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Autism spectrum disorder is a neurodevelopmental disorder whose core deficit is social dysfunction. Previous studies have indicated that structural changes in white matter are associated with autism spectrum disorder. However, few studies have explored the alteration of the large-scale white-matter functional networks in autism spectrum disorder. Here, we identified ten white-matter functional networks on resting-state functional magnetic resonance imaging data using the K-means clustering algorithm. Compared with the white matter and white-matter functional network connectivity of the healthy controls group, we found significantly decreased white matter and white-matter functional network connectivity mainly located within the Occipital network, Middle temporo-frontal network, and Deep network in autism spectrum disorder. Compared with healthy controls, findings from white-matter gray-matter functional network connectivity showed the decreased white-matter gray-matter functional network connectivity mainly distributing in the Occipital network and Deep network. Moreover, we compared the spontaneous activity of white-matter functional networks between the two groups. We found that the spontaneous activity of Middle temporo-frontal and Deep network was significantly decreased in autism spectrum disorder. Finally, the correlation analysis showed that the white matter and white-matter functional network connectivity between the Middle temporo-frontal network and others networks and the spontaneous activity of the Deep network were significantly correlated with the Social Responsiveness Scale scores of autism spectrum disorder. Together, our findings indicate that changes in the white-matter functional networks are associated behavioral deficits in autism spectrum disorder.
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Transtorno do Espectro Autista , Substância Branca , Humanos , Substância Branca/patologia , Imageamento por Ressonância Magnética/métodos , Substância Cinzenta/patologia , Análise por Conglomerados , EncéfaloRESUMO
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder characterized by a core deficit in social processes. However, it is still unclear whether the core clinical symptoms of the disorder can be reflected by the temporal variability of resting-state network functional connectivity (FC). In this article, we examined the large-scale network FC temporal variability at the local region, within-network, and between-network levels using the fuzzy entropy technique. Then, we correlated the network FC temporal variability to social-related scores. We found that the social behavior correlated with the FC temporal variability of the precuneus, parietal, occipital, temporal, and precentral. Our results also showed that social behavior was significantly negatively correlated with the temporal variability of FC within the default mode network, between the frontoparietal network and cingulo-opercular task control network, and the dorsal attention network. In contrast, social behavior correlated significantly positively with the temporal variability of FC within the subcortical network. Finally, using temporal variability as a feature, we construct a model to predict the social score of ASD. These findings suggest that the network FC temporal variability has a close relationship with social behavioral inflexibility in ASD and may serve as a potential biomarker for predicting ASD symptom severity.
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Transtorno do Espectro Autista , Encéfalo , Humanos , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico/métodos , Entropia , Imageamento por Ressonância Magnética/métodos , Vias Neurais/diagnóstico por imagem , Comportamento SocialRESUMO
The regulation of membrane potential and the contractility of vascular smooth muscle cells (VSMCs) by voltage-dependent K+ (Kv) potassium channels are well-established. In this study, native VSMCs from rabbit coronary arteries were used to investigate the inhibitory effect of sertindole, an atypical antipsychotic agent, on Kv channels. Sertindole induced dose-dependent inhibition of Kv channels, with an IC50 of 3.13 ± 0.72 µM. Although sertindole did not cause a change in the steady-state activation curve, it did lead to a negative shift in the steady-state inactivation curve. The application of 1- or 2-Hz train pulses failed to alter the sertindole-induced inhibition of Kv channels, suggesting use-independent effects of the drug. The inhibitory response to sertindole was significantly diminished by pretreatment with a Kv1.5 inhibitor but not by Kv2.1 and Kv7 subtype inhibitors. These findings demonstrate the sertindole dose-dependent and use-independent inhibition of vascular Kv channels (mainly the Kv1.5 subtype) through a mechanism that involves altering steady-state inactivation curves. Therefore, the use of sertindole as an antipsychotic drug may have adverse effects on the cardiovascular system.
