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1.
Mol Psychiatry ; 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32376999

RESUMO

The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABAA receptor densities can identify objective molecular markers in ASD. We measured both total GABAA receptor densities by using [18F]flumazenil positron emission tomography ([18F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy (1H-MRS) in 28 adults with ASD and 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABAA receptor densities between ASD and TD groups. However, 1H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism-Spectrum Quotient (AQ) and Ritvo Autism Asperger's Diagnostic Scale-Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water's relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.

2.
J Magn Reson Imaging ; 51(1): 183-194, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31044459

RESUMO

BACKGROUND: H2 15 O-positron emission tomography (PET) is considered the reference standard for absolute cerebral blood flow (CBF). However, this technique requires an arterial input function measured through continuous sampling of arterial blood, which is invasive and has limitations with tracer delay and dispersion. PURPOSE: To demonstrate a new noninvasive method to quantify absolute CBF with a PET/MRI hybrid scanner. This blood-free approach, called PC-PET, takes the spatial CBF distribution from a static H2 15 O-PET scan, and scales it to the whole-brain average CBF value measured by simultaneous phase-contrast MRI. STUDY TYPE: Observational. SUBJECTS: Twelve healthy controls (HC) and 13 patients with Moyamoya disease (MM) as a model of chronic ischemic disease. FIELD STRENGTH/SEQUENCES: 3T/2D cardiac-gated phase-contrast MRI and H2 15 O-PET. ASSESSMENT: PC-PET CBF values from whole brain (WB), gray matter (GM), and white matter (WM) in HCs were compared with literature values since 2000. CBF and cerebrovascular reactivity (CVR), which is defined as the percent CBF change between baseline and post-acetazolamide (vasodilator) scans, were measured by PC-PET in MM patients and HCs within cortical regions corresponding to major vascular territories. Statistical Tests: Linear, mixed effects models were created to compare CBF and CVR, respectively, between patients and controls, and between different degrees of stenosis. RESULTS: The mean CBF values in WB, GM, and WM in HC were 42 ± 7 ml/100 g/min, 50 ± 7 ml/100 g/min, and 23 ± 3 ml/100 g/min, respectively, which agree well with literature values. Compared with normal regions (57 ± 23%), patients showed significantly decreased CVR in areas with mild/moderate stenosis (47 ± 17%, P = 0.011) and in severe/occluded areas (40 ± 16%, P = 0.016). Data Conclusion: PC-PET identifies differences in cerebrovascular reactivity between healthy controls and cerebrovascular patients. PC-PET is suitable for CBF measurement when arterial blood sampling is not accessible, and warrants comparison to fully quantitative H2 15 O-PET in future studies. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019. J. Magn. Reson. Imaging 2020;51:183-194.

3.
Rev. bras. farmacogn ; 29(6): 739-743, Nov.-Dec. 2019. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-1057846

RESUMO

ABSTRACT Persea americana Mill., Lauraceae, commonly known as the avocado, is native to tropical and subtropical regions, including Brazil. From the leaves of P. americana, one previously undescribed flavonol glycoside (1) together with ten known flavonoids (2-11), four megastigmane glycosides (12-15) and two lignans (16-17) were isolated. Their structures were determined by extensive spectroscopic methods including 1D- and 2D-nuclear magnetic resonance and mass spectrometry data. This is the first investigation that reports megastigmane glycoside and lignan classes within the genus Persea. All the isolated compounds have been assessed through the cell survival of larval zebrafish following neomycin-induced damage and the cell viability of a House Ear Institute-Organ of Corti 1 mouse auditory cell line. Among the tested compounds, juglanin (2) and (+)-lyoniresinol (16) showed significant cell regeneration in neomycin-damaged hair cell without cellular toxicity.

4.
Rev. bras. farmacogn ; 29(5): 578-581, Sept.-Oct. 2019. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-1057839

RESUMO

Abstract Schisandra sphenanthera Rehder & E.H. Wilson, Schisandraceae, is well known as a type of traditional medicine for the treatment of hepatitis, diarrhea and insomnia in Asia. It was also reported to have antiviral and anti-HIV activities. Using various chromatographic resins and isolation techniques, a new lignan (1), erythro-4-(3,4-dimethoxyphenyl)-4-hydroxy-3-methylbutan-2yl-3,4-dimethoxybenzoate, along with fifteen known compounds, were isolated from fruits of S. sphenanthera. The structures of the compounds were identified by extensive spectroscopic and spectrometric methods including 1D and 2D NMR and MS data. All the isolated compounds were evaluated for their cytotoxicity activity against Hela, HepG2 and HCT-116 cells. Among them, compound schisanlactone C showed significant cytotoxicity activity.

