RESUMO
Type 2 diabetes mellitus (T2DM), characterized by hyperglycemia and insulin resistance, has been recognized as a risk factor for cognitive impairment and dementia, including Alzheimer's disease (AD). Insulin receptor substrate2 (IRS2) is a major component of the insulin/insulin-like growth factor-1 signaling pathway. Irs2 deletion leads to life-threatening T2DM, promoting premature death in male mice regardless of their genetic background. Here, we showed for the first time that young adult male mice lacking Irs2 on a C57BL/6J genetic background (Irs2-/-/6J) survived in different experimental environments and displayed hippocampus-associated behavioral alterations. Young adult male Irs2-/-/6J mice also exhibit aberrant alterations in energy and nutrient sensors, such as AMP-activated protein kinase (AMPK) and glucose transporter3 (GLUT3), and reduced core body temperature accompanied by abnormal change in the temperature sensor in the brain. These results suggest that Irs2 deficiency-induced impairments of brain energy metabolism and thermoregulation contribute to hippocampus-associated behavioral changes in young adult male mice.
Assuntos
Deleção de Genes , Hipocampo/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Animais , Regulação da Temperatura Corporal , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
PURPOSE: Docetaxel is known to cause eye disorders. In this study, current status of eye disorders caused by docetaxel administration every 3 weeks in Japanese patients was examined. METHODS: This case-control study targeted patients who were newly administered docetaxel at the Kyoto Okamoto Memorial Hospital between 1 July 2015 and 30 June 2018. Eye disorder occurrence was defined as an event in which the pharmacist confirmed the symptoms in a patient interview and the ophthalmologist diagnosed the disorder. RESULTS: Of the 89 subjects, 7 (7.9%) had eye disorders. The symptoms were watering eyes (7.9%), a stye and eye discharge (2.2% each), corneal and conjunctival disorder, visual acuity reduction, and blepharedema (1.1% each). Four patients who presented with watering eyes, eye discharge, or corneal and conjunctival disorder showed improvement with the use of eye drops such as artificial tears. Two patients who presented with a stye showed improvement with the use of oral cefcapene. One patient with mild symptoms showed spontaneous improvement. However, one patient had irreversible visual acuity reduction. The multivariate logistic regression analysis revealed that a cumulative docetaxel dose of ≥300 mg/m2 (odds ratio: 15.50, 95% confidence interval: 1.37-175.00, p = 0.027) and concomitant cyclophosphamide use (odds ratio: 13.20, 95% confidence interval: 1.13-153.00, p = 0.039) were significant risk factors associated with eye disorders. CONCLUSION: In conclusion, it was determined that docetaxel-related eye disorders might be influenced by the cumulative dose of docetaxel and concomitant cyclophosphamide use. In addition, relatively mild symptoms improved with medication.
Assuntos
Antineoplásicos/efeitos adversos , Docetaxel/efeitos adversos , Oftalmopatias/induzido quimicamente , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Acuidade VisualRESUMO
Paclitaxel and nanoparticle albumin-bound paclitaxel are known to cause adverse events of eye disorders, such as cystoid macular edema. However, at present, the risk factors remain unclear. Therefore, risk factors for eye disorders caused by paclitaxel and nanoparticle albumin-bound paclitaxel were studied. This retrospective study targeted patients who were newly administered paclitaxel or nanoparticle albumin-bound paclitaxel at Kyoto Okamoto Memorial Hospital between April 1, 2012, and March 31, 2017. Eye disorder occurrence was defined as an event in which the pharmacist confirmed the symptoms in a patient interview and the ophthalmologist diagnosed the disorder. To analyze the risk factors, logistic regression analysis using 41 factors was performed. Of 128 subjects, 13 (10.2%) had eye disorders with symptom degrees of Grades 1 and 2. The symptoms were conjunctivitis or subconjunctival hemorrhage (3.1%), visual acuity reduction (2.3%), blurred vision and eye pain (1.6% each), eye mucus, blepharitis, stye, watering eyes, photopsia, and muscae volitantes (0.8% each). In eight patients, the conditions patients improved with spontaneously or with medication use; no improvements were observed the cases of visual acuity reduction, blurred vision, or muscae volitantes. Multivariate logistic regression analysis revealed that a cumulative dose of ≥819 mg/m2 (odds ratio: 5.34, 95% confidence interval: 1.32-21.60, p=0.019) and baseline alkaline phosphatase ≥256 U/L (odds ratio: 3.74, 95% confidence interval: 1.02-13.70, p=0.046) were significant risk factors associated with eye disorders. In conclusion, it was determined that paclitaxel- and nanoparticle albumin-bound paclitaxel-related eye disorders might be influenced by cumulative dose and baseline alkaline phosphatase.
Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Oftalmopatias/induzido quimicamente , Neoplasias/tratamento farmacológico , Paclitaxel/efeitos adversos , Transtornos da Visão/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Albuminas/uso terapêutico , Fosfatase Alcalina/sangue , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/uso terapêutico , Feminino , Hospitais , Humanos , Modelos Logísticos , Edema Macular/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Nanopartículas/efeitos adversos , Razão de Chances , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Estudos Retrospectivos , Fatores de RiscoRESUMO
The sleep disorder narcolepsy results from loss of hypothalamic orexin/hypocretin neurons. Although narcolepsy onset is usually postpubertal, current mouse models involve loss of either orexin peptides or orexin neurons from birth. To create a model of orexin/hypocretin deficiency with closer fidelity to human narcolepsy, diphtheria toxin A (DTA) was expressed in orexin neurons under control of the Tet-off system. Upon doxycycline removal from the diet of postpubertal orexin-tTA;TetO DTA mice, orexin neurodegeneration was rapid, with 80% cell loss within 7 d, and resulted in disrupted sleep architecture. Cataplexy, the pathognomic symptom of narcolepsy, occurred by 14 d when â¼5% of the orexin neurons remained. Cataplexy frequency increased for at least 11 weeks after doxycycline. Temporary doxycycline removal followed by reintroduction after several days enabled partial lesion of orexin neurons. DTA-induced orexin neurodegeneration caused a body weight increase without a change in food consumption, mimicking metabolic aspects of human narcolepsy. Because the orexin/hypocretin system has been implicated in the control of metabolism and addiction as well as sleep/wake regulation, orexin-tTA; TetO DTA mice are a novel model in which to study these functions, for pharmacological studies of cataplexy, and to study network reorganization as orexin input is lost.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Narcolepsia/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neuropeptídeos/antagonistas & inibidores , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Cataplexia/fisiopatologia , Toxina Diftérica/genética , Modelos Animais de Doenças , Doxiciclina/farmacologia , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Líquidos/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Eletroencefalografia , Eletromiografia , Feminino , Alimentos , Masculino , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Narcolepsia/fisiopatologia , Orexinas , Sono/fisiologia , Vigília/fisiologiaRESUMO
We have been investigating the potential use of cell-penetrating peptide-linked polymers as a novel penetration enhancer. Since previous in vivo studies demonstrated that poly(N-vinylacetamide-co-acrylic acid) bearing D-octaarginine, a typical cell-penetrating peptide, enhanced membrane permeation of biomolecules, its potential as an in vitro transfection tool was evaluated in this study. A plasmid DNA encoding green fluorescent protein (pGFP-C1), ß-galactosidase, and bovine serum albumin (BSA) were used as model biomolecules. Anionic pGFP-C1 interacted electrostatically with cationic d-octaarginine-linked polymers. When the ratio of mass concentration of polymers to that of pGFP-C1 reached 2.5, complexes whose size and zeta potential were approximately 200 nm and 15 mV, respectively, were obtained. GFP expression was observed in cells incubated with complexes prepared under conditions in which the polymer/pDNA concentration ratio exceeded 2.5. The expression level elevated with an increase in the concentration ratio, but physicochemical properties of the complexes remained unchanged. Results suggested that free polymers contributed to pGFP-C1 internalization. Another cell study demonstrated that ß-galactosidase premixed with polymers was taken up into cells in its active tetrameric form. Similar electrostatic interaction-driven complex formation was observed for BSA charged negatively in neutral solution. However, it appeared that the internalization processes of BSA differed from those of pGFP-C1. A mass concentration-dependent increase in internalized BSA was observed, irrespective of the polymer/protein concentration ratio. Due to frail interactions, polymers that were released from the complexes and subsequently immobilized on cell membranes might also contribute to membrane permeation of BSA.
