RESUMO
Non-competitive N-methyl-D-aspartate/glutamate receptor (NMDAR) antagonism has been considered to play important roles in the pathophysiology of schizophrenia. In spite of severe neuropsychiatric adverse effects, esketamine (racemic enantiomer of ketamine) has been approved for the treatment of conventional monoaminergic antidepressant-resistant depression. Furthermore, ketamine improves anhedonia, suicidal ideation and bipolar depression, for which conventional monoaminergic antidepressants are not fully effective. Therefore, ketamine has been accepted, with rigorous restrictions, in psychiatry as a new class of antidepressant. Notably, the dosage of ketamine for antidepressive action is comparable to the dose that can generate schizophrenia-like psychotic symptoms. Furthermore, the psychotropic effects of ketamine precede the antidepressant effects. The maintenance of the antidepressive efficacy of ketamine often requires repeated administration; however, repeated ketamine intake leads to abuse and is consistently associated with long-lasting memory-associated deficits. According to the dissociative anaesthetic feature of ketamine, it exerts broad acute influences on cognition/perception. To evaluate the therapeutic validation of ketamine across clinical contexts, including its advantages and disadvantages, psychiatry should systematically assess the safety and efficacy of either short- and long-term ketamine treatments, in terms of both acute and chronic outcomes. Here, we describe the clinical evidence of NMDAR antagonists, and then the temporal mechanisms of schizophrenia-like and antidepressant-like effects of the NMDAR antagonist, ketamine. The underlying pharmacological rodent studies will also be discussed.
Assuntos
Transtorno Depressivo/tratamento farmacológico , Ketamina/efeitos adversos , Esquizofrenia/induzido quimicamente , Animais , Transtorno Depressivo/metabolismo , Cálculos da Dosagem de Medicamento , Humanos , Ketamina/uso terapêutico , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Ideação SuicidaRESUMO
Our previous study suggested that the interleukin (IL)-6 and IL-10 could serve as good biomarkers for chronic inflammatory disease. We previously established an IL-6 and IL-10 reporters assay that could examine reporter activity along with the reference gene in LPS-induced RAW 264.7 cells. In this study, we described new and stable RAW 264.7 derived dual-color IL-6/gapdh and IL-10/gapdh reporters. This assay allowed us to easily determine relative IL-6 and IL-10 levels with 96-well plate within one step. We evaluated the relative IL-6 and IL-10 levels in the LPS-induced stable cells testing 52 natural products by real-time bioluminescence monitoring and time-point determination using a microplate luminometer. The relative IL-6 and IL-6/IL-10 values decreased by the crude ethanol extracts from nutmeg and by 1'S-1'-acetoxychavicol from greater galangal using real-time bioluminescence monitoring. At the same time, the relative IL-10 was induced. The relative IL-6 and IL-6/IL-10 decreased by crude ethanol extracts from nutmeg and 1'S-1'-acetoxychavicol acetate at 6 h. Only crude ethanol extract from nutmeg induced IL-10 at 6 h. We suggested that the use of these stable cells by real-time monitoring could serve as a screening assay for anti-inflammatory activity and may be used to discover new drugs against chronic inflammatory disease.
