RESUMO
Protein glycosylation is a common post-translational modification on extracellular proteins. The conformational dynamics of several glycoproteins have been characterized by hydrogen/deuterium exchange mass spectrometry (HDX-MS). However, it is, in most cases, not possible to extract information about glycan conformation and dynamics due to the general difficulty of separating the deuterium content of the glycan from that of the peptide (in particular, for O-linked glycans). Here, we investigate whether the fragmentation of protonated glycopeptides by collision-induced dissociation (CID) can be used to determine the solution-specific deuterium content of the glycan. Central to this concept is that glycopeptides can undergo a facile loss of glycans upon CID, thereby allowing for the determination of their masses. However, an essential prerequisite is that hydrogen and deuterium (H/D) scrambling can be kept in check. Therefore, we have measured the degree of scrambling upon glycosidic bond cleavage in glycopeptides that differ in the conformational flexibility of their backbone and glycosylation pattern. Our results show that complete scrambling precedes the glycosidic bond cleavage in normal glycopeptides derived from a glycoprotein; i.e., all labile hydrogens have undergone positional randomization prior to loss of the glycan. In contrast, the glycosidic bond cleavage occurs without any scrambling in the glycopeptide antibiotic vancomycin, reflecting that the glycan cannot interact with the peptide moiety due to a conformationally restricted backbone as revealed by molecular dynamics simulations. Scrambling is also inhibited, albeit to a lesser degree, in the conformationally restricted glycopeptides ristocetin and its pseudoaglycone, demonstrating that scrambling depends on an intricate interplay between the flexibility and proximity of the glycan and the peptide backbone.
Assuntos
Glicopeptídeos , Hidrogênio , Glicopeptídeos/química , Deutério , Peptídeos/química , Glicoproteínas/química , Polissacarídeos/químicaRESUMO
In several rodent models, acute administration of the metabotropic glutamate 2/3 (mGlu2/3) receptor antagonist LY341495 induced antidepressant-like effects via a mechanism of action similar to that of ketamine. However, the effects of chronic mGlu2/3 antagonism have not yet been explored. Therefore, we investigated the effects of chronic LY341495 treatment on the mechanistic target of rapamycin complex 1 (mTORC1) signaling and the levels of synaptic proteins in mice subjected to chronic unpredictable stress (CUS). LY341495 (1 mg/kg) was administered daily for 4 weeks to mice with and without CUS exposure. After the final treatment, the forced swimming test (FST) was used to assess antidepressant-like effects. The hippocampal levels of mTORC1-related proteins were derived by Western blotting. Chronic LY341495 treatment reversed the CUS-induced behavioral effects of FST. CUS significantly reduced the phosphorylation of mTORC1 and downstream effectors [eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP-1) and small ribosomal protein 6 (S6)], as well as the expression of synaptic proteins postsynaptic density-95 (PSD-95) and AMPA receptor subunit GluR1 (GluA1) in the hippocampus. However, chronic LY341495 treatment rescued these deficits. Our results suggest that the activation of hippocampal mTORC1 signaling is related to the antidepressant effect of chronic LY341495 treatment in an animal model of CUS-induced depression.
Assuntos
Antidepressivos , Depressão , Aminoácidos , Animais , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Depressão/etiologia , Hipocampo/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Estresse Psicológico , XantenosRESUMO
Positive experiences in early life may improve the capacity to cope with adulthood stress through epigenetic modification. We investigated whether an enriched environment (EE) in the postnatal period affected epigenetic changes in the p11 gene induced by chronic unpredictable stress (CUS) in adult C57BL/6J mice. EE was introduced for 5 weeks during postnatal days 21-55. After EE, the mice were subjected to CUS for 4 weeks. EE prevented depression-like behavior induced by adult CUS. EE prevented a decrease in p11 mRNA and histone H3 acetylation induced by CUS, with changes in the expression of histone deacetylase 5. Moreover, EE prevented changes in trimethylation of histone H3 lysine 4 (H3K4) and H3K27 induced by CUS. Furthermore, EE had positive effects on behavior and epigenetic alterations in adult mice without CUS. These results suggest that one of the underlying mechanisms of early-life EE may involve epigenetic modification of the hippocampal p11 gene promoter.
