrocytes may be the conduit through which QTP is able to exert its neuroprotective effects on GABAergic neurons. The neuroprotective properties of quetiapine (QTP) have not been fully understood. Here, we identify a novel mechanism by which QTP increases the synthesis of ATP in astrocytes and protects GABAergic neurons from aging-induced death in a primary cell culture model. In 12-month-old mice, QTP significantly improves cell number of GABAegic neurons and ameliorates anxiety-like behaviors. Our study indicates that astrocytes may be the conduit through which QTP exerts its neuroprotective effects on GABAergic neurons.


Assuntos
Envelhecimento/psicologia , Antipsicóticos/farmacologia , Ansiedade/psicologia , Astrócitos/fisiologia , Comportamento Animal/efeitos dos fármacos , Dibenzotiazepinas/farmacologia , Neurônios/efeitos dos fármacos , Substâncias Protetoras , Ácido gama-Aminobutírico/fisiologia , Trifosfato de Adenosina/biossíntese , Trifosfato de Adenosina/metabolismo , Animais , Contagem de Células , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultivo Condicionados , Escuridão , Comportamento Exploratório/efeitos dos fármacos , Feminino , Imuno-Histoquímica , Luz , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Cultura Primária de Células , Fumarato de Quetiapina , Regulação para Cima/efeitos dos fármacos
19.
Int J Neuropsychopharmacol ; 18(3)2014 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-25618401

RESUMO

BACKGROUND: In Alzheimer's disease, growing evidence has shown that uncontrolled glial activation and neuroinflammation may contribute independently to neurodegeneration. Antiinflammatory strategies might provide benefits for this devastating disease. The aims of the present study are to address the issue of whether glial activation and proinflammatory cytokine increases could be modulated by quetiapine in vivo and in vitro and to explore the underlying mechanism. METHODS: Four-month-old amyloid precursor protein (APP) and presenilin 1 (PS1) transgenic and nontransgenic mice were treated with quetiapine (5mg/kg/d) in drinking water for 8 months. Animal behaviors, total Aß levels, and glial activation were evaluated by behavioral tests, enzyme-linked immunosorbent assay, immunohistochemistry, and Western blot accordingly. Inflammatory cytokines and the nuclear factor kappa B pathway were analyzed in vivo and in vitro. RESULTS: Quetiapine improves behavioral performance, marginally affects total Aß40 and Aß42 levels, attenuates glial activation, and reduces proinflammatory cytokines in APP/PS1 mice. Quetiapine suppresses Aß1-42-induced activation of primary microglia by decresing proinflammatory cytokines. Quetiapine inhibits the activation of nuclear factor kappa B p65 pathway in both transgenic mice and primary microglia stimulated by Aß1-42. CONCLUSIONS: The antiinflammatory effects of quetiapine in Alzheimer's disease may be involved in the nuclear factor kappa B pathway. Quetiapine may be an efficacious and promising treatment for Alzheimer's disease targeting on neuroinflammation.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Citocinas/metabolismo , Dibenzotiazepinas , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/farmacologia , Precursor de Proteína beta-Amiloide/genética , Animais , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Células Cultivadas , Córtex Cerebral/citologia , Dibenzotiazepinas/farmacologia , Dibenzotiazepinas/uso terapêutico , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Camundongos , Camundongos Transgênicos , Mutação/genética , Presenilina-1/genética , Fumarato de Quetiapina , Reconhecimento Psicológico/efeitos dos fármacos
20.
Curr Alzheimer Res ; 10(9): 979-86, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24117120

RESUMO

Serum levels of ß-amyloid (Aß) peptides may represent an early biomarker in the diagnosis of Alzheimer's disease (AD). In the present study, we investigated the temporal kinetic changes in the levels of serum Aß 1-42 and 40 in an amyloid precursor protein (APP)/presenilin (PS)1 double transgenic mouse model of AD. Serum Aß peptide levels in 2-, 3-, 6-, 9- and 18-month old, and liver Aß 1-40 level in 6-month old mice were measured using enzyme-linked immunosorbent assay (ELISA) kits. Results revealed that serum Aß levels peaked in 3-month old transgenic mice, and the Aß level in non-transgenic and transgenic mice is comparable in liver. Compared to the 6-month old transgenic mice, Congo red staining showed that the 3-month old transgenic mice had minimum brain Aß plaques, corresponding to the early stage of Alzheimer-like plaque pathology, and confocal microscope images showed that the deposition of Aß in their cerebral vessels was minimal. Furthermore, results of the water maze test, showed that memory was normal for the 3- month old transgenic mice when compared to age-matched non-transgenic mice. These results suggest that serum Aß peptide levels may be peaked during the early stage of AD. Monitoring serum Aß peptide levels in the potential AD population may provide an early diagnosis of AD prior to the appearance of clinical symptoms.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/sangue , Encéfalo/patologia , Placa Amiloide/patologia , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Progressão da Doença , Diagnóstico Precoce , Aprendizagem em Labirinto , Camundongos , Camundongos Transgênicos , Placa Amiloide/genética , Presenilina-1/genética
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