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Antipsicóticos , Imidazóis , Indóis , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Animais , Coelhos , Vasos Coronários , Antipsicóticos/toxicidade , Canais de Potássio de Abertura Dependente da Tensão da Membrana/farmacologia , Bloqueadores dos Canais de Potássio/toxicidade , Miócitos de Músculo LisoRESUMO
Voltage-dependent K+ (Kv) channels play an important role in restoring the membrane potential to its resting state, thereby maintaining vascular tone. In this study, native smooth muscle cells from rabbit coronary arteries were used to investigate the inhibitory effect of quetiapine, an atypical antipsychotic agent, on Kv channels. Quetiapine showed a concentration-dependent inhibition of Kv channels, with an IC50 of 47.98 ± 9.46 µM. Although quetiapine (50 µM) did not alter the steady-state activation curve, it caused a negative shift in the steady-state inactivation curve. The application of 1 and 2 Hz train steps in the presence of quetiapine significantly increased the inhibition of Kv current. Moreover, the recovery time constants from inactivation were prolonged in the presence of quetiapine, suggesting that its inhibitory action on Kv channels is use (state)-dependent. The inhibitory effects of quetiapine were not significantly affected by pretreatment with Kv1.5, Kv2.1, and Kv7 subtype inhibitors. Based on these findings, we conclude that quetiapine inhibits Kv channels in both a concentration- and use (state)-dependent manner. Given the physiological significance of Kv channels, caution is advised in the use of quetiapine as an antipsychotic due to its potential side effects on cardiovascular Kv channels.
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Antipsicóticos , Vasos Coronários , Músculo Liso Vascular , Miócitos de Músculo Liso , Bloqueadores dos Canais de Potássio , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Fumarato de Quetiapina , Fumarato de Quetiapina/farmacologia , Animais , Coelhos , Antipsicóticos/farmacologia , Antipsicóticos/toxicidade , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Vasos Coronários/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Masculino , Relação Dose-Resposta a Droga , Potenciais da Membrana/efeitos dos fármacos , Células CultivadasRESUMO
Autism spectrum disorder (ASD) is a pervasive developmental disorder with severe cognitive impairment in social communication and interaction. Previous studies have reported that abnormal functional connectivity patterns within the default mode network (DMN) were associated with social dysfunction in ASD. However, how the altered causal connectivity pattern within the DMN affects the social functioning in ASD remains largely unclear. Here, we introduced the Liang information flow method, widely applied to climate science and quantum mechanics, to uncover the brain causal network patterns in ASD. Compared with the healthy controls (HC), we observed that the interactions among the dorsal medial prefrontal cortex (dMPFC), ventral medial prefrontal cortex (vMPFC), hippocampal formation, and temporo-parietal junction showed more inter-regional causal connectivity differences in ASD. For the topological property analysis, we also found the clustering coefficient of DMN and the In-Out degree of anterior medial prefrontal cortex were significantly decreased in ASD. Furthermore, we found that the causal connectivity from dMPFC to vMPFC was correlated with the clinical symptoms of ASD. These altered causal connectivity patterns indicated that the DMN inter-regions information processing was perturbed in ASD. In particular, we found that the dMPFC acts as a causal source in the DMN in HC, whereas it plays a causal target in ASD. Overall, our findings indicated that the Liang information flow method could serve as an important way to explore the DMN causal connectivity patterns, and it also can provide novel insights into the nueromechanisms underlying DMN dysfunction in ASD.
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Transtorno do Espectro Autista , Humanos , Transtorno do Espectro Autista/diagnóstico por imagem , Mapeamento Encefálico/métodos , Rede de Modo Padrão , Imageamento por Ressonância Magnética/métodos , Vias Neurais/diagnóstico por imagem , Encéfalo/diagnóstico por imagemRESUMO
Paliperidone, an atypical antipsychotic, is widely used to treat schizophrenia. In this study, we explored whether paliperidone inhibited the voltage-dependent K+ (Kv) channels of rabbit coronary arterial smooth muscle cells. Paliperidone reduced Kv channel activity in a concentration-dependent manner with a half-maximal inhibitory concentration (IC50 ) of 16.58 ± 3.03 µM and a Hill coefficient of 0.60 ± 0.04. It did not significantly shift the steady-state activation or inactivation curves, suggesting that the drug did not affect the gating properties of Kv channels. In the presence of paliperidone, the application of 20 repetitive depolarizing pulses at 1 and 2 Hz gradually increased the inhibition of the Kv current. Further, the recovery time constant after Kv channel inactivation was increased by paliperidone, indicating that it inhibited the Kv channel in a use (state)-dependent manner. Its inhibitory effects were reduced by pretreatment with a Kv1.5 subtype inhibitor. However, pretreatment with a Kv2.1 or Kv7 inhibitor did not reduce its inhibitory effect. We conclude that paliperidone inhibits Kv channels (mainly Kv1.5 subtype channels) in a concentration- and use (state)-dependent manner without changing channel gating.