5.
Cancer Res ; 79(22): 5849-5859, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31506334

RESUMO

Genetic and epigenetic changes (e.g., histone methylation) contribute to cancer development and progression, but our understanding of whether and how specific mutations affect a cancer's sensitivity to histone demethylase (KDM) inhibitors is limited. Here, we evaluated the effects of a panel of KDM inhibitors on lung adenocarcinomas (LuAC) with various mutations. Notably, LuAC lines harboring KRAS mutations showed hypersensitivity to the histone H3K27 demethylase inhibitor GSK-J4. Specifically, GSK-J4 treatment of KRAS mutant-containing LuAC downregulated cell-cycle progression genes with increased H3K27me3. In addition, GSK-J4 upregulated expression of genes involved in glutamine/glutamate transport and metabolism. In line with this, GSK-J4 reduced cellular levels of glutamate, a key source of the TCA cycle intermediate α-ketoglutarate (αKG) and of the antioxidant glutathione, leading to reduced cell viability. Supplementation with an αKG analogue or glutathione protected KRAS-mutant LuAC cells from GSK-J4-mediated reductions in viability, suggesting GSK-J4 exerts its anticancer effects by inducing metabolic and oxidative stress. Importantly, KRAS knockdown in mutant LuAC lines prevented GSK-J4-induced decrease in glutamate levels and reduced their susceptibility to GSK-J4, whereas overexpression of oncogenic KRAS in wild-type LuAC lines sensitized them to GSK-J4. Collectively, our study uncovers a novel association between a genetic mutation and KDM inhibitor sensitivity and identifies the underlying mechanisms. This suggests GSK-J4 as a potential treatment option for cancer patients with KRAS mutations. SIGNIFICANCE: This study not only provides a novel association between KRAS mutation and GSK-J4 sensitivity but also demonstrates the underlying mechanisms, suggesting a potential use of GSK-J4 in cancer patients with KRAS mutations.

6.
Nat Prod Res ; : 1-6, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30966790

RESUMO

Two new compounds, one sesquiterpene lactone (1) and one phenylethanoid tautomer (2), together with eleven known compounds (3-13) were isolated from the leaves of Ixeridium dentatum. Their structures were determined by extensive spectroscopic methods, including 1D-, 2D-NMR, and mass spectrometry. All compounds were evaluated for their amylase secretion activity in human salivary gland cells after treatment in 40 mM of high glucose. All compounds showed increased amylase secretion activity. Moreover, previously undescribed compounds (1-2), luteolin 7-O-ß-D-glucopyranoside (10), quercimeritrin (11), and quercetin 3-O-ß-D-xylopyranoside (13) exhibited significant amylase activity, which is comparable to the positive control.

7.
Stroke ; 50(2): 373-380, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30636572

RESUMO

Background and Purpose- Noninvasive imaging of brain perfusion has the potential to elucidate pathophysiological mechanisms underlying Moyamoya disease and enable clinical imaging of cerebral blood flow (CBF) to select revascularization therapies for patients. We used hybrid positron emission tomography (PET)/magnetic resonance imaging (MRI) technology to characterize the distribution of hypoperfusion in Moyamoya disease and its relationship to vessel stenosis severity, through comparisons with a normative perfusion database of healthy controls. Methods- To image CBF, we acquired [15O]-water PET as a reference and simultaneously acquired arterial spin labeling (ASL) MRI scans in 20 Moyamoya patients and 15 age-matched, healthy controls on a PET/MRI scanner. The ASL MRI scans included a standard single-delay ASL scan with postlabel delay of 2.0 s and a multidelay scan with 5 postlabel delays (0.7-3.0s) to estimate and account for arterial transit time in CBF quantification. The percent volume of hypoperfusion in patients (determined as the fifth percentile of CBF values in the healthy control database) was the outcome measure in a logistic regression model that included stenosis grade and location. Results- Logistic regression showed that anterior ( P<0.0001) and middle cerebral artery territory regions ( P=0.003) in Moyamoya patients were susceptible to hypoperfusion, whereas posterior regions were not. Cortical regions supplied by arteries with stenosis on MR angiography showed more hypoperfusion than normal arteries ( P=0.001), but the extent of hypoperfusion was not different between mild-moderate versus severe stenosis. Multidelay ASL did not perform differently from [15O]-water PET in detecting perfusion abnormalities, but standard ASL overestimated the extent of hypoperfusion in patients ( P=0.003). Conclusions- This simultaneous PET/MRI study supports the use of multidelay ASL MRI in clinical evaluation of Moyamoya disease in settings where nuclear medicine imaging is not available and application of a normative perfusion database to automatically identify abnormal CBF in patients.