Assuntos
Anti-Inflamatórios/farmacologia , Interleucina-10/análise , Interleucina-6/análise , Macrófagos/efeitos dos fármacos , Animais , Produtos Biológicos/farmacologia , Biomarcadores Farmacológicos/análise , Avaliação Pré-Clínica de Medicamentos/métodos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interleucina-10/imunologia , Interleucina-6/imunologia , Lipopolissacarídeos/imunologia , Medições Luminescentes/métodos , Macrófagos/imunologia , Camundongos , Células RAW 264.7RESUMO
UNLABELLED: Assembly-activating protein (AAP) of adeno-associated virus serotype 2 (AAV2) is a nucleolar-localizing protein that plays a critical role in transporting the viral capsid VP3 protein to the nucleolus for assembly. Here, we identify and characterize AAV2 AAP (AAP2) nuclear (NLS) and nucleolar (NoLS) localization signals near the carboxy-terminal region of AAP2 (amino acid positions 144 to 184) (AAP2(144-184)). This region contains five basic-amino-acid-rich (BR) clusters, KSKRSRR (AAP2BR1), RRR (AAP2BR2), RFR (AAP2BR3), RSTSSR (AAP2BR4), and RRIK (AAP2BR5), from the amino terminus to the carboxy terminus. We created 30 AAP2BR mutants by arginine/lysine-to-alanine mutagenesis or deletion of AAP2BRs and 8 and 1 green fluorescent protein (GFP)-AAP2BR and ß-galactosidase-AAP2BR fusion proteins, respectively, and analyzed their intracellular localization in HeLa cells by immunofluorescence microscopy. The results showed that AAP2(144-184) has redundant multipartite NLSs and that any combinations of 4 AAP2BRs, but not 3 or less, can constitute a functional NLS-NoLS; AAP2BR1 and AAP2BR2 play the most influential role for nuclear localization, but either one of the two AAP2BRs is dispensable if all 4 of the other AAP2BRs are present, resulting in 3 different, overlapping NLS motifs; and the NoLS is shared redundantly among the five AAP2BRs and functions in a context-dependent manner. AAP2BR mutations not only resulted in aberrant intracellular localization, but also attenuated AAP2 protein expression to various degrees, and both of these abnormalities have a significant negative impact on capsid production. Thus, this study reveals the organization of the intermingling NLSs and NoLSs in AAP2 and provides insights into their functional roles in capsid assembly. IMPORTANCE: Adeno-associated virus (AAV) has become a popular and successful vector for in vivo gene therapy; however, its biology has yet to be fully understood. In this regard, the recent discovery of the assembly-activating protein (AAP), a nonstructural, nucleolar-localizing AAV protein essential for viral capsid assembly, has provided us a new opportunity to better understand the fundamental processes required for virion formation. Here, we identify clusters of basic amino acids in the carboxy terminus of AAP from AAV serotype 2 (AAV2) that act as nuclear and nucleolar localization signals. We also demonstrate their importance in maintaining AAP expression levels and efficient production of viral capsids. Insights into the functions of AAP can elucidate the requirements and process for AAV capsid assembly, which may lead to improved vector production for use in gene therapy. This study also contributes to the growing body of work on nuclear and nucleolar localization signals.
Assuntos
Nucléolo Celular/virologia , Núcleo Celular/virologia , Dependovirus/fisiologia , Sinais de Localização Nuclear , Infecções por Parvoviridae/virologia , Proteínas Virais/metabolismo , Sequência de Aminoácidos , Proteínas do Capsídeo/química , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Dependovirus/química , Dependovirus/genética , Humanos , Dados de Sequência Molecular , Transporte Proteico , Alinhamento de Sequência , Proteínas Virais/química , Proteínas Virais/genética , Montagem de VírusRESUMO
The naphthoquinone pigment, shikonin, is a natural product derived from Lithospermum erythrorhizon and an active component of a Chinese traditional herbal therapeutic. We identified shikonin as a candidate for shortening the circadian period using real-time reporter gene assays based on NIH3T3-derived stable reporter cells. Period length that became shortened in cells incubated with shikonin or etoposide reverted to that of control cells after continued incubation without these compounds. These findings indicated that shikonin and etoposide shorten the circadian period reversibly and through similar mechanisms. Topoisomerase II (Top2)-specific decatenation assays confirmed that shikonin, liker etoposide, is a Top2 inhibitor. Shikonin was incorporated into the nucleus and Top2 was located in the Bmal1 promoter, suggesting the relationship between Bmal1 transcription and Top2 inhibition. Top2a siRNA also shortened period length, suggesting that Top2 is involved in this process. Promoter assays showed that Top2a siRNA, etoposide and shikonin reduce Bmal1 promoter activity. These findings indicated that Top2 is involved in Bmal1 transcription and influences the circadian period, and that shikonin is a novel contributor to the control of period length in mammalian cells.