Assuntos
Proteínas de Fluorescência Verde/metabolismo , Oligopeptídeos/química , Plasmídeos/administração & dosagem , Polímeros/química , Soroalbumina Bovina/metabolismo , beta-Galactosidase/metabolismo , Animais , Bovinos , Permeabilidade da Membrana Celular , Portadores de Fármacos/química , Proteínas de Fluorescência Verde/genética , Células HeLa , Humanos , Soroalbumina Bovina/genética , Transfecção , beta-Galactosidase/genéticaRESUMO
AIM: Type 2 diabetes mellitus (T2DM) is an increased risk factor for Alzheimer's disease (AD); however, the relationship between the 2 conditions is controversial. High-fat diet (HFD) causes cognitive impairment with/without Aß accumulation in middle-aged or aged transgenic (Tg) and knock-in (KI) AD mouse models, except for metabolic disorders, which commonly occur in all mice types. Alternatively, whether HFD in early life has an impact on nutrient metabolism and neurological phenotypes in young AD mouse models is not known. In the present study, we examined the effects of HFD on young APPKINL-G-F/NL-G-F mice, one of the novel KI-AD mouse models. METHODS: The mice were categorized by diet into 2 experimental groups, normal diet (ND) and HFD. Four-week-old wild-type (WT) and APPKINL-G-F/NL-G-F mice were fed ND or HFD for 9 weeks. Both types of mice on ND and HFD were examined during young adulthood. RESULTS: HFD caused T2DM-related metabolic disturbances in both young WT and APPKINL-G-F/NL-G-F mice, whereas impaired thermoregulation and shortage of alternative energy sources specifically occurred in young APPKINL-G-F/NL-G-F mice. However, HFD had no impact on the cognitive function, Aß levels, and phosphorylation of hippocampal insulin receptor substrate 1 (IRS1) at all the 3 Ser sites in both types of mice. CONCLUSION: HFD is effective in causing metabolic disturbances in young WT and APPKINL-G-F/NL-G-F mice but is ineffective in inducing neurological disorders in both types of mice, suggesting that the aging effects, along with long-term HFD, facilitate neurological alterations.
Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Cognição , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Proteínas Substratos do Receptor de Insulina/metabolismo , Camundongos , NutrientesRESUMO
Neuroethics is the study of how neuroscience impacts humans and society. About 15 years have passed since neuroethics was introduced to Japan, yet the field of neuroethics still seeks developed methodologies and an established academic identity. In light of progress in neuroscience and neurotechnology, the challenges for Japanese neuroethics in the 2020 s can be categorized into five topics. (1) The need for further research into the importance of informed consent in psychiatric research and the promotion of public-patient engagement. (2) The need for a framework that constructs a global environment for neuroscience research that utilizes reliable samples and data. (3) The need for ethical support within a Japanese context regarding the construction of brain banks and the research surrounding their use. It is also important to reconsider the moral value of the human neural system and make comparisons with non-human primates. (4) An urgent need to study neuromodulation technologies that intervene in emotions. (5) The need to reconsider neuroscience and neurotechnology from social points of view. Rules for neuroenhancements and do-it-yourself neurotechnologies are urgently needed, while from a broader perspective, it is essential to study the points of contact between neuroscience and public health.
