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1.
Mol Nutr Food Res ; 67(20): e2200496, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37650271

RESUMO

SCOPE: The present study aims to assess the protective effect of Lactobacillus johnsonii JNU3402 (LJ3402) against diet-induced non-alcoholic fatty liver disease (NAFLD) and determine the mechanism underlying its beneficial effect on the liver in mice. METHODS AND RESULTS: Seven-week-old male mice are fed a high-fat diet (HFD) with or without oral supplementation of LJ3402 for 14 weeks. In mice fed an HFD, LJ3402 administration alleviates liver steatosis, diet-induced obesity, and insulin resistance with a decreased hepatic expression of sterol-regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), and an increased phosphorylation of SREBP-1c. The mechanistic study shows that LJ3402 inhibits SREBP-1c transcriptional activity by enhancing protein kinase A (PKA)-mediated phosphorylation and reduces the expression of its lipogenic target genes in AML12 and HepG2 cells, thereby attenuating hepatic lipid accumulation. Moreover, silencing the PKA α catalytic subunit or the inhibition of PKA activity by H89 abolishes LJ3402 suppression of free fatty acid (FFA)-induced SREBP-1c activity in hepatocytes. In addition, LJ3402 administration elevates the plasma lactate levels in mice fed an HFD; this lactate increases PKA-mediated SREBP-1c phosphorylation in AML12 cells with a decreased expression of its target genes, reducing hepatic lipid accumulation. CONCLUSION: LJ3402 attenuates HFD-induced fatty liver in mice through the lactate-PKA-SREBP-1c pathway.


Assuntos
Lactobacillus johnsonii , Hepatopatia Gordurosa não Alcoólica , Masculino , Camundongos , Animais , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Lactobacillus johnsonii/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/metabolismo , Metabolismo dos Lipídeos , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos não Esterificados/farmacologia , Lactatos , Camundongos Endogâmicos C57BL
2.
Sci Rep ; 12(1): 9723, 2022 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-35697846

RESUMO

The production of pharmacological vaccines in plants has been an important goal in the field of plant biotechnology. GA733-2, the protein that is also known as colorectal carcinoma (CRC)-associated antigen, is a strong candidate to produce a colorectal cancer vaccine. Tomato is the one of the major targets for production of an edible vaccine, as tomato is a fruit consumed in fresh form. It also contains high content of vitamins that aid activation of immune response. In order to develop an edible colorectal cancer vaccine, the transgene rGA733-Fc that encodes a fusion protein of GA733-2, the fragment crystallizable (Fc) domain, and the ER retention motif (rGA733-Fc) was introduced into tomato plants (Solanum lycopersicum cv. Micro-Tom). The transgenic plants producing rGA733-Fc (rGA733-FcOX) protein were screened based on stable integration of transgene expression cassette and expression level of rGA733-Fc protein. Further glycosylation pattern analysis revealed that plant derived rGA733-Fc protein contains an oligomannose glycan structure, which is a typical glycosylation pattern found on ER-processing proteins. The red fruits of rGA733-FcOX transgenic tomato plants containing approximately 270 ng/g FW of rGA733-Fc protein were orally administered to C57BL/6 mice. Oral administration of tomato fruits of the rGA733-Fc expressing transgenic plants delayed colorectal cancer growth and stimulated immune responses compared to oral administration of tomato fruits of the h-Fc expressing transgenic plants in the C57BL/6J mice. This is the first study showing the possibility of producing an edible colorectal cancer vaccine using tomato plants. This research would be helpful for development of plant-derived cancer edible vaccines.