Assuntos
Bases de Dados Factuais , Imagem por Ressonância Magnética , Artéria Cerebral Média , Doença de Moyamoya , Tomografia por Emissão de Pósitrons , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média/diagnóstico por imagem , Artéria Cerebral Média/fisiopatologia , Doença de Moyamoya/diagnóstico por imagem , Doença de Moyamoya/fisiopatologia , Marcadores de Spin
8.
Arch Phys Med Rehabil ; 100(1): 26-31, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30055163

RESUMO

OBJECTIVE: To assess the efficacy of electromechanical exoskeleton-assisted gait training on walking ability of stroke patients based on ambulatory function, muscle strength, balance, gait speed, and capacity. DESIGN: Randomized controlled trial. SETTING: University rehabilitation hospital. PARTICIPANTS: Individuals (N=40) with stroke who could stand alone. INTERVENTIONS: Patients were randomly assigned to control and experimental groups. The control group underwent physical therapist-assisted gait training by conventional method. The experimental group underwent electromechanical gait training assisted by an exoskeleton device. Both types of gait training were performed for 30 minutes each day. The therapeutic interventions were provided for 5 days a week for a period of 4 weeks in both groups. MAIN OUTCOME MEASURES: Functional ambulatory category (FAC) before and after gait training. Changes in FAC were the primary outcomes to evaluate the efficacy of electromechanical exoskeleton-assisted gait training. Changes in mobility, walking speed, walking capacity, leg muscle strength, daily activity, and balance were secondary outcomes. RESULTS: FAC in the control group was 2.44±1.55 in the pretraining and 2.75±1.53 in the post-training. FAC in the experimental group was 3.22±1.31 in the pretraining and 3.78±1.44 in the post-training. Although FAC between pre- and post-training sessions improved in both groups, the changes in FAC were statistically significant in the experimental group alone. Most secondary outcomes in both groups also showed improvement after gait training. However, the differential outcomes were not varied between the 2 groups after adjusting the data for age and stroke duration. We did not exclude patients based on time since stroke onset. The average stroke duration was 530.11±389.21 days in the experimental group. The changes in FAC of the experimental group were negatively correlated with stroke duration. No adverse events were noticed during gait training in either group. CONCLUSIONS: Electromechanical exoskeleton-assisted gait training is as effective as conventional gait training by a physical therapist when administered by a gait trainer. As an overground walking system without harness, electromechanical exoskeleton replaced a physical therapist in assisted gait training for patients who stand alone. Because the ambulatory function of stroke patients was affected negatively by stroke duration, the effect of electromechanical-assisted gait training might decline with increased stroke duration.


Assuntos
Terapia por Estimulação Elétrica/métodos , Exoesqueleto Energizado , Transtornos Neurológicos da Marcha/terapia , Reabilitação do Acidente Vascular Cerebral/métodos , Acidente Vascular Cerebral/fisiopatologia , Adulto , Idoso , Avaliação da Deficiência , Terapia por Estimulação Elétrica/instrumentação , Feminino , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Limitação da Mobilidade , Acidente Vascular Cerebral/complicações , Reabilitação do Acidente Vascular Cerebral/instrumentação , Resultado do Tratamento , Teste de Caminhada , Caminhada/fisiologia
9.
Mol Cancer Res ; 17(2): 544-554, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30266755