Assuntos
Neurociências , Encéfalo , Emoções , Humanos , Japão , Princípios MoraisRESUMO
Psychiatric and neurological disorders are afflictions of the brain that can affect individuals throughout their lifespan. Many brain magnetic resonance imaging (MRI) studies have been conducted; however, imaging-based biomarkers are not yet well established for diagnostic and therapeutic use. This article describes an outline of the planned study, the Brain/MINDS Beyond human brain MRI project (BMB-HBM, FY2018 ~ FY2023), which aims to establish clinically-relevant imaging biomarkers with multi-site harmonization by collecting data from healthy traveling subjects (TS) at 13 research sites. Collection of data in psychiatric and neurological disorders across the lifespan is also scheduled at 13 sites, whereas designing measurement procedures, developing and analyzing neuroimaging protocols, and databasing are done at three research sites. A high-quality scanning protocol, Harmonization Protocol (HARP), was established for five high-quality 3 T scanners to obtain multimodal brain images including T1 and T2-weighted, resting-state and task functional and diffusion-weighted MRI. Data are preprocessed and analyzed using approaches developed by the Human Connectome Project. Preliminary results in 30 TS demonstrated cortical thickness, myelin, functional connectivity measures are comparable across 5 scanners, suggesting sensitivity to subject-specific connectome. A total of 75 TS and more than two thousand patients with various psychiatric and neurological disorders are scheduled to participate in the project, allowing a mixed model statistical harmonization. The HARP protocols are publicly available online, and all the imaging, demographic and clinical information, harmonizing database will also be made available by 2024. To the best of our knowledge, this is the first project to implement a prospective, multi-level harmonization protocol with multi-site TS data. It explores intractable brain disorders across the lifespan and may help to identify the disease-specific pathophysiology and imaging biomarkers for clinical practice.
Assuntos
Encefalopatias , Conectoma , Encéfalo/diagnóstico por imagem , Humanos , Longevidade , Imageamento por Ressonância Magnética , Estudos ProspectivosRESUMO
The biological effects of insulin signaling are regulated by the phosphorylation of insulin receptor substrate 1 (IRS1) at serine (Ser) residues. In the brain, phosphorylation of IRS1 at specific Ser sites increases in patients with Alzheimer's disease (AD) and its animal models. However, whether the activation of Ser sites on neural IRS1 is related to any type of memory decline remains unclear. Here, we show the modifications of IRS1 through its phosphorylation at etiology-specific Ser sites in various animal models of memory decline, such as diabetic, aged, and amyloid precursor protein (APP) knock-in NL-G-F (APPKINL-G-F) mice. Substantial phosphorylation of IRS1 at specific Ser sites occurs in type 2 diabetes- or age-related memory deficits independently of amyloid-ß (Aß). Furthermore, we present the first evidence that, in APPKINL-G-F mice showing Aß42 elevation, the increased phosphorylation of IRS1 at multiple Ser sites occurs without memory impairment. Our findings suggest that the phosphorylation of IRS1 at specific Ser sites is a potential marker of Aß-unrelated memory deficits caused by type 2 diabetes and aging; however, in Aß-related memory decline, the modifications of IRS1 may be a marker of early detection of Aß42 elevation prior to the onset of memory decline in AD.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Insulina/metabolismo , Transtornos da Memória/metabolismo , Memória , Envelhecimento , Doença de Alzheimer/complicações , Animais , Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Masculino , Transtornos da Memória/etiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosforilação , Serina/metabolismo , Transdução de SinaisRESUMO
It is a prerequisite for community pharmacists to maintain appropriate communication with patients, but a pharmacist licensee usually must learn communication-skills after starting work as a pharmacist. However, an education system and its evaluation methods are expected to be established, since the extent of self-training and rapidity of skill acquisition may vary largely among pharmacists. Therefore in this study we developed a communication-skills education program suitable for community pharmacies, developed objective-structured clinical examination (OSCE) appraisal charts, and carried out that education and its evaluation for a period of 8 months. The appraisal charts created by us were based on items of the "patient-communication station" categorized as one of the six stations in the five areas of pharmacy OSCE. Our questionnaire for pharmacist trainees after receiving communication-skills education/evaluation resulted in responses including such comments as: the education helped to improve their communication-skills; was useful in actual patient consultations; and increased self-confidence in their work. The OSCE scores gradually increased as the trainees completed more courses in the education program. These results show that the education program, which employs an OSCE appraisal chart, leads to specific outcomes in communication skills learning.