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Antipsicóticos , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Animais , Coelhos , Antipsicóticos/toxicidade , Palmitato de Paliperidona/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/farmacologia , Miócitos de Músculo LisoRESUMO
Voltage-dependent K+ (Kv) channels are widely expressed on vascular smooth muscle cells and regulate vascular tone. Here, we explored the inhibitory effect of encainide, a class Ic anti-arrhythmic agent, on Kv channels of vascular smooth muscle from rabbit coronary arteries. Encainide inhibited Kv channels in a concentration-dependent manner with an IC50 value of 8.91 ± 1.75 µM and Hill coefficient of 0.72 ± 0.06. The application of encainide shifted the activation curve toward a more positive potential without modifying the inactivation curve, suggesting that encainide inhibited Kv channels by altering the gating property of channel activation. The inhibition by encainide was not significantly affected by train pulses (1 and 2 Hz), indicating that the inhibition is not use (state)-dependent. The inhibitory effect of encainide was reduced by pretreatment with the Kv1.5 subtype inhibitor. However, pretreatment with the Kv2.1 subtype inhibitor did not alter the inhibitory effects of encainide on Kv currents. Based on these results, encainide inhibits vascular Kv channels in a concentration-dependent and use (state)-independent manner by altering the voltage sensor of the channels. Furthermore, Kv1.5 is the main Kv subtype involved in the effect of encainide.
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Desmodus rotundus plasminogen activator alpha 1(DSPAα1) is a thrombolytic protein with advantages, such as a long half-life, high accuracy and specificity for thrombolysis, wide therapeutic window, and no neurotoxicity. To date, DSPAα1 has only been expressed in the Chinese hamster ovary, insect cells, transgenic tobacco plants, and Pichia pastoris. To the best of our knowledge, we are the first to report the expression of DSPAα1 in transgenic rabbit mammary glands, extract the product, and analyze its pharmacology activity. An efficient mammary gland-specific expression vector pCL25/DSPAα1 was transferred to prokaryotic zygotes in rabbits by microinjection to generate six DSPAα1 transgenic rabbits. The recombinant DSPAα1 (rDSPAα1) expression in transgenic rabbit milk was 1.19 ± 0.26 mg/mL. The rDSPAα1 purification protocol included pretreatment, ammonium sulfate precipitation, benzamidine affinity chromatography, cation exchange chromatography, and Cibacron blue affinity chromatography; approximately 98% purity was achieved using gel electrophoresis. According to sequencing results, the primary structure of rDSPAα1 was consistent with the theoretical design sequence, and its molecular weight was consistent with that of the natural protein. N-terminal sequencing results indicated rDSPAα1 to be a mature protein, as the goat signal peptide sequence of the expression vector was no longer detected. The fibrinolytic activity of rDSPAα1 was estimated to be 773,333 IU/mg. Fibrin-agarose plate assay and in vitro rat blood clot degradation assay showed that rDSPAα1 had strong thrombolytic activity. In conclusion, we report recombinant DSPAα1 with high thrombolytic activity expressed in transgenic rabbit mammary glands.
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Glândulas Mamárias Animais , Ativadores de Plasminogênio , Sinais Direcionadores de Proteínas , Animais , Células CHO , Cricetinae , Cricetulus , Glândulas Mamárias Animais/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Ativadores de Plasminogênio/genética , Ativadores de Plasminogênio/metabolismo , Coelhos , Ratos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMO
Cardiovascular disease is one of the leading causes of human mortality worldwide, mainly due to atherosclerosis (AS), and the phenotypic transition of vascular smooth muscle cells (VSMCs) is a key event in the development of AS. Exosomes contain a variety of specific nucleic acids and proteins that mediate intercellular communication. The role of exosomes in AS has attracted attention. This review uses the VSMC phenotypic transition in AS as the entry point, introduces the effect of exosomes on AS from different perspectives, and discusses the status quo, deficiencies, and potential future directions in this field to provide new ideas for clinical research and treatment of AS. Video Abstract.