Assuntos
Anexina A2/genética , Depressão/sangue , Depressão/prevenção & controle , Epigênese Genética , Expressão Gênica , Abrigo para Animais , Proteínas S100/genética , Estresse Fisiológico , Acetilação , Animais , Corticosterona/sangue , Hipocampo/metabolismo , Histona Desacetilases/metabolismo , Histonas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genéticaRESUMO
OBJECTIVES: The Korean Medication Algorithm Project for Bipolar Disorder (KMAP-BP) is based on expert consensus and has been revised five times since 2002. This study evaluated the changes in treatment strategies advocated by the KMAP-BP over time. METHODS: The five editions of the KMAP-BP were reviewed, and the recommendations of the KMAP-BP were compared with those of other bipolar disorder (BP) treatment guidelines. RESULTS: The most preferred option for the initial treatment of mania was a combination of a mood stabilizer (MS) and an atypical antipsychotic (AAP). Either MS or AAP monotherapy was also considered a first-line strategy for mania, but not for all types of episodes, including mixed/psychotic mania. In general, although lithium and valproic acid were commonly recommended, valproic acid has been increasingly preferred for all phases of BP. The most notable changes over time included the increasing preference for AAPs for all phases of BP, and lamotrigine for the depressive and maintenance phases. The use of antidepressants for BP has gradually decreased, but still represents a first-line option for severe and psychotic depression. CONCLUSIONS: In general, the recommended strategies of the KMAP-BP were similar to those of other guidelines, but differed in terms of the emphasis on rapid effectiveness, which is often desirable in actual clinical situations. The major limitation of the KMAP-BP is that it is a consensus-based rather than an evidence-based tool. Nevertheless, it may confer advantages in actual clinical practice.
Assuntos
Antipsicóticos , Transtorno Bipolar , Algoritmos , Antidepressivos/uso terapêutico , Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Humanos , República da CoreiaRESUMO
Growing evidence suggests that early life stress (ELS) has long-lasting effects on glucocorticoid receptor (GR) expression and behavior via epigenetic changes of the GR exon 17 promoter. However, it remains unclear whether ELS regulates histone modifications of the GR exon 17 promoter across the life span. We investigated the effects of maternal separation (MS) on histone acetylation and methylation of GR exon 17 promoter in the hippocampus, according to the age of adults. Depression-like behavior and epigenetic regulation of GR expression were examined at young and middle adulthood in mice subjected to MS from postnatal day 1 to 21. In the forced swimming test, young adult MS mice showed no effect on immobility time, but middle-aged MS mice significantly increased immobility time. Young adult and middle-aged MS mice showed decreased GR expression. Their two ages showed decreased histone acetylation with increased histone deacetylases (HDAC5) levels, decreased permissive methylation, and increased repressive methylation at the GR exon 17 promoter. The extent of changes in gene expression and histone modification in middle adulthood was greater than in young adulthood. These results indicate that MS in early life causes long-term negative effects on behavior via histone modification of the GR gene across the life span.
Assuntos
Epigênese Genética , Regulação da Expressão Gênica no Desenvolvimento , Privação Materna , Regiões Promotoras Genéticas , Receptores de Glucocorticoides/genética , Estresse Psicológico , Acetilação , Animais , Feminino , Código das Histonas , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Receptores de Glucocorticoides/metabolismoRESUMO
Plant growth and survival depend upon the activity of membrane transporters that control the movement and distribution of solutes into, around, and out of plants. Although many plant transporters are known, their intrinsic properties make them difficult to study. In barley (Hordeum vulgare), the root anion-permeable transporter Bot1 plays a key role in tolerance to high soil boron, facilitating the efflux of borate from cells. However, its three-dimensional structure is unavailable and the molecular basis of its permeation function is unknown. Using an integrative platform of computational, biophysical, and biochemical tools as well as molecular biology, electrophysiology, and bioinformatics, we provide insight into the origin of transport function of Bot1. An atomistic model, supported by atomic force microscopy measurements, reveals that the protein folds into 13 transmembrane-spanning and five cytoplasmic α-helices. We predict a trimeric assembly of Bot1 and the presence of a Na(+) ion binding site, located in the proximity of a pore that conducts anions. Patch-clamp electrophysiology of Bot1 detects Na(+)-dependent polyvalent anion transport in a Nernstian manner with channel-like characteristics. Using alanine scanning, molecular dynamics simulations, and transport measurements, we show that conductance by Bot1 is abolished by removal of the Na(+) ion binding site. Our data enhance the understanding of the permeation functions of Bot1.
