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1.
J Neurophysiol ; 131(4): 738-749, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38383290

RESUMO

Polysomnography (PSG) is the gold standard for clinical sleep monitoring, but its cost, discomfort, and limited suitability for continuous use present challenges. The flexible electrode sleep patch (FESP) emerges as an economically viable and patient-friendly solution, offering lightweight, simple operation, and self-applicable. Nevertheless, its utilization in young individuals remains uncertain. The objective of this study was to compare sleep data obtained by FESP and PSG in healthy young individuals and analyze agreement for sleep parameters and structure classification. Overnight monitoring with FESP and PSG recordings in 48 participants (mean age: 23 yr) was done. Correlation analysis, Bland-Altman plots, and Cohen's kappa coefficient assessed consistency. Sensitivity, specificity, and predictive values compared classification against PSG. FESP showed strong correlation and consistency with PSG for sleep monitoring. Bland-Altman plots indicated small errors and high consistency. Kappa values (0.70-0.84) suggested substantial agreement for sleep stage classification. Pearson correlation coefficient values for sleep stages (0.75-0.88) and sleep parameters (0.80-0.96) confirm that FESP has a strong application. Intraclass correlation coefficient yielded values between 0.65 and 0.97. In addition, FESP demonstrated an impressive accuracy range of 84.12-93.47% for sleep stage classification. The FESP also features a wearable self-test program with an error rate of no more than 8% for both deep sleep and wake. In young adults, FESP demonstrated reliable monitoring capabilities comparable to PSG. With its low cost and user-friendly design, FESP is a potential alternative for portable sleep assessment in clinical and research applications. Further studies involving larger populations are needed to validate its diagnostic potential.NEW & NOTEWORTHY By comparison with PSG, this study confirmed the reliability of an efficient, objective, low-cost, and noninvasive portable automatic sleep-monitoring device FESP, which provides effective information for long-term family sleep disorder diagnosis and sleep quality monitoring.


Assuntos
Actigrafia , Espiperona/análogos & derivados , Dispositivos Eletrônicos Vestíveis , Humanos , Adulto Jovem , Adulto , Polissonografia , Reprodutibilidade dos Testes , Sono , Eletrodos
2.
BMC Psychiatry ; 24(1): 45, 2024 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-38216979

RESUMO

BACKGROUND: Developmental dyslexia is characterized by reading and writing deficits that persist into adulthood. Dyslexia is strongly associated with academic underachievement, as well as impulsive, compulsive, and criminal behaviors. The aims of this study were to investigate impulsive or compulsive reading comprehension, analyzing the differences in reading errors between two distinct groups -one with Antisocial Personality Disorder (ASPD) and another with Obsessive-Compulsive Personality Disorder (OCPD) and examine their correlation with criminal behavior within a prison population. METHODS: We gathered data from 194 participants: 81 with ASPD and 113 with OCPD from a prison center. Participants took part in interviews to gather data on demographic, criminal, and behavioral data. Additionally, the participants underwent various assessments, including the International Examination for Personality Disorders; Symptom Inventory, and Battery for the Assessment of Reading Processes in Secondary and High School - Revised. RESULTS: Our analysis revealed differences in reading skills between the ASPD and OCPD groups. Specifically, the OCPD group showed poorer performance on lexical selection, semantic categorization, grammar structures, grammatical judgements, and expository comprehension when compared with the ASPD group. Conversely, the OCPD group obtained higher scores on narrative comprehension relative to the ASPD group. CONCLUSIONS: The OCPD group showed slow lexical-phonological coding and phonological activation.


Assuntos
Transtornos da Linguagem , Transtorno Obsessivo-Compulsivo , Espiperona/análogos & derivados , Humanos , Transtorno Obsessivo-Compulsivo/epidemiologia , Compreensão , Prisões
3.
J Forensic Sci ; 69(2): 563-573, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38041250

RESUMO

Radicalization to terrorism is a multifaceted process with no single theory or approach to explain it. Although research has focused on understanding the process, there is still a dearth of studies that examine an empirically driven pathway to terrorism behavior. This study examines a cross-sectional sample of incarcerated men convicted of terrorism in Iraq (N = 160). A questionnaire-guided interview included adverse childhood experiences (ACEs), conduct disorder (CD), antisocial personality disorder (ASPD), religious and political ideology, views about causes of terrorism, and the severity of terrorist acts. Path analysis was employed to examine the relationships between these factors and to identify the model with the best fit. After adjusting for age, employment, and location, results indicated that ACEs positively impacted CD, ASPD, religious guidance, and terrorism attitudes. ASPD positively affected political commitment and terrorism attitudes, but inversely affected current religious commitment. Political commitment inversely influenced terrorism attitudes. Religious commitment positively influenced the prioritization of religion in life, which subsequently impacted terrorism attitudes and behavior severity. Additionally, attitudes toward terrorism directly affected the severity of terrorism behavior. All paths in the final model were statistically significant at p < 0.05. Although these findings may be limited in generalizability due to the unique sample, results support the complex and interdependent nature of childhood and adult experiences on the development of both terrorism attitudes and the severity of terrorism behavior.