RESUMO

Brain metastasis in breast cancer is particularly deadly, but effective treatments remain out of reach due to insufficient information about the mechanisms underlying brain metastasis and the potential vulnerabilities of brain-metastatic breast cancer cells. Here, human breast cancer cells and their brain-metastatic derivatives (BrMs) were used to investigate synthetic lethal interactions in BrMs. First, it was demonstrated that c-MYC activity is increased in BrMs and is required for their brain-metastatic ability in a mouse xenograft model. Specifically, c-MYC enhanced brain metastasis by facilitating the following processes within the brain microenvironment: (i) invasive growth of BrMs, (ii) macrophage infiltration, and (iii) GAP junction formation between BrMs and astrocytes by upregulating connexin 43 (GJA1/Cx43). Furthermore, RNA-sequencing (RNA-seq) analysis uncovered a set of c-MYC-regulated genes whose expression is associated with higher risk for brain metastasis in breast cancer patients. Paradoxically, however, increased c-MYC activity in BrMs rendered them more susceptible to TRAIL (TNF-related apoptosis-inducing ligand)-induced apoptosis. In summary, these data not only reveal the brain metastasis-promoting role of c-MYC and a subsequent synthetic lethality with TRAIL, but also delineate the underlying mechanism. This suggests TRAIL-based approaches as potential therapeutic options for brain-metastatic breast cancer. IMPLICATIONS: This study discovers a paradoxical role of c-MYC in promoting metastasis to the brain and in rendering brain-metastatic cells more susceptible to TRAIL, which suggests the existence of an Achilles' heel, thus providing a new therapeutic opportunity for breast cancer patients.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Animais , Astrócitos/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Conexina 43/metabolismo , Feminino , Junções Comunicantes/genética , Junções Comunicantes/patologia , Xenoenxertos , Humanos , Células MCF-7 , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Proteínas Proto-Oncogênicas c-myc/metabolismo , Mutações Sintéticas Letais , Regulação para Cima
10.
Transl Psychiatry ; 8(1): 264, 2018 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-30504860

RESUMO

Major depressive disorder (MDD) is characterized by the altered integration of reward histories and reduced responding of the striatum. We have posited that this reduced striatal activation in MDD is due to tonically decreased stimulation of striatal dopamine synapses which results in decremented propagation of information along the cortico-striatal-pallido-thalamic (CSPT) spiral. In the present investigation, we tested predictions of this formulation by conducting concurrent functional magnetic resonance imaging (fMRI) and 11C-raclopride positron emission tomography (PET) in depressed and control (CTL) participants. We scanned 16 depressed and 14 CTL participants with simultaneous fMRI and 11C-raclopride PET. We estimated raclopride binding potential (BPND), voxel-wise, and compared MDD and CTL samples with respect to BPND in the striatum. Using striatal regions that showed significant between-group BPND differences as seeds, we conducted whole-brain functional connectivity analysis using the fMRI data and identified brain regions in each group in which connectivity with striatal seed regions scaled linearly with BPND from these regions. We observed increased BPND in the ventral striatum, bilaterally, and in the right dorsal striatum in the depressed participants. Further, we found that as BPND increased in both the left ventral striatum and right dorsal striatum in MDD, connectivity with the cortical targets of these regions (default-mode network and salience network, respectively) decreased. Deficits in stimulation of striatal dopamine receptors in MDD could account in part for the failure of transfer of information up the CSPT circuit in the pathophysiology of this disorder.


Assuntos
Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Dopamina/metabolismo , Adulto , Mapeamento Encefálico , Corpo Estriado/diagnóstico por imagem , Transtorno Depressivo Maior/diagnóstico por imagem , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Tomografia por Emissão de Pósitrons , Racloprida
11.
Arch Plast Surg ; 45(6): 572-577, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30466238

RESUMO

BACKGROUND: Mandibular contouring surgery to produce a more slender and small face has become popular, especially in East Asia. Narrowing genioplasty should be simultaneously performed with mandibular angle resection to achieve satisfactory results. In Korea, T-genioplasty has been frequently performed for chin narrowing. The authors developed a new, safe, and reliable method, termed M-genioplasty, that can provide a more slender and attractive lower face. METHODS: From June 2013 to December 2017, 36 patients underwent M-genioplasty with mandibular angle resection for lower facial contouring. Horizontal and vertical osteotomies were performed obliquely. The resected bone segments were wedge-shaped. The remaining two bone segments were rotated and approximated centrally. The lateral mandible bony stepoff was trimmed off for mandibular angle resection. RESULTS: In all patients, the facial contour sufficiently improved, and most patients were satisfied with the outcome. No severe complications took place during postoperative follow-up. CONCLUSIONS: M-genioplasty can provide more mandibular angle resection and can create a more acute chin angle without bone resorption than other methods, including T-genioplasty. M-genioplasty with mandibular angle resection is a safer, more accurate, and more reliable method for lower facial contouring.