Assuntos
Comunicação , Educação de Pós-Graduação em Farmácia , Farmácias , Currículo , Humanos , Inquéritos e QuestionáriosRESUMO
Polymyxin B, a cyclic cationic polypeptide antibiotic, binds to the lipid A of bacterial endotoxin (lipopolysaccharide; LPS) to inhibit LPS-induced fever. On the basis of a casual observation, we hypothesised that in rats (unlike in rabbits and goats), intravenous (i.v.) polymyxin B would decrease resting body temperature. A single i.v. injection of polymyxin B (10, 100 or 1000 microg/kg) induced a rapid, marked drop in body temperature in a dose-related manner, with no change in physical activity. However, the highest dose (1000 microg/kg) seemed to impair heat-loss mechanisms and/or functions controlling the animal's day-night cycle [because the day-time body temperature remained elevated for two days after the injection (versus the pre-injection level)]. By contrast, rats given 100 or 10 microg/kg of the drug showed a normal day-night cycle after recovery from the initial hypothermic effect of the drug. Therefore, we used the middle dose of polymyxin B (100 microg/kg) in the subsequent experiments. In these experiments, significant decreases in metabolic rate and heat-loss responses were observed immediately after an i.v. injection of polymyxin B (100 microg/kg). By contrast, intracerebroventricular injection of polymyxin B (3 microg) had no effect on resting body temperature. These results suggest that the observed decrease in metabolic rate is responsible for the polymyxin-B-induced hypothermia. Further, rats may react with a reduction in heat-loss responses so as to prevent the body temperature decreasing too far in response to polymyxin B. Thus, polymyxin B modulates or interferes with the peripheral mechanisms underlying body temperature regulation in rats.
Assuntos
Temperatura Corporal/efeitos dos fármacos , Hipotermia/induzido quimicamente , Polimixina B/farmacologia , Animais , Metabolismo Basal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hipotermia/metabolismo , Injeções Intravenosas , Injeções Intraventriculares , Masculino , Atividade Motora/efeitos dos fármacos , Polimixina B/administração & dosagem , Polimixina B/toxicidade , Ratos , Ratos Wistar , Fatores de TempoRESUMO
[structure: see text] Ciguatoxin CTX3C is a representative congener of ciguatoxins, which are known to be the principal causative agents of ciguatera seafood poisoning. The structure of CTX3C spans more than 3 nm and is characterized by 13 ether rings. In this paper, an improved total synthesis of CTX3C is reported. Alteration of the protective group from benzyl ether to 2-naphthylmethyl (NAP) ether drastically increases the yield for final global deprotection and has provided a sufficient amount of sample for further biological studies.
Assuntos
Ciguatoxinas/síntese química , Ciguatera , Ciguatoxinas/química , Estrutura MolecularRESUMO
The preoptic area (POA) occupies a crucial position among the structures participating in thermoregulation, but we know little about its efferent projections for controlling various effector responses. In this study, we used an immunohistochemical analysis of Fos expression during local warming of the preoptic area. To avoid the effects of anesthesia or stress, which are known to elicit Fos induction in various brain regions, we used a novel thermode specifically designed for chronic warming of discrete brain structures in freely moving rats. At an ambient temperature of 22 degrees C, local POA warming increased Fos immunoreactivity in the supraoptic nucleus (SON) and the periaqueductal gray matter (PAG). Exposure of animals to an ambient temperature of 5 degrees C induced Fos immunoreactivity in the magnocellular paraventricular nucleus (mPVN) and the dorsomedial region of the hypothalamus (DMH). Concurrent warming of the POA suppressed Fos expression in these areas. These findings suggest that thermal information from the preoptic area sends excitatory signals to the SON and the PAG, and inhibitory signals to the mPVN and the DMH.