Assuntos
Fatores de Transcrição ARNTL/metabolismo , Ritmo Circadiano/efeitos dos fármacos , Proteínas de Ligação a DNA/antagonistas & inibidores , Medicamentos de Ervas Chinesas/farmacologia , Naftoquinonas/farmacologia , Animais , Antígenos de Neoplasias/genética , DNA Topoisomerases Tipo II/genética , Proteínas de Ligação a DNA/genética , Técnicas de Silenciamento de Genes , Camundongos , Células NIH 3T3 , Proteínas de Ligação a Poli-ADP-Ribose , Transcrição GênicaRESUMO
The Bmal1 gene is essential for the circadian system, and its promoter has a unique open chromatin structure. We examined the mechanism of topoisomerase I (Top1) to understand the role of the unique chromatin structure in Bmal1 gene regulation. Camptothecin, a Top1 inhibitor, and Top1 small interfering RNA (siRNA) enhanced Baml1 transcription and lengthened its circadian period. Top1 is located at an intermediate region between two ROREs that are critical cis-elements of circadian transcription and the profile of Top1 binding indicated anti-phase circadian oscillation of Bmal1 transcription. Promoter assays showed that the Top1-binding site is required for transcriptional suppression and that it functions cooperatively with the distal RORE, supporting that Bmal1 transcription is upregulated by Top1 inhibition. A DNA fragment between the ROREs, where the Top1-binding site is located, behaved like a right-handed superhelical twist, and modulation of Top1 activity by camptothecin and Top1 siRNA altered the footprint profile, indicating modulation of the chromatin structure. These data indicate that Top1 modulates the chromatin structure of the Bmal1 promoter, regulates Bmal1 transcription and influences the circadian period.
Assuntos
Fatores de Transcrição ARNTL/genética , Ritmo Circadiano/genética , DNA Topoisomerases Tipo I/metabolismo , Regulação da Expressão Gênica , Transcrição Gênica , Sítios de Ligação , Camptotecina/farmacologia , Linhagem Celular , Cromatina/química , Cromatina/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Regiões Promotoras Genéticas , Inibidores da Topoisomerase I/farmacologia , Transcrição Gênica/efeitos dos fármacosRESUMO
Plants of the Amaryllidaceae family have been used as therapeutic agents against CNS related maladies such as Alzheimer's disease. The known primary alkaloid constituents have significant biological activity. We identified the Lycoris alkaloids lycorine and lycoricidinol from Amaryllidaceae using a real-time reporter gene assay system based on NIH3T3 cells. These alkaloids have a wide spectrum of pharmacological actions and dose-dependently lengthen the circadian period. When cells that had been incubated with lycorine or lycoricidinol were washed and then incubated without these alkaloids, period length reverted to that of control cells, suggesting that elongation of the circadian period induced by lycorine and lycoricidinol is reversible. Although one of its major activities is the inhibition of protein synthesis, lycorine induced dose-dependent period elongation regardless of the presence of cycloheximide and moreover, cycloheximide, itself did not affect period length, suggesting that lycorine dose-dependently extends the circadian period by a mechanism other than translational inhibition. Real-time RT-PCR showed that lycorine enhanced RORα and Bmal1 transcription, and exogenous expression and knockdown of Bmal1 also caused long and short periods, respectively, thus confirming the phenotype indicated by lycorine. These data indicate that lycorine and lycoricidinol modulate Bmal1 transcription and the circadian period, and also suggest that Lycoris alkaloids are novel contributors to the control of period length in mammalian cells.