12.
Mol Biochem Parasitol ; 226: 24-33, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30455159

RESUMO

We analyzed transcriptome profiles of Anisakis simplex (Nematoda: Anisakidae) 3rd (ASL3) and 4th larvae (ASL4) obtained by RNA-seq, to understand the molecular pathways linked to parasite survival and discover stage-enriched gene expressions. ASL3 were collected from chum salmon and ASL4 were obtained by in vitro culture. Whole transcriptome sequencing was conducted with Illumina sequencer, and de novo assembly was conducted. 47,179 and 41,934 genes were expressed in ASL3 and ASL4 transcriptomes. Of them, 17,633 were known and 29,546 were unmapped sequence for ASL3. 17,126 were known and 24,808 were unmapped sequence for ASL4. Polyubiquitins-related genes and collagen-related genes were the most abundantly expressed in ASL3 and ASL4. Mitochondrial enzyme-related genes were highly expressed both in ASL3 and ASL4. Among the transcripts, 675 were up-regulated in ASL3, while 1015 were up-regulated in ASL4. Several protease-related and protein biosynthesis-related genes were highly expressed in ASL3, all of which are thought to be crucial for invading host tissues. Collagen synthesis-related genes were highly expressed in ASL4, reflecting active biosynthesis of collagens during molting process. This information will extend our understanding of biology of the fish-borne zoonotic parasite A. simplex.


Assuntos
Anisaquíase/veterinária , Anisakis/genética , Doenças dos Peixes/parasitologia , Proteínas de Helminto/genética , Larva/genética , Oncorhynchus keta/parasitologia , Transcriptoma , Animais , Anisaquíase/parasitologia , Anisakis/classificação , Anisakis/crescimento & desenvolvimento , Colágeno/genética , Colágeno/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Proteínas de Helminto/classificação , Proteínas de Helminto/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Larva/crescimento & desenvolvimento , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Anotação de Sequência Molecular , Filogenia , Poliubiquitina/genética , Poliubiquitina/metabolismo
13.
Genes Genomics ; 40(3): 315-320, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29892801

RESUMO

Olive flounder (Paralichthys olivaceus) is one of the most economically important aquaculture fish. However, its production is often affected by various diseases, especially viral hemorrhagic septicemia virus (VHSV) that cause serious economic losses. In this study, we sequenced the whole transcriptome of the P. olivaceus using Illumina RNA-sEq. De novo assembly of control and virus-infected cDNA libraries of head kidney at 13 and 20 °C was accomplished with 2,007,532,438 raw reads, resulting in 244,578 unigenes with an average length of 533 bp and found 65,535 candidate coding unigenes with homology to other species by BLAST analysis. DEG analysis among control and virus-infected head kidney samples of 13 and 20 °C revealed that 1290 up-regulated and 162 down-regulated genes (p ≤ 0.01), linked to metabolism, virulence factors, adhesion and immune-response. We constructed an expressed gene catalog for the P. olivaceus to serve as a resource for marine environmental genomic and immuno-genetic/genomic studies focused on uncovering the molecular mechanisms underlying the responses of P. olivaceus to VHSV under different temperature.