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Aterosclerose , Exossomos , Ácidos Nucleicos , Aterosclerose/metabolismo , Células Cultivadas , Exossomos/metabolismo , Humanos , Músculo Liso Vascular , Miócitos de Músculo Liso/metabolismo , Ácidos Nucleicos/metabolismo , FenótipoRESUMO
BACKGROUND: High levels of apolipoprotein C3 (APOC3) can lead to hypertriglyceridemia, which increases the risk of cardiovascular disease. We aim to create APOC3-knockout (KO) rabbits and explore the effects of APOC3 deletion on the occurrence and development of atherosclerosis. METHODS: An sgRNA anchored to exon 2 of APOC3 was designed to edit embryo genomes using the CRISPR/Cas9 system. The founder rabbits were sequenced, and their lipid profile, inflammatory cytokines, and atherosclerotic plaques were analyzed. RESULTS: When given a normal chow (NC) diet, all APOC3-KO rabbits had 50% lower triglyceride (TG) levels than those of the matched age control group. Additionally, their plasma lipoprotein lipase increased. When fed a high-fat diet, APOC3 deficiency was observed to be more conducive to the maintenance of plasma TG, total cholesterol, and low-density lipoprotein cholesterol levels, and the inhibition of the inflammatory response and the protection against atherosclerosis in rabbits. CONCLUSION: APOC3 deficiency can delay the formation of atherosclerosis-induced HFD in rabbits, indicating this is a novel therapeutic target to treat atherosclerosis.
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Apolipoproteína C-III/metabolismo , Aterosclerose/etiologia , Lipídeos/sangue , Animais , Proteína 9 Associada à CRISPR , Sistemas CRISPR-Cas , Citocinas/sangue , Feminino , Técnicas de Silenciamento de Genes , Intestino Delgado/metabolismo , Fígado/metabolismo , Masculino , Placa Aterosclerótica/etiologia , CoelhosRESUMO
Atherosclerosis is a common pathological change in cardiovascular disease. Vascular smooth muscle cell is the main source of plaque cell and extracellular matrix, and nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcription factor regulating the function of vascular smooth muscle cell. In the process of atherosclerosis, Nrf2 signaling pathway has the following regulatory effects on vascular smooth muscle cell: regulating the phenotype of vascular smooth muscle cell to change to the direction conducive to the alleviation of disease progression; inhibiting the proliferation and migration of vascular smooth muscle cell; mitigating the level of blood lipid; alleviating vascular smooth muscle cell calcification, aging and apoptosis process. This article reviews the specific mechanisms of Nrf2 regulating atherosclerosis, such as phenotypic transformation, proliferation and migration, lipid metabolism, calcification, aging and apoptosis in atherosclerosis, in order to provide a basis for understanding the molecular mechanism of atherosclerosis development and finding therapeutic targets.
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Aterosclerose , Fator 2 Relacionado a NF-E2 , Movimento Celular , Proliferação de Células , Células Cultivadas , Humanos , Músculo Liso Vascular , Miócitos de Músculo Liso , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Congenital hyper-homocysteinemia (HHcy) is caused by a defective cystathionine ß-synthase (CBS) gene, and is frequently associated with dyslipdemia. The aim of this study was to further elucidate the effect of mutated CBS gene on circulating lipids using a rabbit model harboring a homozygous G307S point mutation in CBS. METHODS: CRISPR/Cas9 system was used to edit the CBS gene in rabbit embryos. The founder rabbits were sequenced, and their plasma homocysteine (Hcy) and lipid profile were analyzed. RESULTS: Six CBS-knockout (CBS-KO) founder lines with biallelic modifications were obtained. Mutation in CBS caused significant growth retardation and high mortality rates within 6 weeks after birth. In addition, the 6-week old CBS-KO rabbits showed higher plasma levels of Hcy, triglycerides (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) compared to the age-matched wild-type (WT) controls. Histological analysis of the mutants showed accumulation of micro-vesicular cytoplasmic lipid droplets in the hepatocytes. However, gastric infusion of vitamin B and betaine complex significantly decreased the plasma levels of TG, TC and LDL-C in the CBS-KO rabbits, and alleviated hepatic steatosis compared to the untreated animals. CONCLUSION: A CBSG307S rabbit model was generated that exhibited severe dyslipidemia when fed on a normal diet, indicating that G307S mutation in the CBS gene is a causative factor for dyslipidemia.