Assuntos
Prisioneiros , Espiperona/análogos & derivados , Terrorismo , Masculino , Adulto , Humanos , Iraque , Motivação , Estudos Transversais , Transtorno da Personalidade Antissocial
4.
J Psychiatr Res ; 170: 81-89, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38113678

RESUMO

BACKGROUND: There is sufficient evidence that the index-finger-to-ring-finger-ratio (2D:4D-ratio) is associated with testosterone and estrogen exposure during the fetal stage. More specifically, a lower 2D:4D-ratio (that is; a shorter index finger, compared to a longer ring finger) was associated with a prenatally higher testosterone and lower estrogen exposure during the first trimester of the fetal stage. At a behavioral level, among adults, a lower 2D:4D-ratio was associated with a higher competitive performance among both female and male professional athletes, and with personality traits such as higher scores for mental toughness, dark triad traits, and aggressive behavior, and internet use disorder. Here, we tested, if 2D:4D-ratios differed among three clinical samples of individuals with amphetamine use disorder (AUD), antisocial personality disorder (ASPD), or both AUD and ASPD (AUD + ASPD), and when compared to healthy controls. METHOD: The sample consisted of 44 individuals (mean age: 32.95 years; 22.7% females) diagnosed either with AUD (n = 25), ASPD (n = 10) or both AUD + ASPD (n = 9), and of 36 healthy controls (mean age: 23.28; 25% females). After a thorough clinical assessment, participants provided the scans of their right-hand palm to measure the lengths of their index finger and ring finger. Further, participants with AUD, ASPD and both AUD + ASPD completed a series of self-rating questionnaires on Dark Triad traits, narcissism sensitivity, and intolerance of uncertainty. RESULTS: Compared to healthy controls, participants with AUD, ASPD, or AUD + ASPD showed statistically significantly lower 2D:4D-ratios. Participants with AUD + ASPD showed statistically significantly lowest 2D:4D-ratios, compared to participants with AUD and compared to healthy controls. For the clinical sample, a lower 2D:4D-ratio was associated with higher Dark Triad traits. 2D:4D-ratios were unrelated to narcissism sensitivity or intolerance of uncertainty. Higher scores for Dark Triad traits were associated with higher scores for narcissism sensitivity and intolerance of uncertainty. CONCLUSIONS: Compared to healthy controls, individuals with amphetamine use disorder and concomitant antisocial personality disorder (AUD + ASPD) appeared to have been exposed to particularly high prenatal testosterone and particularly low estrogen concentrations, which, at a behavioral level, might have led to a fast life history for immediate resource acquisition.


Assuntos
Transtorno da Personalidade Antissocial , Espiperona/análogos & derivados , Transtornos Relacionados ao Uso de Substâncias , Adulto , Humanos , Masculino , Feminino , Adulto Jovem , Estrogênios , Testosterona , Anfetaminas
5.
Graefes Arch Clin Exp Ophthalmol ; 261(2): 409-425, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36192457

RESUMO

PURPOSE: Recently, an increasing number of studies relied on the assumption that visually induced changes in choroidal thickness can serve as a proxy to predict future axial eye growth. The retinal signals controlling choroidal thickness are, however, not well defined. We have studied the potential roles of dopamine, released from the retina, in the choroidal response in the chicken. METHODS: Changes in retinal dopamine release and choroidal thickness changes were induced by intravitreal injections of either atropine (250 µg or 360 nMol), atropine combined with a dopamine antagonist, spiperone (500 µMol), or spiperone alone and were tracked by optical coherence tomography (OCT). To visually stimulate dopamine release, other chicks were exposed to flicker light of 1, 10, or 400 Hz (duty cycle 0.2) and choroidal thickness was tracked. In all experiments, dopamine and 3,4-Dihydroxyphenylacetic acid (DOPAC) were measured in vitreous, retina, and choroid by high-performance liquid chromatography with electrochemical detection (HLPC-ED). The distribution of the rate-limiting enzyme of dopamine synthesis, tyrosine hydroxylase (TH), neuronal nitric oxide synthase (nNOS), vascular endothelial growth factor (VEGF), and alpha2A adrenoreceptors (alpha2A-ADR) was studied in the choroid by immunofluorescence. RESULTS: The choroid thickened strongly in atropine-injected eyes, less so in atropine + spiperone-injected eyes and became thinner over the day in spiperone alone-, vehicle-, or non-injected eyes. Flickering light at 20 lx, both 1 and 10 Hz, prevented diurnal choroidal thinning, compared to 400 Hz, and stimulated retinal dopamine release. Correlation analysis showed that the higher retinal dopamine levels or release, the thicker became the choroid. TH-, nNOS-, VEGF-, and alpha2A adrenoreceptor-positive nerve fibers were localized in the choroid around lacunae and in the walls of blood vessels with colocalization of TH and nNOS, and TH and VEGF. CONCLUSIONS: Retinal DOPAC and dopamine levels were positively correlated with choroidal thickness. TH-positive nerve fibers in the choroid were closely associated with peptides known to play a role in myopia development. Findings are in line with the hypothesis that dopamine is related to retinal signals controlling choroidal thickness.