Assuntos
Linguado/genética , Linguado/imunologia , Animais , Composição de Bases , Doenças dos Peixes/imunologia , Perfilação da Expressão Gênica/métodos , Rim Cefálico , Novirhabdovirus/patogenicidade , Temperatura , Sensação Térmica/genética , Transcriptoma/genética
14.
Pharmacogn Mag ; 14(54): 155-161, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29720824

RESUMO

Background: Melissa officinalis L. is a well-known medicinal plant from the family Lamiaceae, which is distributed throughout Eastern Mediterranean region and Western Asia. Objective: In this study, response surface methodology (RSM) was utilized to optimize the extraction conditions for bioactive compounds from the leaves of M. officinalis L. Materials and Methods: A Box-Behnken design (BBD) was utilized to evaluate the effects of three independent variables, namely extraction temperature (°C), methanol concentration (%), and solvent-to-material ratio (mL/g) on the responses of the contents of caffeic acid and rosmarinic acid. Results: Regression analysis showed a good fit of the experimental data. The optimal condition was obtained at extraction temperature 80.53°C, methanol concentration 29.89%, and solvent-to-material ratio 30 mL/g. Conclusion: These results indicate the suitability of the model employed and the successful application of RSM in optimizing the extraction conditions. This study may be useful for standardizing production quality, including improving the efficiency of large-scale extraction systems. SUMMARY: The optimum conditions for the extraction of major phenolic acids from the leaves of Melissa officinalis L. were determined using response surface methodologyBox-Behnken design was utilized to evaluate the effects of three independent variablesQuadratic polynomial model provided a satisfactory description of the experimental dataThe optimized condition for simultaneous maximum contents of caffeic acid and rosmarinic acid was determined. Abbreviations used: RSM: Response surface methodology, BBD: Box-Behnken design, CA: Caffeic acid, RA: Rosmarinic acid, HPLC: High-performance liquid chromatography.

15.
J Cereb Blood Flow Metab ; 38(1): 126-135, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28155582

RESUMO

15O-H2O PET imaging is an accurate method to measure cerebral blood flow (CBF) but it requires an arterial input function (AIF). Historically, image-derived AIF estimation suffers from low temporal resolution, spill-in, and spill-over problems. Here, we optimized tracer dose on a time-of-flight PET/MR according to the acquisition-specific noise-equivalent count rate curve. An optimized dose of 850 MBq of 15O-H2O was determined, which allowed sufficient counts to reconstruct a short time-frame PET angiogram (PETA) during the arterial phase. This PETA enabled the measurement of the extent of spill-over, while an MR angiogram was used to measure the true arterial volume for AIF estimation. A segment of the high cervical arteries outside the brain was chosen, where the measured spill-in effects were minimal. CBF studies were performed twice with separate [15O]-H2O injections in 10 healthy subjects, yielding values of 88 ± 16, 44 ± 9, and 58 ± 11 mL/min/100 g for gray matter, white matter, and whole brain, with intra-subject CBF differences of 5.0 ± 4.0%, 4.1 ± 3.3%, and 4.5 ± 3.7%, respectively. A third CBF measurement after the administration of 1 g of acetazolamide showed 35 ± 23%, 29 ± 20%, and 33 ± 22% increase in gray matter, white matter, and whole brain, respectively. Based on these findings, the proposed noninvasive AIF method provides robust CBF measurement with 15O-H2O PET.


Assuntos
Mapeamento Encefálico/métodos , Encéfalo/irrigação sanguínea , Imagem Multimodal/métodos , Adulto , Circulação Cerebrovascular/fisiologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons
16.
Nat Prod Res ; 32(17): 2111-2115, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28814115

RESUMO

Rhinacanthus nasutus (L.) Kurz (Acanthaceae) is known as traditional medicine for the treatment of various diseases, such as cancer, fungal infections, herpes virus infections and several types of skin diseases in South-East Asian countries. In this study, eight compounds 1-8 were isolated from the aerial parts of R. nasutus. The structures of compounds were determined by the spectroscopic methods, including 1D and 2D NMR. The isolated compounds were evaluated for neuraminidase inhibitory activity. Several lignans, 2,3-bis[(4-hydroxy-3,5-dimethoxyphenyl)methyl]-1,4-butanediol (5) and 8,8'-bisdihydrosiringenin glucoside (6), significantly inhibited neuraminidase activity, which was comparable to the positive controls, mangiferin and oseltamivir. In addition, a structure-based virtual screening against neuraminidase using bioactive components was demonstrated.