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Sistemas CRISPR-Cas , Cistationina beta-Sintase/genética , Dislipidemias/genética , Hiper-Homocisteinemia/genética , Animais , Betaína/farmacologia , Peso Corporal/genética , Modelos Animais de Doenças , Feminino , Técnicas de Inativação de Genes , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/genética , Fígado/patologia , Masculino , Mutação Puntual , Coelhos , Complexo Vitamínico B/farmacologiaRESUMO
Aripiprazole, a third-generation antipsychotic, has been widely used to treat schizophrenia. In this study, we evaluated the effect of aripiprazole on voltage-gated potassium (Kv) channels in rabbit coronary arterial smooth muscle cells using the patch clamp technique. Aripiprazole reduced the Kv current in a concentration-dependent manner with a half-maximal inhibitory concentration of 0.89 ± 0.20 µM and a Hill coefficient of 1.30 ± 0.25. The inhibitory effect of aripiprazole on Kv channels was voltage-dependent, and an additional aripiprazole-induced decrease in the Kv current was observed in the voltage range of full channel activation. The decay rate of Kv channel inactivation was accelerated by aripiprazole. Aripiprazole shifted the steady-state activation curve to the right and the inactivation curve to the left. Application of a repetitive train of pulses (1 and 2 Hz) promoted inhibition of the Kv current by aripiprazole. Furthermore, the recovery time constant from inactivation increased in the presence of aripiprazole. Pretreatment of Kv1.5 subtype inhibitor reduced the inhibitory effect of aripiprazole. However, pretreatment with Kv 7 and Kv2.1 subtype inhibitors did not change the degree of aripiprazole-induced inhibition of the Kv current. We conclude that aripiprazole inhibits Kv channels in a concentration-, voltage-, time-, and use (state)-dependent manner by affecting the gating properties of the channels.
Assuntos
Aripiprazol , Vasos Coronários , Miócitos de Músculo Liso , Bloqueadores dos Canais de Potássio , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Animais , Aripiprazol/farmacologia , Coelhos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/citologia , Bloqueadores dos Canais de Potássio/farmacologia , Masculino , Antipsicóticos/farmacologia , Relação Dose-Resposta a DrogaRESUMO
AIMS: The present study investigated the vasorelaxant mechanisms of an oral antidiabetic drug, anagliptin, using phenylephrine (Phe)-induced pre-contracted rabbit aortic rings. METHODS: Arterial tone measurement was performed in rabbit thoracic aortic rings. RESULTS: Anagliptin induced vasorelaxation in a dose-dependent manner. Pre-treatment with the classical voltagedependent K+ (Kv) channel inhibitors 4-aminopyridine and tetraethylammonium significantly decreased the vasorelaxant effect of anagliptin, whereas pre-treatment with the inwardly rectifying K+ (Kir) channel inhibitor Ba2+, the ATP-sensitive K+ (KATP) channel inhibitor glibenclamide, and the large-conductance Ca2+-activated K+ (BKCa) channel inhibitor paxilline did not attenuate the vasorelaxant effect. Furthermore, the vasorelaxant response of anagliptin was effectively inhibited by pre-treatment with the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid. Neither cAMP/protein kinase A (PKA)-related signaling pathway inhibitors (adenylyl cyclase inhibitor SQ 22536 and PKA inhibitor KT 5720) nor cGMP/protein kinase G (PKG)-related signaling pathway inhibitors (guanylyl cyclase inhibitor ODQ and PKG inhibitor KT 5823) reduced the vasorelaxant effect of anagliptin. Similarly, the anagliptin-induced vasorelaxation was independent of the endothelium. CONCLUSIONS: Based on these results, we suggest that anagliptin-induced vasorelaxation in rabbit aortic smooth muscle occurs by activating Kv channels and the SERCA pump, independent of other vascular K+ channels, cAMP/PKA- or cGMP/PKG-related signaling pathways, and the endothelium.