Assuntos
Neoplasias Colorretais , Solanum lycopersicum , Animais , Antígenos de Neoplasias , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Frutas/genética , Frutas/metabolismo , Imunoterapia , Solanum lycopersicum/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Plantas Geneticamente Modificadas/metabolismo
4.
Integr Cancer Ther ; 20: 15347354211006191, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33884928

RESUMO

Chelidonium majus has been used as a traditional medicine in China and western countries for various diseases, including inflammation and cancer. However, the anti-cancer effect of chelidonine, a major compound of C. majus extracts, on pancreatic cancer remains poorly understood. In this study, we found that treatment with chelidonine inhibited proliferation of BxPC-3 and MIA PaCa-2 human pancreatic cancer cells. Annexin-V/propidium iodide staining assay showed that this growth inhibitory effect of chelidonine was induced through apoptosis. We found that chelidonine treatment upregulated mRNA levels and transcription factor activity in both cell lines. Increases in protein expression levels of p53, GADD45A, p21 and cleaved caspase-3 were also observed, with more distinct changes in MIA PaCa-2 cells compared to the BxPC-3 cells. These results suggest that chelidonine induces pancreatic cancer apoptosis through the p53 and GADD45A pathways. Our findings provide new insights into the use of chelidonine for the treatment of pancreatic cancer.


Assuntos
Neoplasias Pancreáticas , Proteína Supressora de Tumor p53 , Apoptose , Benzofenantridinas/farmacologia , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Proteína Supressora de Tumor p53/genética
6.
ACS Nano ; 14(12): 16973-16983, 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33236883

RESUMO

Extracellular deposition of ß-amyloid (Aß) peptide aggregates is a major characteristic of Alzheimer's disease (AD) brain. Because Aß peptide aggregates aggravate neuropathy and cognitive impairment for AD patients, numerous efforts have been devoted to suppressing Aß self-assembly as a prospective AD treatment option. Here, we report Aß-targeting, red-light-responsive carbon dots (CDs), and their therapeutic functions as a light-powered nanomodulator to spatiotemporally suppress toxic Aß aggregation both in vitro and in vivo. Our aptamer-functionalized carbon dots (Apta@CDs) showed strong targeting ability toward Aß42 species. Moreover, red LED irradiation induced Apta@CDs to irreversibly denature Aß peptides, impeding the formation of ß-sheet-rich Aß aggregates and attenuating Aß-associated cytotoxicity. Consequently, Apta@CDs-mediated photomodualtion modality achieved effective suppression of Aß aggregation in vivo, which significantly reduced the Aß burden at the targeted sites in the brain of 5xFAD mice by ∼40% and ∼25% according to imaging and ELISA analyses, respectively. Our work demonstrates the therapeutic potential of photomodulating CDs for light-driven suppression against Aß self-assembly and related neurotoxicity.

7.
Nat Commun ; 11(1): 1860, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32312952

RESUMO

Ependymal cells (ECs) are multiciliated neuroepithelial cells that line the ventricles of the brain and the central canal of the spinal cord (SC). How ependymal motile cilia are maintained remains largely unexplored. Here we show that zebrafish embryos deficient in Wnt signaling have defective motile cilia, yet harbor intact basal bodies. With respect to maintenance of ependymal motile cilia, plcδ3a is a target gene of Wnt signaling. Lack of Connexin43 (Cx43), especially its channel function, decreases motile cilia and intercellular Ca2+ wave (ICW) propagation. Genetic ablation of cx43 in zebrafish and mice diminished motile cilia. Finally, Cx43 is also expressed in ECs of the human SC. Taken together, our findings indicate that gap junction mediated ICWs play an important role in the maintenance of ependymal motile cilia, and suggest that the enhancement of functional gap junctions by pharmacological or genetic manipulations may be adopted to ameliorate motile ciliopathy.


Assuntos
Cílios/metabolismo , Conexina 43/metabolismo , Conexinas/metabolismo , Epêndima/metabolismo , Medula Espinal/metabolismo , Peixe-Zebra/embriologia , Animais , Diferenciação Celular , Cílios/genética , Conexina 43/genética , Epêndima/patologia , Junções Comunicantes , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Inativação de Genes , Humanos , Masculino , Camundongos , Camundongos Knockout , Transdução de Sinais/genética , Via de Sinalização Wnt/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
8.
Neurosci Lett ; 714: 134579, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31669315