Assuntos
Regulação da Temperatura Corporal/fisiologia , Vias Neurais/metabolismo , Neurônios/metabolismo , Área Pré-Óptica/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Regulação para Cima/fisiologia , Animais , Contagem de Células , Núcleo Hipotalâmico Dorsomedial/citologia , Núcleo Hipotalâmico Dorsomedial/metabolismo , Regulação da Expressão Gênica/fisiologia , Hipertermia Induzida , Imuno-Histoquímica , Masculino , Vias Neurais/citologia , Neurônios/citologia , Núcleo Hipotalâmico Paraventricular/citologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Substância Cinzenta Periaquedutal/citologia , Substância Cinzenta Periaquedutal/metabolismo , Área Pré-Óptica/citologia , Ratos , Ratos Wistar , Núcleo Supraóptico/citologia , Núcleo Supraóptico/metabolismoRESUMO
We treated a young female patient who suffered from severe hypothermia. The etiology of the hypothermia was not identified, though various medical examinations were performed. Intraperitoneal (i.p.) injections of the patient's serum produced a significant and profound hypothermia in rats that was not associated with circulatory shock. The patient's serum was separated into 4 fractions by the use of various types of centrifugal filtration units according to molecular weights (MW), i.e., below 10 kDa, 10-30 kDa, 30-100 kDa, and beyond 100 kDa. The first two fractions never induced hypothermia in rats, but the i.p. injections of the fraction with MW from 30 to 100 kDa consistently produced hypothermia. The fraction with MW beyond 100 kDa caused marked hypothermia in one out of 3 rats tested. The results suggest that the patient was excessively producing endogenous cryogenic substances of which MW may be greater than 30 kDa.
Assuntos
Hipotermia/sangue , Hipotermia/fisiopatologia , Adolescente , Animais , Análise Química do Sangue , Regulação da Temperatura Corporal , Feminino , Humanos , Masculino , Peso Molecular , Ratos , Ratos Wistar , Soro/químicaRESUMO
Lurasidone is a novel antipsychotic agent with high affinity for dopamine D(2), 5-hydroxyltryptamine 5-HT(2A), and 5-HT(7) receptors. Lurasidone has negligible affinity for histamine H(1) and muscarinic M(1) receptors, which are thought to contribute to side effects such as weight gain, sedation, and worsening of cognitive deficits. Our interests focus on why lurasidone has such high selectivity for only a part of these aminergic G-protein coupled receptors (GPCRs) and the different binding profile from ziprasidone, which has the same benzisothiazolylpiperazine moiety as lurasidone. In order to address these issues, we constructed structural models of lurasidone-GPCR complexes by homology modeling of receptors, exhaustive docking of ligand, and molecular dynamics simulation-based refinement of complexes. This computational study gave reliable structural models for D(2), 5-HT(2A), and 5-HT(7), which had overall structural complementarities with a salt bridge anchor at the center of the lurasidone molecule, but not for H(1) and M(1) owing to steric hindrance between the norbornane-2,3-dicarboximide and/or cyclohexane part of lurasidone and both receptors. By comparison with the structural models of olanzapine-GPCRs and ziprasidone-GPCRs constructed using the same computational protocols, it was suggested that the bulkiness of the norbornane-2,3-dicarboximide part and the rigidity and the bulkiness of the cyclohexyl linker gave lurasidone high selectivity for the desired aminergic GPCRs. Finally, this structural insight was validated by a binding experiment of the novel benzisothiazolylpiperazine derivatives. This knowledge on the structural mechanism behind the receptor selectivity should help to design new antipsychotic agents with preferable binding profiles, and the established computational protocols realize virtual screening and structure-based drug design for other central nervous system drugs with desired selectivity for multiple targets.