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We explored the vasorelaxant effects of ipragliflozin, a sodium-glucose cotransporter-2 inhibitor, on rabbit femoral arterial rings. Ipragliflozin relaxed phenylephrine-induced pre-contracted rings in a dose-dependent manner. Pre-treatment with the ATP-sensitive K+ channel inhibitor glibenclamide (10 µM), the inwardly rectifying K+ channel inhibitor Ba2+ (50 µM), or the Ca2+-sensitive K+ channel inhibitor paxilline (10 µM) did not influence the vasorelaxant effect. However, the voltage-dependent K+ (Kv) channel inhibitor 4-aminopyridine (3 mM) reduced the vasorelaxant effect. Specifically, the vasorelaxant response to ipragliflozin was significantly attenuated by pretreatment with the Kv7.X channel inhibitors linopirdine (10 µM) and XE991 (10 µM), the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors thapsigargin (1 µM) and cyclopiazonic acid (10 µM), and the cAMP/protein kinase A (PKA)-associated signaling pathway inhibitors SQ22536 (50 µM) and KT5720 (1 µM). Neither the cGMP/protein kinase G (PKG)-associated signaling pathway nor the endothelium was involved in ipragliflozin-induced vasorelaxation. We conclude that ipragliflozin induced vasorelaxation of rabbit femoral arteries by activating Kv channels (principally the Kv7.X channel), the SERCA pump, and the cAMP/PKA-associated signaling pathway independent of other K+ (ATP-sensitive K+, inwardly rectifying K+, and Ca2+-sensitive K+) channels, cGMP/PKG-associated signaling, and the endothelium.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico , Artéria Femoral , Glucosídeos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Transdução de Sinais , Tiofenos , Vasodilatação , Animais , Coelhos , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/fisiologia , Vasodilatação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Tiofenos/farmacologia , Masculino , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , Vasodilatadores/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidoresRESUMO
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder with severe cognitive impairment. Several studies have reported that brain functional network connectivity (FNC) has great potential for identifying ASD from healthy control (HC) and revealing the relationships between the brain and behaviors of ASD. However, few studies have explored dynamic large-scale FNC as a feature to identify individuals with ASD. This study used a time-sliding window method to study the dynamic FNC (dFNC) on the resting-state fMRI. To avoid arbitrarily determining the window length, we set a window length range of 10-75 TRs (TR = 2 s). We constructed linear support vector machine classifiers for all window length conditions. Using a nested 10-fold cross-validation framework, we obtained a grand average accuracy of 94.88% across window length conditions, which is higher than those reported in previous studies. In addition, we determined the optimal window length using the highest classification accuracy of 97.77%. Based on the optimal window length, we found that the dFNCs were located mainly in dorsal and ventral attention networks (DAN and VAN) and exhibited the highest weight in classification. Specifically, we found that the dFNC between DAN and temporal orbitofrontal network (TOFN) was significantly negatively correlated with social scores of ASD. Finally, using the dFNCs with high classification weights as features, we construct a model to predict the clinical score of ASD. Overall, our findings demonstrated that the dFNC could be a potential biomarker to identify ASD and provide new perspectives to detect cognitive changes in ASD.
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Transtorno do Espectro Autista , Humanos , Transtorno do Espectro Autista/diagnóstico por imagem , Mapeamento Encefálico/métodos , Vias Neurais/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodosRESUMO
Lurasidone is a second-generation antipsychotic drug used to treat schizophrenia, mania, and bipolar disorder. The drug is an antagonist of the 5-HT2A and D2 receptors. No effect of lurasidone on the voltage-gated K+ (Kv) channels has yet been identified. Here, we show that lurasidone inhibits the vascular Kv channels of rabbit coronary arterial smooth muscle cells in a dose-dependent manner with an IC50 of 1.88 ± 0.21 µM and a Hill coefficient of 0.98 ± 0.09. Although lurasidone (3 µM) did not affect the activation kinetics, the drug negatively shifted the inactivation curve, suggesting that the drug interacted with the voltage sensors of Kv channels. Application of 1 or 2 Hz train steps in the presence of lurasidone significantly increased Kv current inhibition. The recovery time after channel inactivation increased in the presence of lurasidone. These results suggest that the inhibitory action of lurasidone is use (state)-dependent. Pretreatment with a Kv 1.5 subtype inhibitor effectively reduced the inhibitory effect of lurasidone. However, the inhibitory effect on Kv channels did not markedly change after pretreatment with a Kv 2.1 or a Kv7 subtype inhibitor. In summary, lurasidone inhibits vascular Kv channels (primarily the Kv1.5 subtype) in a concentration- and use (state)-dependent manner by shifting the steady-state inactivation curve.