Assuntos
Galinhas , Dopamina , Animais , Galinhas/metabolismo , Dopamina/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Espiperona , Retina/metabolismo , Corioide/metabolismo , Atropina/farmacologia , Tomografia de Coerência Óptica
6.
Front Public Health ; 11: 1257629, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38192549

RESUMO

Background: Previous research has outlined the health benefits of exercise including its therapeutic potential for substance use disorders (SUD). These data have already been utilized and it is now common to find exercise as part of SUD treatment and relapse prevention programs. However, we need to better understand different exercise regimens and determine which would be the most beneficial for SUDs. Recently, high intensity interval training (HIIT) has gained attention in comparison with aerobic and resistance exercise. Little is known regarding the neurobiological mechanisms of HIIT, including its effects on dopamine signaling and receptor levels in the brain. The present study examined the effects of chronic HIIT exercise on dopamine signaling as measured by dopamine type 1-like receptor (D1R)-like, dopamine type 2-like receptor (D2R)-like, and tyrosine hydroxylase (TH) quantification in the brains of male and female rats as measured by [3H] SCH 23390 and [3H] spiperone autoradiography, and TH-immunoreactive optical density values. Methods: Rats were separated in two groups: sedentary and HIIT exercise. Exercise was on a treadmill for 30 min daily (10 3 min cycles) for six weeks with progressive speed increased up to 0.8 mph (21.5 m/min). Results: Results showed for D2R-like binding, a significant effect across the ventral caudate putamen (V CPU) between sexes, such that mean D2R-like binding was 14% greater for males than females. In the nucleus accumbens shell (Nac Shell), the HIIT Exercise rats showed 16% greater D2R-like binding as compared to the sedentary rats. No significant effects of HIIT exercise were found across groups for brain D1R-like binding levels or TH expression. Conclusion: These results suggest that HIIT exercise can modulate dopamine signaling by way of increased D2R. These findings support the premise that HIIT exercise plays an important role in dopamine signaling and, may provide a potential mechanism for how HIIT exercise can impact the brain and behavior.


Assuntos
Dopamina , Treinamento Intervalado de Alta Intensidade , Feminino , Masculino , Animais , Ratos , Encéfalo , Transdução de Sinais , Espiperona
7.
J Health Care Poor Underserved ; 33(3): 1401-1418, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36245171

RESUMO

Epidemiological estimates of substance use disorders (SUD) are critical for the planning of evidence-informed intervention and services. In this study, 250 incarcerated individuals in Nigeria were interviewed with the Mini International Neuropsychiatric Inventory (MINI) to diagnose SUD and antisocial personality disorder (ASPD). Most of the participants were males (97.6%), and the mean age was 35.4 (SD=13.5) years. Substance use disorder and ASPD were prevalent in 57.6% and 11.2% of the participants, respectively. Of those diagnosed with SUD, 35.2% and 22.4% had poly-SUD and mono-SUD respectively. Psychotic and dependence syndromes involving cannabis misuse were the most prevalent poly-SUD, and mono-SUD was characterized by alcohol, nicotine, and opioid dependence syndromes. Substance use disorder was more likely in participants charged with robbery and convicted, while ASPD was associated with prior and long-term imprisonment. There is a need for effective integration of treatment for ASPD/SUD into correctional mental health services in settings with inadequate health care using an appropriate model and a viable strategy.