Assuntos
Isoindóis/metabolismo , Receptores de Neurotransmissores/metabolismo , Tiazóis/metabolismo , Sequência de Aminoácidos , Humanos , Cloridrato de Lurasidona , Dados de Sequência Molecular , Homologia de Sequência de AminoácidosRESUMO
We investigated the effects of redecoration of a hospital isolation room with natural materials on thermoregulatory, cardiovascular and hormonal parameters of healthy subjects staying in the room. Two isolation rooms with almost bilaterally-symmetrical arrangements were used. One room (RD) was redecorated with wood paneling and Japanese paper, while the other (CN) was unchanged (with concrete walls). Seven healthy male subjects stayed in each room for over 24 h in the cold season. Their rectal temperature (T(re)) and heart rate, and the room temperature (T(a)) and relative humidity were continuously measured. Arterial blood pressures, arterial vascular compliance, thermal sensation and thermal comfort were measured every 4 h except during sleeping. Blood was sampled after the stay in the rooms. In RD, T(a) was significantly higher by about 0.4 degrees C and relative humidity was lower by about 5% than in CN. Diurnal T(re) levels of subjects in RD significantly differed from those in CN, i.e., T(re)s were significantly higher in RD than in CN especially in the evening. In RD, the subjects felt more thermally-comfortable than in CN. Redecoration had minimal effects on cardiovascular parameters. Plasma levels of catecholamines and antidiuretic hormone did not differ, while plasma cortisol level was significantly lower after staying in RD than in CN by nearly 20%. The results indicate that, in the cold season, redecoration with natural materials improves the thermal environment of the room and contributes to maintaining core temperature of denizens at preferable levels. It also seems that redecoration of room could attenuate stress levels of isolated subjects.
Assuntos
Arquitetura Hospitalar/métodos , Isolamento de Pacientes/psicologia , Estresse Fisiológico/prevenção & controle , Adulto , Pressão Sanguínea , Regulação da Temperatura Corporal , Clima Frio , Frequência Cardíaca , Humanos , Hidrocortisona/sangue , Masculino , Estresse Fisiológico/fisiopatologiaRESUMO
We investigated changes in responsiveness to noradrenaline (NA) and gene expression in aorta, and plasma nitrite/nitrate (NOx) levels in heat-acclimated rats. Male rats were exposed for 10 consecutive days to either 32 degrees C in the second half of the dark phase (HI) or to 32 degrees C constantly (HC). Controls were kept at 24 degrees C. After heat acclimation, thoracic aorta was excised and blood was taken in the first (Dark1) and second (Dark2) halves of the dark phase, and in the light phase. Contractile response to NA in HI was significantly depressed in Dark1 and Dark2, whereas in HC the contraction response to NA was significantly attenuated in all phases. Endothelial NO synthase (eNOS) mRNA expression was significantly enhanced in HI in Dark2. Inducible NOS mRNA was undetectable. mRNA expression of period2 was not modified by heat acclimation. Plasma NOx concentrations in HI were significantly elevated in Dark1 and Dark2, while in HC, the level was significantly raised in all phases. Our results suggest that in rats, heat acclimation improves distensibility of thoracic aorta due to attenuated responsiveness to NA, which might be attributable in part to an upregulated eNOS expression and an increase in circulating NO. The phases of the day when such changes occurred appear to be closely related to the periods when the animals were previously subjected to heat.
Assuntos
Aclimatação , Aorta Torácica/metabolismo , Proteínas de Ciclo Celular/metabolismo , Temperatura Alta , Óxido Nítrico Sintase Tipo II/metabolismo , Norepinefrina/metabolismo , Proteínas Nucleares/metabolismo , Vasoconstrição , Adenina/metabolismo , Animais , Aorta Torácica/enzimologia , Regulação da Temperatura Corporal , Proteínas de Ciclo Celular/genética , Regulação para Baixo , Indução Enzimática , Masculino , Óxido Nítrico/sangue , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo III , Proteínas Nucleares/genética , Proteínas Circadianas Period , Fotoperíodo , RNA Mensageiro/metabolismo , Ratos , Ratos WistarRESUMO
We have reported that after rats were acclimated to heat for about 5 h daily at a fixed time, the pattern of day-night variations of core temperature (T(cor)) altered, i.e., their T(cor) fell, especially during the period when they had previously been exposed to heat. The suprachiasmatic nucleus (SCN) of the hypothalamus is known to be indispensable for the genesis of circadian rhythms of T(cor). We therefore investigated the involvement of the SCN in the characteristic fall in T(cor) in heat-acclimated rats. The rats were exposed to an ambient temperature of 33 degrees C only in the last half of the dark phase for 10 consecutive days. After the heat exposure schedule, the nocturnal pattern of T(cor) variations and Fos expression in the dorsomedial SCN altered so that the T(cor) and the number of Fos immunoreactive cells decreased in the last half of the dark phase. The bilateral lesions of the SCN of rats were made electrically, and the electrical lesions of the SCNs abolished the daily cycle of T(cor). In the SCN-lesioned rats, theT(cor) levels were significantly lowered after the 10-day heat exposure schedule. However, their T(cor) did not specifically drop during the period when they had previously been exposed to heat. These findings suggest that the SCN is crucial for establishing a time memory for heat stress, and it plays a minimal role in heat acclimation-induced changes in T(cor) in rats.