Assuntos
Fatores de Transcrição ARNTL/metabolismo , Alcaloides de Amaryllidaceae/farmacologia , Ritmo Circadiano/efeitos dos fármacos , Fenantridinas/farmacologia , Fatores de Transcrição ARNTL/genética , Animais , Núcleo Celular/metabolismo , Cicloeximida/farmacologia , Técnicas de Silenciamento de Genes , Genes Reporter , Lycoris/química , Mamíferos , Camundongos , Células NIH 3T3 , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fosforilação , Plasmídeos/genética , Plasmídeos/metabolismo , Biossíntese de Proteínas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Transcrição Gênica , TransfecçãoRESUMO
Atherosclerosis is considered the major cause of cardiovascular and cerebrovascular diseases, which are the leading causes of death worldwide. Excessive nitric oxide production and inflammation result in dysfunctional vascular endothelial cells, which are critically involved in the initiation and progression of atherosclerosis. The present study aimed to identify a bioactive compound from Jerusalem artichoke leaves with anti-inflammatory activity that might prevent atherosclerosis. We isolated bioactive heliangin that inhibited NO production in LPS-induced macrophage-like RAW 264.7 cells. Heliangin suppressed ICAM-1, VCAM-1, E-selectin, and MCP-1 expression, as well as NF-κB and IκBα phosphorylation, in vascular endothelial cells stimulated with TNF-α. These results suggested that heliangin suppresses inflammation by inhibiting excessive NO production in macrophages and the expression of the factors leading to the development of atherosclerosis via the NF-κB signaling pathway in vascular endothelial cells. Therefore, heliangin in Jerusalem artichoke leaves could function in the prevention of atherosclerosis that is associated with heart attacks and strokes.
Assuntos
Aterosclerose , Células Endoteliais/metabolismo , Helianthus/química , Lactonas , Folhas de Planta/química , Sesquiterpenos , Transdução de Sinais/efeitos dos fármacos , Animais , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Lactonas/química , Lactonas/farmacologia , Camundongos , Células RAW 264.7 , Sesquiterpenos/química , Sesquiterpenos/farmacologiaRESUMO
During the early stages of the ongoing COVID-19 pandemic, suicides did not increase in most countries/regions. Japan, however, was an exception to this, reporting increased numbers of female suicides with no changes in male suicide. To explore the trends of increasing suicides, the fluctuations of personal consumption (as an indicator of lifestyle) and standardized suicide death rate (SDR) disaggregated by age, sex, and prefecture, were determined using a linear mixed-effect model. Additionally, fixed effects of personal consumption on SDR during the pandemic were also analyzed using hierarchical linear regression models with robust standard errors. During the first wave of the pandemic, SDR for both sexes decreased slightly but increased during the second half of 2020. SDR of females younger than 70 years old and males younger than 40 years old continued to increase throughout 2021, whereas SDR for other ages of both sexes did not increase. Personal consumption expenditures on out-of-home recreations (travel agencies, pubs, and hotels) and internet/mobile communication expenses decreased, but expenditures on home-based recreations (contents distribution) increased during the pandemic. Increased expenditures on internet/mobile communication were related to increasing SDR of both sexes. Increasing expenditures on content distributions were related to increasing females' SDR without affecting that of males. Decreasing expenditures on pubs were related to increasing SDR of both sexes in the non-metropolitan region. These findings suggest that transformed individual lifestyles, extended time at home with a decreased outing for contact with others, contributed to the progression of isolation as a risk of suicide. Unexpectedly, increasing compensatory contact with others using internet/mobile communication enhanced isolation resulting in increased suicide risk.
Assuntos
COVID-19 , Suicídio , Adulto , Idoso , COVID-19/epidemiologia , Feminino , Humanos , Internet , Japão/epidemiologia , Masculino , PandemiasRESUMO
A combination of pharmaceutical and non-pharmaceutical interventions as well as social restrictions has been recommended to prevent the spread of coronavirus disease 2019 (COVID-19). Therefore, social contact surveys play an essential role as the basis for more effective measures. This study attempts to explore the fundamental basis of the expansion of COVID-19. Temporal bidirectional causalities between the numbers of newly confirmed COVID-19 cases (NCCC) and individual mobilisations with consumption motives across prefecture borders in three metropolitan regions in Japan were analysed using vector autoregression models. Mobilisation with consumption in pubs from Kanto to Tokai contributed to the spread of COVID-19 in both regions. Meanwhile, causal mobilisation with consumption motives in Kansai also contributed to the expansion of COVID-19; however, the pattern was dependent on the industrial characteristics of each prefecture in Kansai. Furthermore, the number of pub visitors in Kanto immediately decreased when NCCC increased in Kanto. In contrast, the causal mobilisations for the expansion of COVID-19 in the Tokai and Kansai regions were unaffected by the increasing NCCC. These findings partially proved the validity of the conventional governmental measures to suppress pub visitors across prefectural borders. Nevertheless, the individual causal mobilisations with consumption motives that contributed to the increasing COVID-19 cases are not identical nationwide, and thus, regional characteristics should be considered when devising preventive strategies.