Assuntos
Prisioneiros , Transtornos Relacionados ao Uso de Substâncias , Adulto , Transtorno da Personalidade Antissocial/complicações , Transtorno da Personalidade Antissocial/epidemiologia , Transtorno da Personalidade Antissocial/terapia , Atenção à Saúde , Feminino , Humanos , Masculino , Nicotina , Espiperona/análogos & derivados , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/terapia
8.
J Affect Disord ; 317: 22-28, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36028010

RESUMO

OBJECTIVE: The study aimed to compare acyl ghrelin (AG), des-acyl ghrelin (DAG), and leptin levels considered to be used as biological markers in the etiopathogenesis of antisocial personality disorder (ASPD) with healthy controls, and to investigate the relationship between these hormones and aggression and impulsivity. METHOD: The study included 45 patients with ASPD and 61 healthy people in the control group. Sociodemographic data form, Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Barratt Impulsiveness Scale (BIS-11), and Buss-Durkee Aggression Scale (BDAS) were applied to all participants. Fasting venous blood samples were taken from all participants at the same time of the day and the height and weight of the participants were measured. RESULTS: It was found that the mean serum AG and DAG levels were significantly higher than that of healthy controls whereas leptin hormone levels were significantly lower in patients compared to healthy controls. BDI, BAI, BIS-11, and BDAS scores of the patients were significantly higher compared to healthy controls. There was a positive correlation between AG and DAG hormone levels and impulsivity and aggression. DISCUSSION: The present study is the first in the literature to examine AG, DAG, and leptin hormone levels of patients diagnosed with ASPD. According to the results of the study, it is believed that changes in serum leptin and ghrelin levels will bring a new perspective in terms of understanding the pathophysiological mechanism of ASPD. Further studies are required to explain the definitive roles of these hormones in ASPD.


Assuntos
Transtorno da Personalidade Antissocial , Grelina , Humanos , Comportamento Impulsivo , Leptina , Espiperona/análogos & derivados
9.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1867(12): 159222, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35988872

RESUMO

N-Acyl-phosphatidylethanolamines (NAPEs), a minor class of membrane glycerophospholipids, accumulate along with their bioactive metabolites, N-acylethanolamines (NAEs) during ischemia. NAPEs can be formed through N-acylation of phosphatidylethanolamine by cytosolic phospholipase A2ε (cPLA2ε, also known as PLA2G4E) or members of the phospholipase A and acyltransferase (PLAAT) family. However, the enzyme responsible for the NAPE production in brain ischemia has not yet been clarified. Here, we investigated a possible role of cPLA2ε using cPLA2ε-deficient (Pla2g4e-/-) mice. As analyzed with brain homogenates of wild-type mice, the age dependency of Ca2+-dependent NAPE-forming activity showed a bell-shape pattern being the highest at the first week of postnatal life, and the activity was completely abolished in Pla2g4e-/- mice. However, liquid chromatography-tandem mass spectrometry revealed that the NAPE levels of normal brain were similar between wild-type and Pla2g4e-/- mice. In contrast, post-mortal accumulations of NAPEs and most species of NAEs were only observed in decapitated brains of wild-type mice. These results suggested that cPLA2ε is responsible for Ca2+-dependent formation of NAPEs in the brain as well as the accumulation of NAPEs and NAEs during ischemia, while other enzyme(s) appeared to be involved in the maintenance of basal NAPE levels.


Assuntos
Isquemia Encefálica , Fosfatidiletanolaminas , Aciltransferases/metabolismo , Animais , Isquemia Encefálica/genética , Modelos Animais de Doenças , Glicerofosfolipídeos , Camundongos , Fosfatidiletanolaminas/metabolismo , Fosfolipases A , Fosfolipases A2 Citosólicas , Espiperona/análogos & derivados
10.
Int J Offender Ther Comp Criminol ; 66(15): 1703-1725, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-34989271

RESUMO

A prevailing view among researchers and mental health clinicians is that symptoms of antisocial personality disorder (ASPD)/psychopathy decrease as affected individuals reach middle age. In the current investigation, informants were surveyed about the behavior of individuals who they believed showed traits of ASPD/psychopathy and were over the age of 50. A final sample of 1,215 respondents rated the index individuals according to the ASPD/psychopathy traits derived from the pre-publication first draft of the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition, revealing high endorsement of traits associated with ASPD. Survey respondents reported their observations that individuals who met a threshold for putative ASPD/psychopathy continued to engage in antisocial behavior after age 50, and as a result the respondents endured significant harm, including material losses, financial losses, and various self-reported mental health problems. Those who knew the index individuals both before and after the age of 50 were specifically asked whether there was a change in the individual's engagement in manipulation, deceit, and antisocial behavior; 93% of respondents reported that the behavior was just as bad or worse after age 50. Other researchers have suggested that the DSM diagnostic criteria do not accurately describe ASPD/psychopathy symptoms and behavior in older adults, and that the disorder remains stable, but its manifestation changes with age. This study supports those conclusions.