Assuntos
Hordeum/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Plantas/metabolismo , Sódio/metabolismo , Ânions/metabolismo , Sítios de Ligação , Boratos/metabolismo , Sistema Livre de Células , Simulação por Computador , Bicamadas Lipídicas/metabolismo , Lipossomos/metabolismo , Proteínas de Membrana Transportadoras/química , Modelos Moleculares , Permeabilidade , Pichia/metabolismo , Proteínas de Plantas/química , Dobramento de Proteína , Multimerização Proteica , Triticum/metabolismoRESUMO
AIM: Early life stress can induce epigenetic changes through genetic and environmental interactions and is a risk factor for depression. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression and antidepressant drug action. We investigated epigenetic changes at the BDNF exon I promoter in the hippocampus of adult rats subjected to maternal separation (MS) during early life and treated with an antidepressant drug as adults. METHODS: Rat pups were subjected to MS from postnatal day 1 to 21 and received chronic escitalopram (ESC) as adults. We assessed the effects of MS and ESC on BDNF exon I and DNA methyltransferases (DNMT) mRNA levels (quantitative reverse-transcription polymerase chain reaction), acetylated histone H3, and MeCP2 binding to the BDNF promoter I (chromatin immunoprecipitation followed by real-time polymerase chain reaction), and BDNF protein levels (enzyme-linked immunosorbent assay). RESULTS: The levels of BDNF protein, exon I mRNA, histone H3 acetylation, and DNMT1 and DNMT3a mRNA were altered in the MS group compared with the control group. Significant decreases were observed in the BDNF protein, exon I mRNA, and histone H3 acetylation levels and there were significant increases in DNMT1 and DNMT3a mRNA levels. The comparison between the MS + ESC and MS groups revealed significant increases in BDNF protein, exon I mRNA, and histone H3 acetylation levels and significant decreases in MeCP2 and DNMT1 and DNMT3a mRNA levels. CONCLUSION: These findings indicate that MS induced epigenetic changes at the BDNF exon I promoter and these changes were prevented by antidepressant drug treatment during adulthood.
Assuntos
Antidepressivos de Segunda Geração/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citalopram/farmacologia , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Epigênese Genética/fisiologia , Hipocampo/metabolismo , Histonas/metabolismo , Privação Materna , Proteína 2 de Ligação a Metil-CpG/metabolismo , RNA Mensageiro/metabolismo , Acetilação , Animais , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferase 1/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferases/efeitos dos fármacos , DNA Metiltransferase 3A , Epigênese Genética/efeitos dos fármacos , Éxons , Feminino , Hipocampo/efeitos dos fármacos , Histonas/efeitos dos fármacos , Masculino , Proteína 2 de Ligação a Metil-CpG/efeitos dos fármacos , Gravidez , Regiões Promotoras Genéticas , RNA Mensageiro/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Recent studies have shown that antipsychotic drugs have epigenetic effects. However, the effects of antipsychotic drugs on histone modification remain unclear. Therefore, we investigated the effects of antipsychotic drugs on the epigenetic modification of the BDNF gene in the rat hippocampus. Rats were subjected to chronic restraint stress (6 h/d for 21 d) and then were administered with either olanzapine (2 mg/kg) or haloperidol (1 mg/kg). The levels of histone H3 acetylation and MeCP2 binding at BDNF promoter IV were assessed with chromatin immunoprecipitation assays. The mRNA levels of total BDNF with exon IV, HDAC5, DNMT1, and DNMT3a were assessed with a quantitative RT-PCR procedure. Chronic restraint stress resulted in the downregulation of total and exon IV BDNF mRNA levels and a decrease in histone H3 acetylation and an increase in MeCP2 binding at BDNF promoter IV. Furthermore, there were robust increases in the expression of HDAC5 and DNMTs. Olanzapine administration largely prevented these changes. The administration of haloperidol had no effect. These findings suggest that the antipsychotic drug olanzapine induced histone modification of BDNF gene expression in the hippocampus and that these epigenetic alterations may represent one of the mechanisms underlying the actions of antipsychotic drugs.