Assuntos
Acanthaceae/química , Neuraminidase/antagonistas & inibidores , Inibidores Enzimáticos/química , Lignanas/química , Lignanas/farmacologia , Estrutura Molecular , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Análise Espectral
17.
Pharmacogn Mag ; 13(52): 673-676, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29200732

RESUMO

Background: Dryopteris erythrosora (D.C. Eaton) Kuntze is a species of fern in the family of Dryopteridaceae, which is distributed throughout East Asia. The genus Dryopteris has been used as traditional medicine, especially to treat hepatitis and protect liver. However, only few studies of chemical constituents of D. erythrosora have been conducted so far. Objective: In this study, we investigated the phytochemical constituents of D. erythrosora. Materials and Methods: The 80% methanol extract of the aerial part of D. erythrosora was used for the isolation of phenolic compounds. The isolated compounds were elucidated by various spectroscopic methods including nuclear magnetic resonance and mass spectrometry. Results: The present phytochemical investigation on the aerial part of D. erythrosora led to the isolation of two new phenolic glycosides, 1 and 2, as well as nine known flavonoids including two flavones (3 and 4) and seven flavonols (5-11). Conclusion: In this study, two new phenolic glycosides together with nine known flavonoids were isolated from the aerial part of D. erythrosora. Among them, compounds 4, 8, and 11 were isolated for the first time in Dryopteridaceae family from the present investigation. These results helped us to enrich our understanding of the chemical constituents of D. erythrosora and to identify compounds 1 and 2 which could be potential chemotaxonomic markers for the species. SUMMARY: The genus Dryopteris has been used as traditional medicine, especially to treat hepatitis and protect liverTwo new phenolic glycosides were isolated from D. erythrosoraNine known flavonoids (3-11) were isolated from D. erythrosoraCompounds 4, 8, and 11 were isolated for the first time in Dryopteridaceae family. Abbreviations used: HPLC: High-performance liquid chromatography; Q-TOF LC/MS: Quadrupole-time-of-flight liquid chromatography/mass spectrometry; NMR: Nuclear magnetic resonance; TMS: Tetramethylsilane.

18.
Stroke ; 48(9): 2441-2449, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28765286

RESUMO

BACKGROUND AND PURPOSE: Arterial spin labeling (ASL) MRI is a promising, noninvasive technique to image cerebral blood flow (CBF) but is difficult to use in cerebrovascular patients with abnormal, long arterial transit times through collateral pathways. To be clinically adopted, ASL must first be optimized and validated against a reference standard in these challenging patient cases. METHODS: We compared standard-delay ASL (post-label delay=2.025 seconds), multidelay ASL (post-label delay=0.7-3.0 seconds), and long-label long-delay ASL acquisitions (post-label delay=4.0 seconds) against simultaneous [15O]-positron emission tomography (PET) CBF maps in 15 Moyamoya patients on a hybrid PET/MRI scanner. Dynamic susceptibility contrast was performed in each patient to identify areas of mild, moderate, and severe time-to-maximum (Tmax) delays. Relative CBF measurements by each ASL scan in 20 cortical regions were compared with the PET reference standard, and correlations were calculated for areas with moderate and severe Tmax delays. RESULTS: Standard-delay ASL underestimated relative CBF by 20% in areas of severe Tmax delays, particularly in anterior and middle territories commonly affected by Moyamoya disease (P<0.001). Arterial transit times correction by multidelay acquisitions led to improved consistency with PET, but still underestimated CBF in the presence of long transit delays (P=0.02). Long-label long-delay ASL scans showed the strongest correlation relative to PET, and there was no difference in mean relative CBF between the modalities, even in areas of severe delays. CONCLUSIONS: Post-label delay times of ≥4 seconds are needed and may be combined with multidelay strategies for robust ASL assessment of CBF in Moyamoya disease.


Assuntos
Encéfalo/diagnóstico por imagem , Circulação Cerebrovascular , Doença de Moyamoya/diagnóstico por imagem , Adolescente , Adulto , Encéfalo/irrigação sanguínea , Circulação Colateral , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Radioisótopos de Oxigênio , Tomografia por Emissão de Pósitrons , Marcadores de Spin
19.
J Nucl Med ; 58(12): 2004-2009, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28572487