Assuntos
Transtorno da Personalidade Antissocial , Idoso , Transtorno da Personalidade Antissocial/diagnóstico , Transtorno da Personalidade Antissocial/psicologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Humanos , Pessoa de Meia-Idade , Espiperona/análogos & derivados , Inquéritos e Questionários
11.
Int Immunopharmacol ; 101(Pt A): 108308, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34741870

RESUMO

BACKGROUND: Aim of this study is investigates the influence of spiperone on hydrolase activity pathway in chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: Differentially expressed genes (DEGs) were calculated by the limma package from microarray data GSE20257, and analysed via gene set enrichment analysis (GSEA) for identifying COPD related pathways. The regulation of hydrolase activity pathway related drugs was predicted by connectivity Map analysis (CMap). Western blotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were used to investigate the effect of spiperone on regulation of hydrolase activity pathway in vitro experiment. RESULTS: A total of 378 DEGs were identified by the limma package. GSEA suggested that the regulation of hydrolase activity pathway was involved in the development of COPD. CMap of hub genes of regulation of hydrolase activity pathwayshown the most significant compound was spiperone. Results of vitro experiment verify that cigarette smoke extract (CSE) can increase the expression of fibronectin 1 (FN1) and epidermal growth factor (EGF), coinsided with decrease the expression of chemokine (C-X3-C motif) ligand 1 (CX3CL1), chemokoine (C-C motif) ligand 20 (CCL20), complement component 3 (C3) and slithomolog 2 (SLIT2) in BESA-2B cells and U937 cells. Spiperone can reverse the effect of CSE in BESA-2B cells and U937 cells. CONCLUSION: Regulation of hydrolase activity pathway was involved in the occurrence of COPD, spiperone was a potential drug for the treatment of COPD by affecting the regulation of hydrolase activity pathway. This study had provided new insights into the potential pathogenesis and treatment of COPD.


Assuntos
Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Espiperona/uso terapêutico , Adulto , Western Blotting , Feminino , Humanos , Hidrolases/efeitos dos fármacos , Hidrolases/metabolismo , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Doença Pulmonar Obstrutiva Crônica/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcriptoma , Células U937
12.
J Chem Neuroanat ; 118: 102035, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34597812

RESUMO

Early-life viral infections critically influence the brain development and have been variously reported to cause neuropsychiatric diseases such as Schizophrenia, Parkinson's diseases, demyelinating diseases, etc. To investigate the alterations in the dopaminergic system, myelination and associated behavioral impairments following neonatal viral infection, the viral immune activation model was created by an intraperitoneal injection of Poly I:C (5 mg/kg bw/ip) to neonatal rat pups on PND-7. The DA-D2 receptor binding was assessed in corpus striatum by using 3H-Spiperone at 3, 6 and 12 weeks of age. MOG immunolabelling was performed to check myelination stature and myelin integrity, while corpus callosum calibre was assessed by Luxol fast blue staining. Relative behavioral tasks i.e., motor activity, motor coordination and neuromuscular strength were assessed by open field, rotarod and grip strength meter respectively at 3, 6 and 12 weeks of age. Following Poly I:C exposure, a significant decrease in DA-D2 receptor binding, reduction in corpus callosum calibre and MOG immunolabelling indicating demyelination and a significant decrease in locomotor activity, neuromuscular strength and motor coordination signify motor deficits and hypokinetic influence of early life viral infection. Thus, the findings suggest that early life poly I:C exposure may cause demyelination and motor deficits by decreasing DA-D2 receptor binding affinity.


Assuntos
Comportamento Animal/efeitos dos fármacos , Bainha de Mielina/efeitos dos fármacos , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Poli I-C/toxicidade , Receptores de Dopamina D2/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Corpo Caloso/citologia , Corpo Caloso/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Força Muscular/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Wistar , Espiperona/farmacologia
13.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070506

RESUMO

Concentration of hyaluronic acid (HA) in the lungs increases in idiopathic pulmonary fibrosis (IPF). HA is involved in the organization of fibrin, fibronectin, and collagen. HA has been proposed to be a biomarker of fibrosis and a potential target for antifibrotic therapy. Hyaluronidase (HD) breaks down HA into fragments, but is a subject of rapid hydrolysis. A conjugate of poloxamer hyaluronidase (pHD) was prepared using protein immobilization with ionizing radiation. In a model of bleomycin-induced pulmonary fibrosis, pHD decreased the level of tissue IL-1ß and TGF-ß, prevented the infiltration of the lung parenchyma by CD16+ cells, and reduced perivascular and peribronchial inflammation. Simultaneously, a decrease in the concentrations of HA, hydroxyproline, collagen 1, total soluble collagen, and the area of connective tissue in the lungs was observed. The effects of pHD were significantly stronger compared to native HD which can be attributed to the higher stability of pHD. Additional spiperone administration increased the anti-inflammatory and antifibrotic effects of pHD and accelerated the regeneration of the damaged lung. The potentiating effects of spiperone can be explained by the disruption of the dopamine-induced mobilization and migration of fibroblast progenitor cells into the lungs and differentiation of lung mesenchymal stem cells (MSC) into cells of stromal lines. Thus, a combination of pHD and spiperone may represent a promising approach for the treatment of IPF and lung regeneration.