Assuntos
COVID-19 , COVID-19/epidemiologia , Causalidade , Humanos , Japão/epidemiologia , Motivação , Inquéritos e QuestionáriosRESUMO
Change-related potentials elicited by an abrupt sound feature's change are attenuated by a leading weak sound (prepulse inhibition: PPI). We investigated whether the PPI index is associated with the catechol-methyltransferase (COMT) Val158Met polymorphism (rs4680), which is involved in the metabolism of dopamine in the prefrontal cortex. Healthy subjects with normal hearing were recruited (n = 70). A train of 100-Hz clicks 650 ms in duration was used. The test stimulus was an abrupt increase in sound intensity (+10 dB) from the baseline (70 dB) provided at 400 ms after the sound onset. Three consecutive clicks at 30, 40, and 50 ms before the change's onset were greater (+3 or +5 dB) from the baseline as a prepulse. The targeting auditory evoked potential component was Change-N1 peaking approx. 130 ms after the change onset. We calculated the inhibition level as the% inhibition of the Change-N1 amplitude by a prepulse. The %PPI in the Met-carriers was significantly greater than that in the Val/Val-individuals. Our results suggest that dopamine might play a role in the PPI of the change-related response. We propose that this index has the potential to identify an intermediate phenotype in psychiatric disorders such as schizophrenia.
Assuntos
Catecol O-Metiltransferase , Inibição Pré-Pulso , Estimulação Acústica/métodos , Catecol O-Metiltransferase/genética , Dopamina/metabolismo , Potenciais Evocados Auditivos/genética , Humanos , Inibição Pré-Pulso/genéticaRESUMO
We showed that an ethanol extract from Zanthoxylum piperitum can shorten the circadian rhythm at the cellular level and that this activity was due to hydroxy-ß-sanshool, a secondary metabolite in this plant. An ethanol extract of Z. piperitum was repeatedly fractionated using solid phase extraction and reverse-phase HPLC, then the circadian rhythms of cells to which the fractions were loaded were monitored using real-time reporter gene assays. We purified one HPLC peak and identified it as hydroxy-ß-sanshool using liquid chromatography (LC)-precision-mass spectrometry (MS). This compound shortened the period of Bmal1 and Per2 at the cellular level. Incubation cells for 24 h with hydroxy-ß-sanshool resulted in upregulated Per2 promoter activity. Hydroxy-ß-sanshool also dose-dependently upregulated expression of the clock genes Bmal1, Per1, Per2 and Cry1 and the clock-controlled oxidative stress responsive genes Gpx1and Sod2.
Assuntos
Relógios Circadianos , Zanthoxylum , Fatores de Transcrição ARNTL/genética , Amidas , Etanol , Japão , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Zanthoxylum/químicaRESUMO
Investigation of enhancers to improve recombinant adeno-associated virus 2 (rAAV2) productivity by human embryonic kidney 293 cells (HEK293) suspension culture showed that the addition of ethanol improved the productivity and packaged genome integrity of rAAV2. Further optimization showed that adding ethanol in the range of 0.09%-1.11% (v/v) during rAAV2 production effectively improved rAAV2 productivity and quality. In addition, ethanol addition improved cell viability. Furthermore, proteome and pathway analysis of the cells during rAAV2 production showed that the addition of ethanol resulted in the upregulation of pathways related to intercellular signaling, gene expression, cell morphology, intercellular maintenance, and others. In contrast, pathways related to cell death, immunity, and reactions to infection were downregulated. These changes in pathway regulation were responsible for the improvement in rAAV2 productivity, packaged genome integrity, and cell viability during rAAV2 production. The results of this study can be applied to the production of viral vectors for in vivo gene therapy in an inexpensive and safe manner.