Assuntos
Antipsicóticos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Epigênese Genética/fisiologia , Hipocampo/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Animais , Antipsicóticos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Doença Crônica , Epigênese Genética/efeitos dos fármacos , Expressão Gênica , Hipocampo/efeitos dos fármacos , Masculino , Olanzapina/farmacologia , Olanzapina/uso terapêutico , Ratos , Ratos Sprague-Dawley , Restrição Física/efeitos adversos , Estresse Psicológico/genéticaRESUMO
BACKGROUND: Recent studies have suggested that the activation of mammalian target of rapamycin (mTOR) signaling may be related to antidepressant action. Therefore, the present study evaluated whether antidepressant drugs would exert differential effects on mTOR signaling in the rat hippocampus under conditions of chronic restraint stress. Male Sprague-Dawley rats were subjected to restraint stress for 6 h/days for 21 days with either escitalopram (10 mg/kg) or paroxetine (10 mg/kg) administered after the chronic stress procedure. Western blot analyses were used to assess changes in the levels of phospho-Ser2448-mTOR, phospho-Thr37/46-4E-BP-1, phospho-Thr389-p70S6 K, phospho-Ser422-eIF4B, phospho-Ser240/244-S6, phospho-Ser473-Akt, and phospho-Thr202/Tyr204-ERK in the hippocampus. RESULTS: Chronic restraint stress significantly decreased the levels of phospho-mTOR complex 1 (mTORC1), phospho-4E-BP-1, phospho-p70S6 K, phospho-eIF4B, phospho-S6, phospho-Akt, and phospho-ERK (p < 0.05); the administration of escitalopram and paroxetine increased the levels of all these proteins (p < 0.05 or 0.01). Additionally, chronic restraint stress reduced phospho-mTORC1 signaling activities in general, while escitalopram and paroxetine prevented these changes in phospho-mTORC1 signaling activities. CONCLUSION: These findings provide further data that contribute to understanding the possible relationships among mTOR activity, stress, and antidepressant drugs.
Assuntos
Antidepressivos de Segunda Geração/farmacologia , Citalopram/farmacologia , Hipocampo/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/efeitos dos fármacos , Paroxetina/farmacologia , Estresse Psicológico/metabolismo , Animais , Hipocampo/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Ratos , Ratos Sprague-Dawley , Restrição Física/efeitos adversos , Transdução de Sinais/efeitos dos fármacosRESUMO
AIMS: We examined prescription patterns in maintenance treatment for recovered bipolar patients and compared these with acute treatments. METHODS: Using retrospective methods, the bipolar patients in clinical recovery (Clinical Global Impression Bipolar Version score ≤ 2 for 6 months) after acute episode were selected. We reviewed differences between prescription patterns at remission and after a maintenance period of at least 6 months. RESULTS: A total of 340 bipolar disorder patients were selected. During the maintenance period, more than half of the patients (192, 56.5%) took a mood stabilizer (MS) + antipsychotic (AP) combination. Among the MS, valproate (149, 43.8%) was most prescribed, and lithium (98, 28.8%) was second, but as patients moved into maintenance treatment, lithium use decreased, and the use of lamotrigine (86, 25.3%) increased. Preferred AP were quetiapine (125, 36.8%), aripiprazole (67, 19.7%), risperidone (48, 14.1%), and olanzapine (39, 11.5%). The use of olanzapine in maintenance was greatly decreased compared with that during acute treatment (67, 19.7%). Most patients did not take an antidepressant (AD), but the proportion using one or more AD was increased during maintenance (17.9% to 30.3%), and bupropion (28, 8.2%) was the preferred AD. Doses were decreased in all drugs, but lamotrigine was maintained at a dose of 133.2 ± 68.5 mg/day. CONCLUSIONS: The most common prescription combination for bipolar maintenance treatment was MS + AP. The use of AP was decreased, whereas the use of AD in combination with MS and/or AP was increased. The doses of MS and AP were generally decreased during the maintenance periods, with the exception of lamotrigine.