Assuntos
Ácido Hialurônico/metabolismo , Hialuronoglucosaminidase/farmacologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/efeitos dos fármacos , Espiperona/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Hialuronoglucosaminidase/administração & dosagem , Hialuronoglucosaminidase/farmacocinética , Hidroxiprolina/metabolismo , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/enzimologia , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Queratinas/metabolismo , Pulmão/enzimologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Poloxâmero/química , Receptores de IgG/metabolismo , Espiperona/administração & dosagem , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
14.
FEBS J ; 288(5): 1514-1532, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32783364

RESUMO

Dopamine receptors are G protein-coupled receptors that have several essential functions in the central nervous system. A better understanding of the regulatory mechanisms of ligand binding to the receptor may open new possibilities to affect the downstream signal transduction pathways. The majority of the available ligand binding assays use either membrane preparations, cell suspensions, or genetically modified receptors, which may give at least partially incorrect understanding of ligand binding. In this study, we implemented an assay combining fluorescence and bright-field microscopy to measure ligand binding to dopamine D3 receptors in live mammalian cells. For membrane fluorescence intensity quantification from microscopy images, we developed a machine learning-based user-friendly software membrane tools and incorporated it into a data management software aparecium that has been previously developed in our workgroup. For the experiments, a fluorescent ligand NAPS-Cy3B was synthesized by conjugating a dopaminergic antagonist N-(p-aminophenethyl)spiperone with a fluorophore Cy3B. The subnanomolar affinity of NAPS-Cy3B makes it a suitable ligand for the characterization of D3 receptors in live HEK293 cells. Using a microplate compatible automated widefield fluorescence microscope, together with the membrane tools software, enables the detection and quantification of ligand binding with a high-throughput. The live cell assay is suitable for the characterization of fluorescent ligand binding and also in the competition experiments for the screening of novel unlabeled dopaminergic ligands. We propose that this simple yet more native-like approach is feasible in GPCR research, as it enables the detection of ligand binding in an environment containing more components involved in the signal transduction cascade.


Assuntos
Bioensaio , Carbocianinas/química , Antagonistas de Dopamina/farmacologia , Receptores Dopaminérgicos/metabolismo , Software , Espiperona/análogos & derivados , Dopamina/metabolismo , Dopamina/farmacologia , Antagonistas de Dopamina/síntese química , Células HEK293 , Humanos , Processamento de Imagem Assistida por Computador/métodos , Processamento de Imagem Assistida por Computador/estatística & dados numéricos , Cinética , Ligantes , Aprendizado de Máquina , Microscopia de Fluorescência/métodos , Microscopia de Fluorescência/estatística & dados numéricos , Ligação Proteica , Espiperona/química
15.
Int J Chron Obstruct Pulmon Dis ; 16: 3575-3591, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35002229

RESUMO

BACKGROUND: Endothelial dysfunction and destruction of the pulmonary microcirculation are important pathogenic factors in chronic obstructive pulmonary disease (COPD). In COPD, bronchial obstruction is associated with endothelial dysfunction. Thus, new pharmacological treatment options aimed at restoring the pulmonary endothelium represent a clinical need in COPD therapy. Notch1 has been shown to protect cells against apoptosis, inflammation, and oxidative stress caused by cigarette smoke extract (CSE). Therefore, drug which effect on Notch1 may be a potential therapeutic target for COPD in the future. METHODS: In this study, we assessed the potential of spiperone to mediate regeneration of pulmonary endothelium in model of pulmonary emphysema induced by a CSE and lipopolysaccharide (LPS) in female C57BL/6 mice. RESULTS: Spiperone increased the number of capillaries as well as the expression of the CD31 in the alveolar tissue compared to the controls. Moreover, application of spiperone prevented alveolar wall destruction (DI), and reduced the area of emphysema. Lastly, we demonstrated that spiperone positively influenced mobilization and migration of endothelial progenitor cells (EPC, CD45-CD34+CD31+), CD309+-endothelial cells, and angiogenesis precursors (CD45-CD117+CD309+) into the lung. Spiperone administration significantly reduced the number Notch1 positive CD309+-endothelial cells and Notch1+ EPCs. CONCLUSION: Overall, our results suggest that spiperone mediates endothelial regeneration in an animal model of COPD. Thus, it could represent a novel therapeutic approach for treatment of emphysema associated with COPD.