RESUMO

Nondystrophic myotonias are disorders of Na+ (Nav1.4 or SCN4A) and Cl- (CLCN1) channels in skeletal muscles, and frequently show phenotype heterogeneity. The molecular mechanism underlying their pathophysiology and phenotype heterogeneity remains unclear. As zebrafish models have been recently exploited for studies of the pathophysiology and phenotype heterogeneity of various human genetic diseases, a zebrafish model may be useful for delineating nondystrophic myotonias. Here, we generated transgenic zebrafish expressing a human mutant allele of SCN4A, referred to as Tg(mylpfa:N440K), and needle electromyography revealed increased number of myotonic discharges and positive sharp waves in the muscles of Tg(mylpfa:N440K) than in controls. In addition, forced exercise test at a water temperature of 24 °C showed a decrease in the distance moved, time spent in and number of visits to the zone with stronger swimming resistance. Finally, a forced exercise test at a water temperature of 18 °C exhibited a higher number of dive-bombing periods and drifting-down behavior than in controls. These findings indicate that Tg(mylpfa:N440K) is a good vertebrate model of exercise- and cold-induced human nondystrophic myotonias. This zebrafish model may contribute to provide insight into the pathophysiology of myotonia in sodium channelopathy and could be used to explore a new therapeutic avenue.


Assuntos
Temperatura Baixa , Modelos Animais de Doenças , Músculo Esquelético/fisiopatologia , Miotonia Congênita/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Esforço Físico , Peixe-Zebra , Animais , Animais Geneticamente Modificados , Eletromiografia , Mutação de Sentido Incorreto , Miotonia/genética , Miotonia/fisiopatologia , Miotonia Congênita/fisiopatologia , Transtornos Miotônicos/genética , Transtornos Miotônicos/fisiopatologia , Paralisia Periódica Hiperpotassêmica/genética , Paralisia Periódica Hiperpotassêmica/fisiopatologia
9.
Sci Rep ; 9(1): 20152, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882939

RESUMO

Browning of white adipose tissue (WAT) is currently considered a potential therapeutic strategy to treat diet-induced obesity. While some probiotics have protective effects against diet-induced obesity, the role of probiotics in adipose browning has not been explored. Here, we show that administration of the probiotic bacterium Lactobacillus amylovorus KU4 (LKU4) to mice fed a high-fat diet (HFD) enhanced mitochondrial levels and function, as well as the thermogenic gene program (increased Ucp1, PPARγ, and PGC-1α expression and decreased RIP140 expression), in subcutaneous inguinal WAT and also increased body temperature. Furthermore, LKU4 administration increased the interaction between PPARγ and PGC-1α through release of RIP140 to stimulate Ucp1 expression, thereby promoting browning of white adipocytes. In addition, lactate, the levels of which are elevated in plasma of HFD-fed mice following LKU4 administration, elicited the same effect on the interaction between PPARγ and PGC-1α in 3T3-L1 adipocytes, leading to a brown-like adipocyte phenotype that included enhanced Ucp1 expression, mitochondrial levels and function, and oxygen consumption rate. Together, these data reveal that LKU4 facilitates browning of white adipocytes through the PPARγ-PGC-1α transcriptional complex, at least in part by increasing lactate levels, leading to inhibition of diet-induced obesity.


Assuntos
Tecido Adiposo/metabolismo , Dieta Hiperlipídica , Lactobacillus acidophilus/fisiologia , Obesidade/etiologia , Obesidade/metabolismo , PPAR gama/metabolismo , Probióticos , Transdução de Sinais , Células 3T3-L1 , Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Biomarcadores , Linhagem Celular , Dieta Hiperlipídica/efeitos adversos , Suscetibilidade a Doenças , Expressão Gênica , Humanos , Metabolismo dos Lipídeos , Camundongos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fenótipo , Probióticos/administração & dosagem , Ligação Proteica
10.
Biosens Bioelectron ; 146: 111753, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31600627