Assuntos
Transtorno Bipolar/tratamento farmacológico , Quimioterapia de Manutenção , Padrões de Prática Médica/estatística & dados numéricos , Adulto , Quimioterapia Combinada/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicotrópicos/uso terapêutico , Indução de Remissão , República da Coreia , Estudos Retrospectivos , Fatores de TempoRESUMO
OBJECTIVES: Mood-stabilizing drugs, such as lithium (Li) and valproate (VPA), are widely used for the treatment of bipolar disorder, a disease marked by recurrent episodes of mania and depression. Growing evidence suggests that Li exerts neurotrophic and neuroprotective effects, leading to an increase in neural plasticity. The present study investigated whether other mood-stabilizing drugs produce similar effects in primary hippocampal neurons. METHODS: The effects of the mood-stabilizing drugs Li, VPA, carbamazepine (CBZ), and lamotrigine (LTG) on hippocampal dendritic outgrowth were examined. Western blotting analysis was used to measure the expression of synaptic proteins - that is, brain-derived neurotrophic factor (BDNF), postsynaptic density protein-95 (PSD-95), neuroligin 1 (NLG1), ß-neurexin, and synaptophysin (SYP). To determine neuroprotective effects, we used a B27-deprivation cytotoxicity model which causes hippocampal cell death upon removal of B27 from the culture medium. RESULTS: Li (0.5-2.0 mM), VPA (0.5-2.0 mM), CBZ (0.01-0.10 mM), and LTG (0.01-0.10 mM) significantly increased dendritic outgrowth. The neurotrophic effect of Li and VPA was blocked by inhibition of phosphatidylinositol 3-kinase, extracellular signal-regulated kinase, and protein kinase A signaling; the effects of CBZ and LTG were not affected by inhibition of these signaling pathways. Li, VPA, and CBZ prevented B27 deprivation-induced decreases in BDNF, PSD-95, NLG1, ß-neurexin, and SYP levels, whereas LTG did not. CONCLUSIONS: These results suggest that Li, VPA, CBZ, and LTG exert neurotrophic effects by promoting dendritic outgrowth; however, the mechanism of action differs. Furthermore, certain mood-stabilizing drugs may exert neuroprotective effects by enhancing synaptic protein levels against cytotoxicity in hippocampal cultures.
Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar , Dendritos/efeitos dos fármacos , Compostos de Lítio/farmacologia , Neurônios/efeitos dos fármacos , Triazinas/farmacologia , Ácido Valproico/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Moléculas de Adesão Celular Neuronais/efeitos dos fármacos , Moléculas de Adesão Celular Neuronais/metabolismo , Proteína 4 Homóloga a Disks-Large , Hipocampo/citologia , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lamotrigina , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Fármacos Neuroprotetores , Fosfatidilinositol 3-Quinases , Ratos , Sinaptofisina/efeitos dos fármacos , Sinaptofisina/metabolismoRESUMO
We demonstrate that chitosan prepatterns can generate not only highly periodic DNA pattern but also various types of graphitic carbon materials such as single-walled carbon nanotubes (SWNTs), graphene oxide (GO) and reduced graphene oxide (RGO). Scanning electron microscopy (SEM), fluorescence imaging and Raman spectroscopic results revealed that the graphitic carbon materials were selectively deposited on the surface of the periodic chitosan patterns by the electrostatic interaction between protonated amine groups of chitosan and the negative charged carbon materials. One proof-of-concept application of the system to the fabrication of electrical devices based on the micropatterns of SWNTs and RGO was also demonstrated. The strategy to use highly surface active chitosan pattern that can easily fabricate highly periodic pattern via a variety of lithographic tools may pave the way for the production of periodic arrays of graphitic carbon materials for large area device integration.