Assuntos
Fumar Cigarros , Células Progenitoras Endoteliais , Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Animais , Fumar Cigarros/efeitos adversos , Células Progenitoras Endoteliais/metabolismo , Endotélio/metabolismo , Endotélio/patologia , Feminino , Humanos , Lipopolissacarídeos/farmacologia , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , Doença Pulmonar Obstrutiva Crônica/patologia , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/tratamento farmacológico , Regeneração , Espiperona/metabolismo , Espiperona/farmacologia , Espiperona/uso terapêutico
16.
Nat Commun ; 11(1): 6442, 2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33353947

RESUMO

In addition to the serotonin 5-HT2A receptor (5-HT2AR), the dopamine D2 receptor (D2R) is a key therapeutic target of antipsychotics for the treatment of schizophrenia. The inactive state structures of D2R have been described in complex with the inverse agonists risperidone (D2Rris) and haloperidol (D2Rhal). Here we describe the structure of human D2R in complex with spiperone (D2Rspi). In D2Rspi, the conformation of the extracellular loop (ECL) 2, which composes the ligand-binding pocket, was substantially different from those in D2Rris and D2Rhal, demonstrating that ECL2 in D2R is highly dynamic. Moreover, D2Rspi exhibited an extended binding pocket to accommodate spiperone's phenyl ring, which probably contributes to the selectivity of spiperone to D2R and 5-HT2AR. Together with D2Rris and D2Rhal, the structural information of D2Rspi should be of value for designing novel antipsychotics with improved safety and efficacy.


Assuntos
Antipsicóticos/química , Receptores de Dopamina D2/química , Espiperona/química , Animais , Sítios de Ligação , Células HEK293 , Humanos , Ligantes , Camundongos , Modelos Moleculares , Ligação Proteica
17.
Sci Rep ; 10(1): 13242, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764736

RESUMO

Animal models have demonstrated a link between dysregulation of the retinal dopamine system and the development of myopia (short-sightedness). We have previously demonstrated that topical application of levodopa in chicks can inhibit the development of form-deprivation myopia (FDM) in a dose-dependent manner. Here, we examine whether this same protection is observed in lens-induced myopia (LIM), and whether levodopa's protection against FDM and LIM occurs through a dopamine D1- or D2-like receptor mechanism. To do this, levodopa was first administered daily as an intravitreal injection or topical eye drop, at one of four ascending doses, to chicks developing LIM. Levodopa's mechanism of action was then examined by co-administration of levodopa injections with D1-like (SCH-23390) or D2-like (spiperone) dopamine antagonists in chicks developing FDM or LIM. For both experiments, levodopa's effectiveness was examined by measuring axial length and refraction after 4 days of treatment. Levodopa inhibited the development of LIM in a dose-dependent manner similar to its inhibition of FDM when administered via intravitreal injections or topical eye drops. In both FDM and LIM, levodopa injections remained protective against myopia when co-administered with SCH-23390, but not spiperone, indicating that levodopa elicits its protection through a dopamine D2-like receptor mechanism in both paradigms.


Assuntos
Benzazepinas/administração & dosagem , Levodopa/administração & dosagem , Miopia/tratamento farmacológico , Espiperona/administração & dosagem , Animais , Benzazepinas/farmacologia , Galinhas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Injeções Intravítreas , Lentes/efeitos adversos , Levodopa/farmacologia , Masculino , Miopia/etiologia , Miopia/metabolismo , Soluções Oftálmicas , Receptores de Dopamina D2/metabolismo , Espiperona/farmacologia
18.
Bull Exp Biol Med ; 168(6): 718-723, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32328949

RESUMO

We studied the effects of spiperone, a selective blocker of dopamine D2 receptors, on the model of pulmonary emphysema provoked by administration of elastase and D-galactosamine hydrochloride to female C57BL/6 mice and characterized by activation of proteases in the lungs and systemic deficiency of its inhibitor α1-antitrypsin. In this model, spiperone prevented the development of inflammatory reaction and reduced the area of emphysematous expanded alveolar tissue. The expression of angiogenic marker CD31 in the lungs increased under these conditions. Regeneration of the damaged microvascular bed under the action of spiperone resulted from recruiting of Notch1+ endothelial progenitor cells (CD45-CD31+CD34+) into the lungs and blockade of the inhibitory effect of dopamine on phosphorylation of VEGF-2 receptors in endothelial cells of different maturity. In addition, spiperone produced a protective effect on hepatocytes and restored the production and secretion of α1-antitrypsin by these cells.