RESUMO

Nicotinamide adenine nucleotide phosphate (NADPH) has been known to be involved in the multiple pathways of cell metabolism. However, conventional quantification assays for NADPH have required breaking down the cell membranes of around one million cells per assay, and monitoring NADPH flux in living cells has been limited by a few available tools. Here, we visualized NADPH levels in human cervical cancer cells HeLa using metagenome-derived blue fluorescent protein (mBFP), which specifically binds to NADPH and enhances the intrinsic fluorescence of NADPH up to 10-fold when imaged by two-photon microscopy to reduce photodamage. Adding an oxidizing agent such as diamide to HeLa cells that expressed mBFP led to an immediate decrease of intracellular NADPH depending on glucose availability in culture media. Furthermore, inhibiting glucose-6-phosphate dehydrogenase (G6PD) in the pentose phosphate pathway with dehydroandrosterone (DHEA) and knockdown of G6PD transcripts gradually decreased NADPH when diamide was added to living cells. These results demonstrate that introducing a bacterial mBFP gene into mammalian cells is a straightforward approach to monitoring intracellular NADPH flux in real time at the single-cell level. Moreover, this strategy can be expanded to tracking the spatio-temporal changes in NADPH even in single-cell organelles such as mitochondria and chloroplasts, which will allow us to more precisely assess the efficacy of biochemically or biophysically metabolic perturbations in animal and plant cells.


Assuntos
Técnicas Biossensoriais/métodos , Corantes Fluorescentes/análise , Proteínas Luminescentes/análise , NADP/análise , Corantes Fluorescentes/metabolismo , Células HeLa , Humanos , Proteínas Luminescentes/metabolismo , Microscopia de Fluorescência por Excitação Multifotônica/métodos , NADP/metabolismo
11.
Oncogene ; 38(49): 7416-7432, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31420606

RESUMO

The cell surface receptor tyrosine kinase (RTK) exists in a dynamic state, however, it remains unknown how single membrane-spanning RTK proteins are retained in the plasma membrane before their activation. This study was undertaken to investigate how RTK proteins are anchored in the plasma membrane before they bind with their respective extracellular ligands for activation through protein-protein interaction, co-localization, and functional phenotype studies. Here we show that unconventional myosin-I MYO1D functions to hold members of the EGFR family (except ErbB3) at the plasma membrane. MYO1D binds only with unphosphorylated EGFRs and anchors them to underlying actin cytoskeleton at the plasma membrane. The C-terminal end region of the MYO1D tail domain containing a ß-meander motif is critical for direct binding with kinase domain of the EGFR family, and expression of the tail domain alone suppresses the oncogenic action of full-length MYO1D. Overexpressed MYO1D increases colorectal and breast cancer cell motility and viability through upregulating EGFR level, and thereby promotes colorectal tumor progression in a syngeneic mouse model. MYO1D is upregulated in human colorectal cancer tissues from advanced stages. Collectively, molecular motor MYO1D plays a distinct role in the dynamic regulation of EGFR family levels by holding them at the plasma membrane before their activation. Overexpressed MYO1D contributes to colorectal carcinogenesis possibly as a novel oncogene and thus may serve as an additional target for suppression of RTK signaling in cancer treatment.


Assuntos
Carcinogênese/patologia , Membrana Celular/metabolismo , Neoplasias Colorretais/patologia , Miosinas/fisiologia , Citoesqueleto de Actina/metabolismo , Animais , Apoptose , Carcinogênese/genética , Carcinogênese/metabolismo , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Domínios Proteicos , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Biochem Biophys Res Commun ; 518(1): 80-86, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31421829

RESUMO

Noxa is a weak apoptosis activator consisting of a BH3 domain and a mitochondrial-targeting domain (MTD). BH3 binds Mcl-1 and Bcl2A1 and inactivates their anti-apoptotic activities, while MTD delivers BH3 to mitochondria. Previously we revealed that MTD may also function as an inducer of necrosis via conjugation with octa-arginine, which induces cytosolic Ca2+ influx from mitochondria. However, the mechanism(s) underlying this process has not been elucidated yet. Here, we show that calcium influx induced by an MTD peptide fused with octa-arginine residue (R8:MTD) originates not only from mitochondria but also from the extracellular space. However, calcium spikes were not sufficient for necrosis. R8:MTD induced mitochondrial permeability transition pore opening, fragmentation, and swelling. These mitochondrial events induced by MTD appeared to be necessary for necrosis induction, since DIDS, a VDAC inhibitor, inhibited the mitochondrial swelling and cell death induced by MTD. We show that R8:MTD disrupted endoplasmic reticulum (ER) structures but not peroxisomes or Golgi, indicating that R8:MTD causes necrosis by inducing ER events as well.