Assuntos
Vetores Genéticos , Proteoma , Dependovirus , Etanol , Células HEK293 , Humanos , RimRESUMO
It is beneficial to treat chronic inflammatory condition in patients through diets that inhibit the production of proinflammatory cytokines and mediators such as tumor necrosis factor-α (TNF-α) and nitric oxide (NO). Since less attention has been paid to alkaloids in the diets than to polyphenols in this regard, we aimed at investigating anti-inflammatory activity of herb-derived alkaloids through suppression of TNF-α and NO production in lipopolysaccharide (LPS)-stimulated mouse RAW264 and/or human THP-1 cells. A harmala alkaloid, harmine, an opium alkaloid, papaverine, and Lycoris alkaloids, lycorine and lycoricidinol, showed TNF-α suppressive activities stronger than or comparable to that of a reference polyphenol, butein, in RAW264 cells (IC(50)=4, 10, 2.1, 0.02, and 8 µM, respectively). Other alkaloids showed no or marginal to moderate inhibitory activities. Similar tendency of inhibition was found for NO production in RAW264 cells and TNF-α production in THP-1 cells. In addition, harmine was found to suppress interleukin-6 (IL-6) production in RAW264 cells. The above four inhibitory alkaloids had essentially no antioxidative property in the superoxide anion scavenging assay. Western blotting and reverse transcriptase-polymerase chain reaction (RT-PCR) showed that harmine caused neither prevention of nuclear factor-κB (NF-κB) translocation into the nucleus nor inhibition of p38 mitogen activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) phosphorylation, while that the LPS-induced transcription of TNF-α and inducible NO synthase was dose-dependently attenuated by harmine. This result suggests that the molecular mechanism of harmine action is different from those of many other anti-inflammatory phytochemicals. In conclusion, some herbal alkaloids like harmine, in spite of lacking antioxidative property, have potential as anti-inflammatory agents that strongly suppress TNF-α and NO production by a unique mechanism.
Assuntos
Alcaloides/química , Anti-Inflamatórios/química , Macrófagos/metabolismo , Óxido Nítrico/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Linhagem Celular Tumoral , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Camundongos , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
An abrupt change in a sound feature (test stimulus) elicits a specific cerebral response, which is attenuated by a weaker sound feature change (prepulse) preceding the test stimulus. As an exploratory study, we investigated whether and how the magnitude of the change of the prepulse affects the degree of prepulse inhibition (PPI). Sound stimuli were 650 ms trains of clicks at 100 Hz. The test stimulus was an abrupt sound pressure increase (by 10 dB) in the click train. Three consecutive clicks, weaker (-5 dB, -10 dB, -30 dB, or gap) than the baseline, at 30, 40, and 50 ms before the test stimulus, were used as prepulses. Magnetic responses to the ten types of stimuli (test stimulus alone, control, four types of tests with prepulses, and four types of prepulses alone) were recorded in 10 healthy subjects. The change-related N1m component, peaking at approximately 130 ms, and its PPI were investigated. The degree of PPI caused by the -5 dB prepulse was significantly weaker than that caused by other prepulses. The degree of PPI caused by further decreases in prepulse magnitude showed a plateau level between the -10 dB and gap prepulses. The results suggest that there is a physiologically significant range of sensory changes for PPI, which plays a role in the change detection for survival.