Assuntos
Quitosana/química , Eletrodos , Grafite/química , Impressão Molecular/métodos , Nanotubos de Carbono/química , Semicondutores , Cristalização/métodos , Condutividade Elétrica , Desenho de Equipamento , Análise de Falha de Equipamento , Teste de Materiais , Nanotubos de Carbono/ultraestrutura , Óxidos/química , Tamanho da Partícula , Tensoativos/químicaRESUMO
Recent studies suggest that ketamine produces antidepressant actions via stimulation of mammalian target of rapamycin (mTOR), leading to increased levels of synaptic proteins in the prefrontal cortex. Thus, mTOR activation may be related to antidepressant action. However, the mTOR signalling underlying antidepressant drug action has not been well investigated. The aim of the present study was to determine whether alterations in mTOR signalling were observed following treatment with antidepressant drugs, using ketamine as a positive control. Using Western blotting, we measured changes in the mTOR-mediated proteins and synaptic proteins in rat hippocampal cultures. Dendritic outgrowth was determined by neurite assay. Our findings demonstrated that escitalopram, paroxetine and tranylcypromine significantly increased levels of phospho-mTOR and its down-stream regulators (phospho-4E-BP-1 and phospho-p70S6K); fluoxetine, sertraline and imipramine had no effect. All drugs tested increased up-stream regulators (phospho-Akt and phospho-ERK) levels. Increased phospho-mTOR induced by escitalopram, paroxetine or tranylcypromine was significantly blocked in the presence of specific PI3K, MEK or mTOR inhibitors, respectively. All drugs tested also increased hippocampal dendritic outgrowth and synaptic proteins levels. The mTOR inhibitor, rapamycin, significantly blocked these effects on escitalopram, paroxetine and tranylcypromine whereas fluoxetine, sertraline and imipramine effects were not affected. The effects of escitalopram, paroxetine and tranylcypromine paralleled those of ketamine. This study presents novel in vitro evidence indicating that some antidepressant drugs promote dendritic outgrowth and increase synaptic protein levels through mTOR signalling; however, other antidepressant drugs seem to act via a different pathway. mTOR signalling may be a promising target for the development of new antidepressant drugs.
Assuntos
Antidepressivos/farmacologia , Hipocampo/citologia , Neurônios/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Proteínas de Transporte/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Embrião de Mamíferos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Neuritos/efeitos dos fármacos , Neurônios/citologia , Proteína Oncogênica v-akt/metabolismo , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismoRESUMO
This study introduces a novel approach for investigating hot-deformed NdFeB magnets by combining the minimal stress deformation process (MSDP) with the design of experiment (DoE) methodology. This study focused on enhancing the crystallographic alignment, particularly the c-axis alignment of the Nd2Fe14B grains, to optimize the magnetic properties. By utilizing the Box-Behnken design matrix and response surface regression, critical processes and variables were identified, determining that a hot-pressing temperature of 700 °C is crucial for achieving optimal grain alignment. Changing the strain rate to 0.019 mm/s under a stress of 110 MPa led to significant enhancements in the alignment, yielding magnets with a remanence of approximately 13.4 kG and a coercivity of 21 kOe. These findings highlight the effectiveness of combining the MSDP and DoE for predicting and achieving improved magnetic properties. Despite the challenges associated with understanding the complexity of crystal alignment mechanisms, this integrated approach successfully improved magnetic characteristics. The methodology represents a significant advancement in the fabrication of high-performance hot-deformed NdFeB magnets, marking a notable contribution to the field.