Assuntos
Retículo Endoplasmático/metabolismo , Mitocôndrias/metabolismo , Peptídeos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/química , Ácido 4,4'-Di-Isotiocianoestilbeno-2,2'-Dissulfônico/farmacologia , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Citosol/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Espaço Extracelular/metabolismo , Células HeLa , Humanos , Mitocôndrias/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Dilatação Mitocondrial/efeitos dos fármacos , Peptídeos/química , Domínios Proteicos , Canais de Ânion Dependentes de Voltagem/antagonistas & inibidores , Canais de Ânion Dependentes de Voltagem/metabolismo
13.
J Comp Neurol ; 527(8): 1388-1400, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30620049

RESUMO

Terminal Schwann cells (SCs) are nonmyelinating glia that are a prominent component of the neuromuscular junction (NMJ) where motor neurons form synapses onto muscle fibers. These cells play important roles not only in development and maintenance of the neuromuscular synapse but also restoring synaptic function after nerve damage. In response to muscle denervation, terminal SCs undergo dramatic changes in their gene expression patterns as well as in their morphology, such as extending elaborate processes into inter-junctional space. These SC processes serve as a path to guide axon terminal sprouts from nearby innervated junctions, promoting rapid reinnervation of denervated fibers. We studied the role of terminal SCs in synapse reformation by using two different fluorescent proteins to simultaneously label motor axons and SCs; we examined these junctions repeatedly in living animals using a fluorescence microscope. Here, we show that alterations in the patterns of muscle innervation following recovery from nerve injury can be explained by SC guidance of regenerating axons. In turn, this guidance leads to remodeling of the NMJ itself.


Assuntos
Regeneração Nervosa/fisiologia , Junção Neuromuscular , Traumatismos dos Nervos Periféricos/fisiopatologia , Células de Schwann , Sinapses , Animais , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Músculo Esquelético/inervação
14.
J Endocrinol ; 237(2): 87-100, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29507043

RESUMO

Obesity is a major threat to public health, and it is strongly associated with insulin resistance and fatty liver disease. Here, we demonstrated that administration of Lactobacillus acidophilus NS1 (LNS1) significantly reduced obesity and hepatic lipid accumulation, with a concomitant improvement in insulin sensitivity, in high-fat diet (HFD)-fed mice. Furthermore, administration of LNS1 inhibited the effect of HFD feeding on the SREBP-1c and PPARα signaling pathways and reduced lipogenesis with an increase in fatty acid oxidation in ex vivo livers from HFD-fed mice. These LNS1 effects were confirmed in HepG2 cells and ex vivo livers by treatment with LNS1 culture supernatant (LNS1-CS). Interestingly, AMPK phosphorylation and activity in the liver of HFD-fed mice were increased by administration of LNS1. Consistently, chemical inhibition of AMPK with compound C, a specific inhibitor of AMPK, dramatically reduced the effect of LNS1-CS on lipid metabolism in HepG2 cells and ex vivo livers by modulating the SREBP-1c and PPARα signaling pathways. Furthermore, administration of LNS1 to HFD-fed mice significantly improved insulin resistance and increased Akt phosphorylation in the liver, white adipose tissue and skeletal muscle. Together, these data suggest that LNS1 may prevent diet-induced obesity and related metabolic disorders by improving lipid metabolism and insulin sensitivity through an AMPK→SREBP-1c/PPARα signaling pathway.