RESUMO
Electroconvulsive therapy (ECT) is applied to treatment-resistant mood disorders. Its therapeutic effect on neurocognition remains unclear. We report the case of a 55-year-old man with treatment-resistant bipolar depression who underwent ECT series. We longitudinally monitored his neurocognition with the Brief Assessment of Cognition in Schizophrenia-Japanese version (BACS-J). The patient's scores on all of the BACS-J domains except working memory recovered after the ECT series. Interestingly, his verbal memory, motor speed, and executive function recovered 1 month after ECT, whereas his verbal fluency and attention scores recovered approx. 1 year after ECT. The BACS can be useful for monitoring ECT's longitudinal effects on individuals' cognitive recovery. Further studies with a large sample size are needed to confirm our present findings.
RESUMO
Change-N1 peaking 90-180 ms after changes in a sound feature of a continuous sound is clearly attenuated by a preceding change stimulus (called a "prepulse"). Here, we investigated the effects of a preceding decrease in sound pressure on the degree of inhibition of the subsequent Change-N1 amplitude. Using 100-Hz click train sounds, we obtained Change-N1s from 11 healthy volunteers. The two types of test stimuli were an abrupt 10-dB increase from the baseline (70 dB) and the insertion of a 0.45-ms inter-aural time difference in the middle of the sound. Three consecutive clicks at 30, 40, and 50 ms before the change onset that was used as a prepulse were weaker than the background by 5 or 10 dB. The Change-N1 elicited by the two test stimuli was attenuated more strongly by the weaker prepulse, which was not congruent with the theory that the inhibition of the subsequent sensory/sensory-motor processing depends on the sound pressure level of a prepulse. These results suggest that a change in any type of sound feature elicits a change-related response that is inhibited by any type of preceding change stimulus, which reflects auto-inhibition of the change-responding circuit.
Assuntos
Potenciais Evocados Auditivos , Reflexo de Sobressalto , Estimulação Acústica , Humanos , Inibição Psicológica , Inibição Pré-PulsoRESUMO
An abrupt change in a sound feature (Test) in a continuous sound elicits an auditory evoked potential, peaking at approx. 100-180 ms (Change-N1) after the change onset. Change-N1 is attenuated by a preceding weak change stimulus (Prepulse), in the phenomenon known as prepulse inhibition (PPI). In this electroencephalographic study, we compared these two indexes among scalp electrodes. Change-N1 was elicited by an abrupt 10-dB increase in sound pressure in repeats of a 70-dB click sound at 100 Hz and was recorded using 22 electrodes in 31 healthy subjects. The prepulse was a 10-dB decrease in three consecutive clicks at 30, 40, and 50 ms before the Test onset. Four stimuli (Test alone, Test with Prepulse, Prepulse alone, and background alone) were presented randomly through headphones at an even probability. The results demonstrated that: (1) Electrodes at the frontal/central midline were reconfirmed to be suitable to record Change-N1; (2) Change-N1 showed right-hemisphere predominance; (3) There was no difference in the %PPI among regions (prefrontal/frontal/central) and hemispheres (midline/left/right); and (4) the Change-N1 amplitude and its PPI at prefrontal electrodes were positively correlated with those at the frontal electrodes. These results support the use of Change-N1 and its PPI as a tool to evaluate the change detection sensitivity and inhibitory function in individuals. The use of prefrontal electrodes can be an option for a screening test.