RESUMO

The purpose of this study was to assess safety, biodistribution, and radiation dosimetry in humans for the highly selective σ-1 receptor PET agent 18F-6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one (18F-FTC-146). Methods: Ten healthy volunteers (5 women, 5 men; age ± SD, 34.3 ± 6.5 y) were recruited, and written informed consent was obtained from all participants. Series of whole-body PET/MRI examinations were acquired for up to 3 h after injection (357.2 ± 48.8 MBq). Blood samples were collected, and standard vital signs (heart rate, pulse oximetry, and body temperature) were monitored at regular intervals. Regions of interest were delineated, time-activity curves were calculated, and organ uptake and dosimetry were estimated. Results: All subjects tolerated the PET/MRI examination well, and no adverse reactions to 18F-FTC-146 were reported. High accumulation of 18F-FTC-146 was observed in σ-1 receptor-dense organs such as the pancreas and spleen, moderate uptake in the brain and myocardium, and low uptake in bone and muscle. High uptake was also observed in the kidneys and bladder, indicating renal tracer clearance. The effective dose of 18F-FTC-146 was 0.0259 ± 0.0034 mSv/MBq (range, 0.0215-0.0301 mSv/MBq). Conclusion: First-in-human studies with clinical-grade 18F-FTC-146 were successful. Injection of 18F-FTC-146 is safe, and absorbed doses are acceptable. The potential of 18F-FTC-146 as an imaging agent for a variety of neuroinflammatory diseases is currently under investigation.


Assuntos
Azepinas/farmacocinética , Benzotiazóis/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Adulto , Azepinas/efeitos adversos , Azepinas/síntese química , Benzotiazóis/efeitos adversos , Benzotiazóis/síntese química , Feminino , Voluntários Saudáveis , Humanos , Marcação por Isótopo , Imagem por Ressonância Magnética , Masculino , Imagem Multimodal , Radiometria , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/síntese química , Receptores sigma/efeitos dos fármacos , Receptores sigma/metabolismo , Distribuição Tecidual , Imagem Corporal Total
20.
Mol Imaging Biol ; 19(5): 779-786, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28280965

RESUMO

PURPOSE: Sigma-1 receptors (S1Rs) play an important role in many neurological disorders. Simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) with S1R radioligands may provide valuable information for diagnosing and guiding treatment for these diseases. Our previously reported S1R radioligand, [18F]FTC-146, demonstrated high affinity for the S1R (K i = 0.0025 nM) and excellent selectivity for the S1R over the sigma-2 receptor (S2Rs; K i = 364 nM) across several species (from mouse to non-human primate). Herein, we report the clinical-grade radiochemistry filed with exploratory Investigational New Drug (eIND) and first-in-human PET/MRI evaluation of [18F]FTC-146. PROCEDURES: [18F]FTC-146 is prepared via a direct [18F] fluoride nucleophilic radiolabeling reaction and formulated in 0.9 % NaCl containing no more than 10 % ethanol through sterile filtration. Quality control (QC) was performed based on USP 823 before doses were released for clinical use. The safety and whole body biodistribution of [18F]FTC-146 were evaluated using a simultaneous PET/MR scanner in two representative healthy human subjects. RESULTS: [18F]FTC-146 was synthesized with a radiochemical yield of 3.3 ± 0.7 % and specific radioactivity of 8.3 ± 3.3 Ci/µmol (n = 10, decay corrected to EOB). Both radiochemical and chemical purities were >95 %; the prepared doses were stable for 4 h at ambient temperature. All QC test results met specified clinical criteria. The in vivo PET/MRI investigations showed that [18F]FTC-146 rapidly crossed the blood brain barrier and accumulated in S1R-rich regions of the brain. There were also radioactivity distributed in the peripheral organs, i.e., the lungs, spleen, pancreas, and thyroid. Furthermore, insignificant uptake of [18F]FTC-146 was observed in cortical bone and muscle. CONCLUSION: A reliable and automated radiosynthesis for providing routine clinical-grade [18F]FTC-146 for human studies was established in a modified GE TRACERlab FXFN. PET/MRI demonstrated the initial tracer biodistribution in humans, and clinical studies investigating different S1R-related diseases are in progress.


Assuntos
Azepinas/química , Azepinas/síntese química , Benzotiazóis/química , Benzotiazóis/síntese química , Imagem por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Adulto , Azepinas/farmacocinética , Benzotiazóis/farmacocinética , Feminino , Humanos , Masculino , Distribuição Tecidual
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