Assuntos
Lactobacillus acidophilus/fisiologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade/prevenção & controle , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Células Hep G2 , Humanos , Metabolismo dos Lipídeos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/dietoterapia , Obesidade/etiologia , Transdução de Sinais
16.
Oncotarget ; 7(42): 69032-69040, 2016 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-27626182

RESUMO

We investigated roles of plasma homocysteine and MTHFR gene in relation to risks and treatment responses of depression in ACS. A sample of 969 patients with recent ACS were recruited and 711 followed 1 year later. In addition, of 378 baseline participants with depressive disorder, 255 were randomized to a 24-week double blind trial of escitalopram (N = 127) or placebo (N = 128). A higher homocysteine concentration was independently associated with prevalent depressive disorder at baseline irrespective of MTHFR genotype; and with both incident and persistent depressive disorder at follow-up only in the presence of TT genotype. MTHFR genotype was not itself associated with depressive disorder after ACS. No associations were found with 24-week antidepressant treatment responses. Plasma homocysteine could be a biomarker for depressive disorder particularly in the acute phase of ACS. Focused interventions for those with higher homocysteine level and MTHFR TT genotype might reduce the risk of later depressive disorder.


Assuntos
Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/psicologia , Depressão/sangue , Depressão/complicações , Homocisteína/sangue , Síndrome Coronariana Aguda/complicações , Adulto , Idoso , Antidepressivos/uso terapêutico , Biomarcadores Tumorais/genética , Citalopram/administração & dosagem , Método Duplo-Cego , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Polimorfismo Genético , Valor Preditivo dos Testes , República da Coreia
17.
Int J Cardiol ; 219: 225-30, 2016 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-27336191

RESUMO

BACKGROUND: This study is aimed to investigate the determinants of suicidal ideation as well as to assess escitalopram treatment effects on suicidal ideation in patients with acute coronary syndrome (ACS). METHODS: A total of 1152 patients were consecutively recruited at baseline, 2 to 14weeks after a confirmed ACS episode. Of 446 baseline participants with comorbid depressive disorders, 300 were randomized to a 24-week double-blind trial of escitalopram or placebo treatment. Suicidal ideation was determined using the "suicidal thoughts" item of the Montgomery and Asberg Depression Rating Scale. Socio-demographic and clinical characteristics, including depressive and anxiety symptoms, cardiovascular risk factors, and current cardiac status, were assessed. RESULTS: Suicidal ideation was independently associated with past history of depression, depressive and anxiety disorders, and higher troponin I levels. Escitalopram treatment was significantly more efficacious in reducing and treating suicidal ideation than placebo treatment over a 24-week period. These effects were largely explained by remission status of depressive and anxiety disorders. CONCLUSIONS: Suicidal ideation is associated with unfavorable psychiatric and ACS status during the acute phase of ACS. Successful treatment of depression and anxiety with escitalopram had significant beneficial effects on suicidal ideation in these patients.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/psicologia , Antidepressivos de Segunda Geração/uso terapêutico , Citalopram/uso terapêutico , Ideação Suicida , Síndrome Coronariana Aguda/epidemiologia , Idoso , Ansiedade/tratamento farmacológico , Ansiedade/epidemiologia , Ansiedade/psicologia , Estudos Transversais , Depressão/tratamento farmacológico , Depressão/epidemiologia , Depressão/psicologia , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Resultado do Tratamento
18.
J Neurosci ; 34(18): 6323-33, 2014 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-24790203

RESUMO

Schwann cells (SCs) at neuromuscular junctions (NMJs) play active roles in synaptic homeostasis and repair. We have studied how SCs contribute to reinnervation of NMJs using vital imaging of mice whose motor axons and SCs are transgenically labeled with different colors of fluorescent proteins. Motor axons most commonly regenerate to the original synaptic site by following SC-filled endoneurial tubes. During the period of denervation, SCs at the NMJ extend elaborate processes from the junction, as shown previously, but they also retract some processes from territory they previously occupied within the endplate. The degree of this retraction depends on the length of the period of denervation. We show that the topology of the remaining SC processes influences the branching pattern of regenerating axon terminals and the redistribution of acetylcholine receptors (AChRs). Upon arriving at the junction, regenerating axons follow existing SC processes within the old synaptic site. Some of the AChR loss that follows denervation is correlated with failure of portions of the old synaptic site that lack SC coverage to be reinnervated. New AChR clustering is also induced by axon terminals that follow SC processes extended during denervation. These observations show that SCs participate actively in the remodeling of neuromuscular synapses following nerve injury by their guidance of axonal reinnervation.