Assuntos
Aclimatação/fisiologia , Regulação da Temperatura Corporal/fisiologia , Ritmo Circadiano/fisiologia , Memória/fisiologia , Núcleo Supraquiasmático/fisiologia , Animais , Relógios Biológicos/fisiologia , Temperatura Corporal/fisiologia , Temperatura Alta , Masculino , Ratos , Ratos Wistar , Estresse Fisiológico/fisiopatologia , Fatores de TempoRESUMO
We investigated the effects of heat acclimation on venous and arterial compliance in humans. Four male and four female volunteers were exposed to an ambient temperature of 40 degrees C and relative humidity of 40% for 4 h (1330-1730 hours) per day for 9-10 consecutive days. The calf venous compliance (CV) was estimated using venous occlusion plethysmography with a mercury-in-silastic strain gauge placed around the right calf at its maximum girth. The compliance of the small (CSA) and large (CLA) arteries were assessed by reflective and capacitance compliance by analyzing the radial artery blood pressure waveforms, basing on the use of a modified Windkessel model. The calf CV, CSA, CLA, systolic and diastolic blood pressures, heart rate and core temperature were determined twice a day, 0930-1100 hours (AM test) and 1500-1630 hours (PM test), in both heat-acclimated and non-heat-acclimated (control) conditions. Heat acclimation appeared to decrease blood pressures, heart rate and significantly lowered core temperature only in the PM test. In the control condition, the calf CV was not affected by the time of day and the CSA was significantly depressed in the PM test. After acclimation to heat, the calf CV significantly increased and the CSA did not decrease in the PM test. The results presented suggest that repeated heat exposure in humans, for 4 h at a fixed time daily, increases the calf CV and the CSA particularly during the period when the subjects were previously exposed to heat.
Assuntos
Artérias/fisiopatologia , Regulação da Temperatura Corporal/fisiologia , Temperatura Alta , Perna (Membro)/fisiologia , Veias/fisiopatologia , Adulto , Pressão Sanguínea/fisiologia , Complacência (Medida de Distensibilidade) , Feminino , Humanos , Perna (Membro)/irrigação sanguínea , Masculino , Pletismografia/métodos , Fatores de TempoRESUMO
More than 20,000 people suffer annually from ciguatera seafood poisoning in subtropical and tropical regions. The extremely low content of the causative neurotoxins, designated as ciguatoxins, in fish has hampered isolation, detailed biological studies, and preparation of anti-ciguatoxin antibodies for detecting these toxins. Furthermore, the large (3 nm in length) and complex molecular structure of ciguatoxins has impeded chemists from completing their total synthesis. In this article, the full details of studies leading to the total synthesis of ciguatoxin CTX3C are provided. The key elements of the first-generation approach include O,O-acetal formation from the right and left wing fragments, conversion from O,O-acetal to O,S-acetal, a radical reaction to cyclize the G ring, a ring-closing metathesis reaction to close the F ring, and final removal of the 2-naphtylmethyl protective groups. Subsequent studies provided a second-generation total synthesis, which is more concise and results in a higher yield. Second-generation synthesis was accomplished by using a direct method of constructing the key intermediate O,S-acetal from alpha-chlorosulfide and a secondary alcohol. These syntheses ensure a practical supply of ciguatoxin for biological applications.