Assuntos
Potenciais Evocados Auditivos , Inibição Neural , Adulto , Eletroencefalografia , Feminino , Lobo Frontal/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Filtro SensorialRESUMO
N-(3,5-Dihydroxybenzoyl)-6-hydroxytryptamine (2) was a novel inhibitor of L-3,4-dihydroxyphenylalanine (DOPA) oxidase activity of human HMV-II melanoma tyrosinase. The IC50 values for 2 and three reference compounds, N-(3,5-dihydroxybenzoyl)serotonin, 6-hydroxyindole, and kojic acid, were 9.1, 842, 22, and 310 µM, respectively, indicating that the 6-hydroxyindole moiety was more effective than 5-hydroxyindole as the pharmacophore of polyphenolic tyrosinase inhibitors and that the inhibitory activity of 6-hydroxyindole was strengthened by the link with a resorcinol group. Furthermore, compound 2 exhibited a unique property of inactivating the human tyrosinase in the presence of low concentrations of DOPA. This inactivation was attenuated by high concentrations of DOPA and for the most part was irreversible as confirmed by activity stain in native polyacrylamide gel electrophoresis and by removal of 2 and DOPA using gel permeation chromatography. Tyrosinase is the enzyme that oxidizes tyrosine to DOPA and further oxidizes DOPA to the melanin precursor dopaquinone. A compound such as 2 that inactivates the enzyme in the presence of a small amount of DOPA is therefore attractive as a new type of tyrosinase inhibitor. Unfortunately, 2 hardly suppressed the melanogenesis in melanoma cell culture. However, the above strong inhibitory activity and the unique property in the combination with DOPA suggest that this compound is a useful lead in designing new antimelanogenic agents.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Levodopa/metabolismo , Melanoma/enzimologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Serotonina/análogos & derivados , Linhagem Celular Tumoral , Humanos , Monofenol Mono-Oxigenase/metabolismo , Serotonina/química , Serotonina/farmacologiaRESUMO
A recent study showed that N-acylserotonin derivatives have strong inhibitory activity against tyrosinase. To clarify the role of the 5-hydroxy group in the indole ring, 2-, 4-, 5-, 6-, and 7-hydroxyindole and 11 related compounds such as 5-hydroxyindan and 6-hydroxyquinoline were tested for their inhibition of catecholase activity of tyrosinase from human HMV-II melanoma cells. 6-Hydroxyindole (5) and 7-hydroxyindole (6) were potent inhibitors, while 5-hydroxyindole (4) was a weaker inhibitor than the above-mentioned compounds (IC50 = 20, 79, 366, and 342 microM for 5, 6, 4, and kojic acid, respectively). 2-Hydroxycarbazole was also active (IC50 = 190 microM), 5-hydroxyindan, 4-aminophenol, and harmalol were slightly active, and other compounds were inactive as an inhibitor. A similar pattern of inhibition was found with these compounds against mouse B16 melanoma tyrosinase, but with some differences from that for HMV-II tyrosinase. Kinetic analysis with HMV-II tyrosinase showed that the inhibition by hydroxyindoles 4, 5, and 6 was competitive with respect to the substrate L-DOPA. Melanin formation in HMV-II cells was suppressed by 14% with 10 microM 5 without cytotoxicity, but 30 or 100 microM 5 decreased the cell viability. The present results suggest that 6-hydroxyindole is a potential and useful pharmacophore of antimelanogenic agents and that the position of a phenolic hydroxy group in a specific heterocyclic ring such as in indole is possibly optimized to yield more active inhibitors for tyrosinase.
Assuntos
Indóis/farmacologia , Melanoma/enzimologia , Monofenol Mono-Oxigenase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Hidroxilação , Cinética , Melanoma/patologia , Monofenol Mono-Oxigenase/efeitos dos fármacosRESUMO
Gymnema inodorum (GI) is an indigenous medicinal plant and functional food in Thailand that has recently helped to reduce plasma glucose levels in healthy humans. It is renowned for the medicinal properties of gymnemic acid and its ability to suppress glucose absorption. However, the effects of gymnemic acids on adipogenesis that contribute to the accumulation of adipose tissues associated with obesity remain unknown. The present study aimed to determine the effects of gymnemic acids derived from GI tea on adipogenesis. We purified and identified GiA-7 and stephanosides C and B from GI tea that inhibited adipocyte differentiation in 3T3-L1 cells. These compounds also suppressed the expression of peroxisome proliferator-activated receptor gamma (Pparγ)-dependent genes, indicating that they inhibit lipid accumulation and the early stage of 3T3-L1 preadipocyte differentiation. Only GiA-7 induced the expression of uncoupling protein 1 (Ucp1) and pparγ coactivator 1 alpha (Pgc1α), suggesting that GiA-7 induces mitochondrial activity and beige-like adipocytes. This is the first finding of stephanosides C and B in Gymnema inodorum. Our results suggested that GiA-7 and stephanosides C and B from GI tea could help to prevent obesity.