Assuntos
Regulação da Expressão Gênica/fisiologia , Regeneração Nervosa/fisiologia , Junção Neuromuscular/fisiopatologia , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Células de Schwann/fisiologia , Animais , Denervação , Modelos Animais de Doenças , Feminino , Proteínas Luminescentes/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Junção Neuromuscular/metabolismo , Junção Neuromuscular/ultraestrutura , Receptores Colinérgicos/metabolismo , Recuperação de Função Fisiológica , Células de Schwann/ultraestrutura , Fatores de Tempo
19.
J Neurosci ; 33(50): 19480-91, 2013 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-24336714

RESUMO

Injuries to peripheral nerves can cause paralysis and sensory disturbances, but such functional impairments are often short lived because of efficient regeneration of damaged axons. The time required for functional recovery, however, increases with advancing age (Verdú et al., 2000; Kawabuchi et al., 2011). Incomplete or delayed recovery after peripheral nerve damage is a major health concern in the aging population because it can severely restrict a person's mobility and independence. A variety of possible causes have been suggested to explain why nervous systems in aged individuals recover more slowly from nerve damage. Potential causes include age-related declines in the regenerative potential of peripheral axons and decreases in the supply or responsivity to trophic and/or tropic factors. However, there have been few direct analyses of age-related axon regeneration. Our aim here was to observe axons directly in young and old mice as they regenerate and ultimately reoccupy denervated neuromuscular synaptic sites to learn what changes in this process are age related. We find that damaged nerves in aged animals clear debris more slowly than nerves in young animals and that the greater number of obstructions regenerating axons encounter in the endoneurial tubes of old animals give rise to slower regeneration. Surprisingly, however, axons from aged animals regenerate quickly when not confronted by debris and reoccupy neuromuscular junction sites efficiently. These results imply that facilitating clearance of axon debris might be a good target for the treatment of nerve injury in the aged.


Assuntos
Axônios/fisiologia , Músculo Esquelético/inervação , Regeneração Nervosa/fisiologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Nervos Periféricos/fisiologia , Fatores Etários , Animais , Denervação , Camundongos , Bainha de Mielina/fisiologia , Junção Neuromuscular/fisiologia , Recuperação de Função Fisiológica/fisiologia , Células de Schwann/fisiologia
20.
Proc Natl Acad Sci U S A ; 107(33): 14863-8, 2010 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-20679195

RESUMO

The cellular basis of age-related behavioral decline remains obscure but alterations in synapses are likely candidates. Accordingly, the beneficial effects on neural function of caloric restriction and exercise, which are among the most effective anti-aging treatments known, might also be mediated by synapses. As a starting point in testing these ideas, we studied the skeletal neuromuscular junction (NMJ), a large, accessible peripheral synapse. Comparison of NMJs in young adult and aged mice revealed a variety of age-related structural alterations, including axonal swellings, sprouting, synaptic detachment, partial or complete withdrawal of axons from some postsynaptic sites, and fragmentation of the postsynaptic specialization. Alterations were significant by 18 mo of age and severe by 24 mo. A life-long calorie-restricted diet significantly decreased the incidence of pre- and postsynaptic abnormalities in 24-mo-old mice and attenuated age-related loss of motor neurons and turnover of muscle fibers. One month of exercise (wheel running) in 22-mo-old mice also reduced age-related synaptic changes but had no effect on motor neuron number or muscle fiber turnover. Time-lapse imaging in vivo revealed that exercise partially reversed synaptic alterations that had already occurred. These results demonstrate a critical effect of aging on synaptic structure and provide evidence that interventions capable of extending health span and lifespan can partially reverse these age-related synaptic changes.


Assuntos
Envelhecimento/fisiologia , Restrição Calórica , Junção Neuromuscular/fisiopatologia , Condicionamento Físico Animal/fisiologia , Animais , Imuno-Histoquímica , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Neurônios Motores/metabolismo , Neurônios Motores/fisiologia , Músculo Esquelético/anormalidades , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Junção Neuromuscular/anormalidades , Junção Neuromuscular/metabolismo , Receptores Colinérgicos/metabolismo , Sinapses/metabolismo
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