RESUMO
Recent evidence has suggested that atypical antipsychotic drugs regulate synaptic plasticity. We investigated whether some atypical antipsychotic drugs (olanzapine, aripiprazole, quetiapine, and ziprasidone) altered the expression of synapse-associated proteins in rat hippocampal neuronal cultures under toxic conditions induced by B27 deprivation. A typical antipsychotic, haloperidol, was used for comparison. We measured changes in the expression of various synaptic proteins including postsynaptic density protein-95 (PSD-95), brain-derived neurotrophic factor (BDNF), and synaptophysin (SYP). Then we examined whether these drugs affected the dendritic morphology of hippocampal neurons. We found that olanzapine, aripiprazole, and quetiapine, but not haloperidol, significantly hindered the B27 deprivation-induced decrease in the levels of these synaptic proteins. Ziprasidone did not affect PSD-95 or BDNF levels, but significantly increased the levels of SYP under B27 deprivation conditions. Moreover, olanzapine and aripiprazole individually significantly increased the levels of PSD-95 and BDNF, respectively, even under normal conditions, whereas haloperidol decreased the levels of PSD-95. These drugs increased the total outgrowth of hippocampal dendrites via PI3K signaling, whereas haloperidol had no effect in this regard. Together, these results suggest that the up-regulation of synaptic proteins and dendritic outgrowth may represent key effects of some atypical antipsychotic drugs but that haloperidol may be associated with distinct actions.
Assuntos
Antipsicóticos/farmacologia , Dendritos/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Hipocampo/citologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Sinaptofisina/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Células Cultivadas , Dendritos/metabolismo , Proteína 4 Homóloga a Disks-Large , Hipocampo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Ratos , Ratos Sprague-Dawley , Sinaptofisina/genética , Regulação para CimaRESUMO
We propose a method of manipulating the coercivity of anisotropic hydrogenation-disproportionation-desorption-recombination (HDDR) powders to fabricate high-remanence and fine-grained Nd-Fe-B magnets using only hot-pressing without a subsequent hot-deformation process. By reducing the Nd content of anisotropic HDDR precursors such that their coercivity (Hcj) is lowered, the c-axis of each HDDR particle is well-aligned parallel to the direction of the applied magnetic field during the magnetic alignment step. This is because the magnetic repulsive force between adjacent particles, determined by their remanent magnetization, decreases as a result of the low coercivity of each particle. Therefore, after hot-pressing the low-Hcj HDDR powders, a significantly higher remanence (11.2 kG) is achieved in the bulk than that achieved by hot-pressing the high-Hcj HDDR powders (8.2 kG). It is clearly confirmed by the large-scale electron backscatter diffraction (EBSD) analysis that the alignment of the c-axis of each anisotropic HDDR particle in the bulk is improved when low-Hcj HDDR powders are used to fabricate hot-pressed magnets. This coercivity manipulation of HDDR powders can be a helpful method to expand the use of HDDR powders in fabricating anisotropic Nd-Fe-B bulk magnets.
RESUMO
BACKGROUND: The Korean Medication Algorithm Project for Depressive Disorder (KMAP-DD) is an expert consensus guideline for depressive disorder created in 2002, and since then, four revisions (2006, 2012, 2017, 2021) have been published. In this study, changes in the content of the KMAP-DD survey and recommendations for each period were examined. METHODS: The development process of the KMAP-DD was composed of two stages. First, opinions from experts with abundant clinical experience were gathered through surveys. Next, a final guideline was prepared through discussion within the working committee regarding the suitability of the results with reference to recent clinical studies or other guidelines. RESULTS: In mild depressive symptoms, antidepressant (AD) monotherapy was preferred, but when severe depression or when psychotic features were present, a combination of AD and atypical antipsychotics (AD + AAP) was preferred. AD monotherapy was preferred in most clinical subtypes. AD monotherapy was preferred for mild depressive symptoms, and AD + AAP was preferred for severe depression and depression with psychotic features in children, adolescents, and the elderly. CONCLUSIONS: This study identified the changes in the KMAP-DD treatment strategies and drug preferences in each period over the past 20 years. This work is expected to aid clinicians in establishing effective treatment strategies.