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Antipsicóticos , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Animais , Coelhos , Cloridrato de Lurasidona/farmacologia , Antipsicóticos/farmacologia , Vasos Coronários , Miócitos de Músculo LisoRESUMO
Vascular smooth muscle cells (VSMCs) are the primary cell type involved in the atherosclerosis process; senescent VSMCs are observed in both aged vessels and atherosclerotic plaques. Factors associated with the atherosclerotic process, including oxidative stress, inflammation, and calcium-regulating factors, are closely linked to senescence in VSMCs. A number of experimental studies using traditional cellular aging markers have suggested that anti-aging biochemical agents could be used to treat atherosclerosis. However, doubt has recently been cast on such potential due to the increasingly apparent complexity of VSMCs status and an incomplete understanding of the role that these cells play in the atherosclerosis process, as well as a lack of specific or spectrum-limited cellular aging markers. The utility of anti-aging drugs in atherosclerosis treatment should be reevaluated. Promotion of a healthy lifestyle, exploring in depth the characteristics of each cell type associated with atherosclerosis, including VSMCs, and development of targeted drug delivery systems will ensure efficacy whilst evaluation of the safety and tolerability of drug use should be key aims of future anti-atherosclerosis research. This review summarizes the characteristics of VSMC senescence during the atherosclerosis process, the factors regulating this process, as well as an overview of progress toward the development and application of anti-aging drugs.
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Objective: The current study was to evaluate the association of office blood pressure (OBP) and 24h ambulatory blood pressure (ABP) with left ventricular (LV) structure and function in hypertensive patients. Whether the association was modified by sex was also evaluated. Methods: A total of 694 hypertensive patients without cardiovascular disease were retrospectively included from the inpatient clinic. Regression analysis was performed to evaluate the association of OBP and 24h ABP parameters with LV mass index (LVMi), e' velocity and left ventricular hypertrophy (LVH) with adjustment for covariates including age, obesity, diabetes mellitus, obstructive sleep apnea, estimated glomerular filtration rate and antihypertensive drugs. Results: There was no difference in OBP by sex. Compared to women, men had a higher 24h (132.6 ± 11.3 vs 129.3 ± 10.0 mm Hg), daytime (136.6 ± 12.9 vs 132.8 ± 9.5 mm Hg) and nighttime (130.3 ± 9.2 vs 125.1 ± 6.6 mm Hg) SBP. The proportion of patients with non-dipping pattern and reverse dipper pattern was also higher in men. In the overall participants, 24h, daytime and nighttime SBP, non-dipping and reverse dipper pattern were associated with LVMi, e' velocity and LVH, which were not observed in OBP. The magnitude of the association between 24h, daytime and nighttime SBP, non-dipping and reverse dipper pattern with LVMi, e' velocity and LVH was stronger in men than in women (P-value for interaction <0.05). Conclusion: Twenty-four-hour ABP appears to be better than OBP in association with LV structural and functional alterations, and this association was modified by sex.
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Background: Remarkable evidence indicates that psychological stress is significantly associated with stroke. However, a uniform recommendation to identify and alleviate poststroke psychological stress responses and improve postmorbid outcomes is not currently available. Thus, this systematic review aimed to summarize the types of poststroke psychological stress, measurement tools, contributing factors, and outcomes. Methods: This systematic review was undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A literature search was conducted in PubMed, Web of Science, Embase, CNKI, WanFangData, and CQVIP from database inception to November 2021. Cross-sectional and longitudinal studies were included in this research. Quality assessment was performed based on the National Institutes of Health (NIH) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Results: Eighteen quantitative, peer-reviewed studies were included for analysis. Selected articles mainly investigated perceived stress and posttraumatic stress disorder after stroke. We classified the contributing factors into four categories: sociodemographic factors, clinical disease factors, psychological factors, and behavioral and lifestyle factors. The postmorbid outcomes were divided into three categories: clinical disease outcomes, psychological outcomes, and behavioral and quality of life outcomes. Conclusions: Compared to common patients, stroke survivors with the following characteristics suffered an increased psychological stress response: younger age, the presence of caregivers, depression, unsuitable coping strategies, etc. Meanwhile, lower quality of life, worse drug compliance, worse functional independence, and more severe mental disorders were significantly associated with increased psychological stress symptoms. Further studies are required to provide more trustworthy and meaningful references for mitigating the damage caused by psychological stress after stroke.