Assuntos
Antagonistas de Dopamina/farmacologia , Células Progenitoras Endoteliais/efeitos dos fármacos , Enfisema Pulmonar/tratamento farmacológico , Receptor Notch1/genética , Receptores de Dopamina D2/genética , Espiperona/farmacologia , Deficiência de alfa 1-Antitripsina/tratamento farmacológico , Animais , Células Progenitoras Endoteliais/metabolismo , Células Progenitoras Endoteliais/patologia , Feminino , Galactosamina/administração & dosagem , Regulação da Expressão Gênica , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica/efeitos dos fármacos , Elastase Pancreática/administração & dosagem , Fosforilação/efeitos dos fármacos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/genética , Enfisema Pulmonar/metabolismo , Receptor Notch1/agonistas , Receptor Notch1/metabolismo , Receptores de Dopamina D2/metabolismo , Regeneração/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo , Deficiência de alfa 1-Antitripsina/enzimologia , Deficiência de alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/patologia
19.
Sci Rep ; 9(1): 19512, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31862967

RESUMO

Emotional hyperthermia is the increase in body temperature that occurs as a response to an animal detecting a salient, survival-relevant stimulus. Brown adipose tissue (BAT) thermogenesis, controlled via its sympathetic innervation, contributes to this temperature increase. Here, we have used an intruder rat experimental model to determine whether quinpirole-mediated activation of dopamine D2 receptors attenuates emotional hyperthermia in conscious rats. In anesthetized rats, we determined whether systemic quinpirole reduces BAT nerve discharge induced by activation of the medullary raphé and the lateral habenula (LHb). We measured BAT and body temperature with chronically implanted thermistors in conscious, freely moving, individually housed, male rats (resident rats). Either vehicle or quinpirole was administered, intraperitoneally, to the resident rat 30 min before introduction of a caged intruder rat. Quinpirole, in a dose-dependent manner, reduced intruder-elicited increases in BAT and body temperature. Pre-treatment with the D2 antagonist spiperone, but not the selective D1 antagonist SCH-23390, prevented this quinpirole-elicited decrease. In anesthetized rats, quinpirole abolished BAT sympathetic nerve discharge elicited by bicuculline-mediated activation of the LHb, but not the medullary raphé. Thus, activation of dopamine D2 receptors reduces the BAT thermogenesis that contributes to emotional hyperthermia. We provide evidence that these dopamine D2 receptors are located in the thermogenic pathway between the LHb and the lower brainstem pre-sympathetic control centre in the medullary raphé.


Assuntos
Tecido Adiposo Marrom/metabolismo , Habenula/metabolismo , Receptores de Dopamina D2/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Animais , Benzazepinas/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Masculino , Quimpirol/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/antagonistas & inibidores , Espiperona/farmacologia , Estresse Psicológico/metabolismo , Temperatura , Termogênese/efeitos dos fármacos
20.
Anim Reprod Sci ; 208: 106122, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31405473

RESUMO

The vitellogenesis-inhibiting hormone (VIH), also known as gonad-inhibiting hormone, is a neuropeptide hormone in crustaceans that belongs to the crustacean hyperglycemic hormone (CHH)-family peptide. There is regulation vitellogenesis by VIH during gonad maturation in crustaceans. A full-length Scylla olivacea VIH (Scyol-VIH) was identified through reverse transcription polymerase chain reaction and rapid amplification of cDNA ends. The open reading frame consists of 378 nucleotides, which encodes a 126-amino acid precursor protein, including a 22-residue signal peptide and a 103-amino acid mature peptide in which 6 highly conserved cysteine residues are present. There was expression of the Scyol-VIH gene in immature female Scylla olivacea in the eyestalk, brain and ventral nerve cord. The Scyol-VIH gene expression was localized to the eyestalk X-organ, brain neuronal clusters 6 and 11, and in multiple neuronal clusters of the ventral nerve cord. The relative abundance of Scyol-VIH mRNA transcript in the eyestalk was relatively greater in immature stage females, then decreased as ovarian maturation progressed. Furthermore, eyestalk Scyol-VIH increased after dopamine (5 µg/g BW) injection. The present research provides fundamental information about Scyol-VIH and its potential effect in controlling reproduction.


Assuntos
Braquiúros/fisiologia , Dopamina/farmacologia , Hormônios de Invertebrado/metabolismo , Ovário/crescimento & desenvolvimento , RNA Mensageiro/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Braquiúros/genética , Clonagem Molecular , Dopamina/administração & dosagem , Dopaminérgicos/farmacologia , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônios de Invertebrado/genética , Ovário/metabolismo , Filogenia , RNA Mensageiro/genética , Serotonina/administração & dosagem , Serotonina/farmacologia , Serotoninérgicos/administração & dosagem , Serotoninérgicos/farmacologia , Maturidade Sexual , Espiperona/administração & dosagem , Espiperona/farmacologia , Fatores de Tempo
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