RESUMO
BACKGROUND: We investigated the effects of liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, on a depression-like phenotype in mice exposed to chronic unpredictable stress (CUS). Learning and memory were also assessed using the Morris water maze (MWM) test. METHODS: Liraglutide (0.3 mg/kg/day for 21 days) was administered to mice with or without exposure to CUS. After 21 days of CUS, the forced swim test (FST) was performed to assess its antidepressant effect. To evaluate cognitive function, liraglutide was administered to mice under stress-free conditions for 21 days, and then the MWM test was performed on 6 consecutive days. RESULTS: Chronic liraglutide treatment reduced FST immobility in mice with and without CUS. In the probe trial of the Morris water maze test, the search error rate was reduced and the time spent and path length in the target quadrant and the number of platform crossings were increased. LIMITATION: Additional animal model experiments and molecular level studies are needed to support the results obtained in this study. CONCLUSIONS: Liraglutide appears to exert antidepressant effects and could improve cognitive function. Based on these results, GLP-1 agonists could have potential as novel antidepressants.
Assuntos
Liraglutida , Teste do Labirinto Aquático de Morris , Camundongos , Animais , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Depressão/tratamento farmacológico , Aprendizagem em Labirinto , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Cognição , Peptídeo 1 Semelhante ao Glucagon , Modelos Animais de Doenças , Comportamento Animal , Estresse PsicológicoRESUMO
Objective: : Attention-deficit/hyperactivity disorder (ADHD) is prevalent in adults, and psychiatric comorbidities are common in adults with ADHD. We aimed to examine the prevalence of adult ADHD with several common psychiatric conditions in a community sample in Korea and the association between adult ADHD and risk of psychiatric comorbidities. Methods: : This study used a cross-sectional survey design. We provided supplementary and optional self-report questionnaires, including the Korean version of the World Health Organization Adult ADHD Self-Report Scale (ASRS) short screening scale, Patient Health Questionnaire-9 for screening for depression, Alcohol Use Disorders Identification Test alcohol consumption questions, and the Korean version of the Mood Disorders Questionnaire, to Korean adults who visited one of six centers of a large private healthcare company for the National General Health Examination. Results: : A total of 17,799 subjects included in this study, and 430 (2.4%) were positive on the ASRS screen. ADHD was significantly associated with the 19-30-year-old age group (odds ratio [OR] = 3.938), lower income (OR = 1.298), depression (OR = 11.563), and bipolar disorder (OR = 3.162). Conclusion: : Adult ADHD was highly associated with depression and bipolar disorder, suggesting that clinicians should carefully evaluate and treat such psychiatric disorders in adults with ADHD symptoms.
RESUMO
The objective of this study was to compare recommendations of the Korean Medication Algorithm Project for Bipolar Disorder 2022 (KMAP-BP 2022) with other recently published guidelines for treating bipolar disorder. We reviewed a total of six recently published global treatment guidelines and compared treatment recommendation of the KMAP-BP 2022 with those of other guidelines. For initial treatment of mania, there were no significant differences across treatment guidelines. All guidelines recommended mood stabilizer (MS) or atypical antipsychotic (AAP) monotherapy or a combination of an MS with an AAP as a first-line treatment strategy in a same degree for mania. However, the KMAP-BP 2022 recommended MS + AAP combination therapy for psychotic mania, mixed mania and psychotic depression as treatment of choice. Aripiprazole, quetiapine and olanzapine were the first-line AAPs for nearly all phases of bipolar disorder across guidelines. Some guideline suggested olanzapine is a second-line options during maintenance treatment, related to concern about long-term tolerability. Most guidelines advocated newer AAPs (asenapine, cariprazine, long-acting injectable risperidone, and aripiprazole once monthly) as first-line treatment options for all phases while lamotrigine was recommended for depressive and maintenance phases. Lithium and valproic acid were commonly used as MSs in all phases of bipolar disorder. KMAP-BP 2022 guidelines were similar to other guidelines, reflecting current changes in prescription patterns for bipolar disorder based on accumulated research data. Strong preference for combination therapy was characteristic of KMAP-BP 2022, predominantly in the treatment of psychotic mania, mixed mania and psychotic depression.