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1.
Mar Drugs ; 22(1)2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38248667

RESUMO

Brown seaweed is a promising source of polysaccharides and phenolics with industrial utility. This work reports the development of a green enzyme-assisted extraction method for simultaneously extracting polysaccharides and phenolics from the brown seaweed Padina gymnospora. Different enzymes (Cellulast, Pectinex, and Alcalase), individually and in combination, were investigated, with Alcalase alone showing the highest efficiency for the simultaneous extraction of polysaccharides and phenolics. Yields from Alcalase-assisted aqueous extraction were higher than those obtained using either water alone or conventional ethanol extraction. Alcalase-assisted extraction was subsequently optimized using a response surface methodology to maximize compound recovery. Maximal polysaccharide and phenolic recovery was obtained under the following extraction conditions: a water-to-sample ratio of 61.31 mL/g, enzyme loading of 0.32%, temperature of 60.5 °C, and extraction time of 1.95 h. The extract was then fractionated to obtain alginate-, fucoidan-, and phenolic-rich fractions. Fractions exhibited potent 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity with IC50 values of 140.55 µg/mL, 126.21 µg/mL, and 48.17 µg/mL, respectively, which were higher than those obtained from conventional extraction methods. The current work shows that bioactive polysaccharides and phenolics can be obtained together in high yield through a single aqueous-only green and efficient Alcalase-assisted extraction.


Assuntos
Phaeophyceae , Alga Marinha , Polissacarídeos , Fenóis , Subtilisinas , Verduras , Água
2.
Glia ; 71(2): 431-449, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36271704

RESUMO

As the understanding of immune responses in Alzheimer's disease (AD) is in its early phases, there remains an urgency to identify the cellular and molecular processes driving chronic inflammation. In AD, a subpopulation of astrocytes acquires a neurotoxic phenotype which prompts them to lose typical physiological features. While the underlying molecular mechanisms are still unknown, evidence suggests that myeloid differentiation primary response 88 (MyD88) adaptor protein may play a role in coordinating these cells' immune responses in AD. Herein, we combined studies in human postmortem samples with a conditional genetic knockout mouse model to investigate the link between MyD88 and astrocytes in AD. In silico analyses of bulk and cell-specific transcriptomic data from human postmortem brains demonstrated an upregulation of MyD88 expression in astrocytes in AD versus non-AD individuals. Proteomic studies revealed an increase in glial fibrillary acidic protein in multiple brain regions of AD subjects. These studies also showed that although overall MyD88 steady-state levels were unaffected by AD, this protein was enriched in astrocytes near amyloid plaques and neurofibrillary tangles. Functional studies in mice indicated that the deletion of astrocytic MyD88 protected animals from the acute synaptic toxicity and cognitive impairment caused by the intracerebroventricular administration of ß-amyloid (Aß). Lastly, unbiased proteomic analysis revealed that loss of astrocytic MyD88 resulted in altered astrocyte reactivity, lower levels of immune-related proteins, and higher expression of synaptic-related proteins in response to Aß. Our studies provide evidence of the pivotal role played by MyD88 in the regulation of astrocytes response to AD.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Humanos , Animais , Camundongos , Peptídeos beta-Amiloides/metabolismo , Astrócitos/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Proteômica , Doença de Alzheimer/patologia
3.
J Hepatol ; 79(6): 1385-1395, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37572794

RESUMO

BACKGROUND & AIMS: Biliary atresia (BA) is poorly understood and leads to liver transplantation (LT), with the requirement for and associated risks of lifelong immunosuppression, in most children. We performed a genome-wide association study (GWAS) to determine the genetic basis of BA. METHODS: We performed a GWAS in 811 European BA cases treated with LT in US, Canadian and UK centers, and 4,654 genetically matched controls. Whole-genome sequencing of 100 cases evaluated synthetic association with rare variants. Functional studies included whole liver transcriptome analysis of 64 BA cases and perturbations in experimental models. RESULTS: A GWAS of common single nucleotide polymorphisms (SNPs), i.e. allele frequencies >1%, identified intronic SNPs rs6446628 in AFAP1 with genome-wide significance (p = 3.93E-8) and rs34599046 in TUSC3 at sub-threshold genome-wide significance (p = 1.34E-7), both supported by credible peaks of neighboring SNPs. Like other previously reported BA-associated genes, AFAP1 and TUSC3 are ciliogenesis and planar polarity effectors (CPLANE). In gene-set-based GWAS, BA was associated with 6,005 SNPs in 102 CPLANE genes (p = 5.84E-15). Compared with non-CPLANE genes, more CPLANE genes harbored rare variants (allele frequency <1%) that were assigned Human Phenotype Ontology terms related to hepatobiliary anomalies by predictive algorithms, 87% vs. 40%, p <0.0001. Rare variants were present in multiple genes distinct from those with BA-associated common variants in most BA cases. AFAP1 and TUSC3 knockdown blocked ciliogenesis in mouse tracheal cells. Inhibition of ciliogenesis caused biliary dysgenesis in zebrafish. AFAP1 and TUSC3 were expressed in fetal liver organoids, as well as fetal and BA livers, but not in normal or disease-control livers. Integrative analysis of BA-associated variants and liver transcripts revealed abnormal vasculogenesis and epithelial tube formation, explaining portal vein anomalies that co-exist with BA. CONCLUSIONS: BA is associated with polygenic susceptibility in CPLANE genes. Rare variants contribute to polygenic risk in vulnerable pathways via unique genes. IMPACT AND IMPLICATIONS: Liver transplantation is needed to cure most children born with biliary atresia, a poorly understood rare disease. Transplant immunosuppression increases the likelihood of life-threatening infections and cancers. To improve care by preventing this disease and its progression to transplantation, we examined its genetic basis. We find that this disease is associated with both common and rare mutations in highly specialized genes which maintain normal communication and movement of cells, and their organization into bile ducts and blood vessels during early development of the human embryo. Because defects in these genes also cause other birth defects, our findings could lead to preventive strategies to lower the incidence of biliary atresia and potentially other birth defects.


Assuntos
Atresia Biliar , Criança , Animais , Camundongos , Humanos , Atresia Biliar/genética , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Peixe-Zebra/genética , Canadá
4.
Ecotoxicol Environ Saf ; 167: 354-364, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30359902

RESUMO

Of 942 organic micro-pollutants screened, 167 compounds were detected at least once in the atmosphere in some primitive waste processing sites and an urban area in northern Vietnam by using a polyurethane foam-based passive air sampling (PUF-PAS) method and an Automated Identification and Quantification System with a Database (AIQS-DB) for GC-MS. Total concentrations of organic pollutants were higher in samples collected from an urban area of Hanoi city (2300-2600 ng m-3) as compared with those from an end-of-life vehicle (ELV) dismantling area in Bac Giang (900-1700 ng m-3) and a waste recycling cooperative in Thai Nguyen (870-1300 ng m-3). Domestic chemicals (e.g., n-alkanes, phthalate ester plasticizers, and synthetic phenolic antioxidants) dominated the organic pollutant patterns in all the samples, especially in the urban area. Pesticides (e.g., permethrins, chlorpyrifos, and propiconazole) were found in the atmosphere around the ELV sites at more elevated concentrations than the other areas. Levels of polycyclic aromatic hydrocarbons and their derivatives in the Bac Giang and Thai Nguyen facilities were significantly higher than those measured in Hanoi urban houses, probably due to the waste processing activities. Daily intake doses of organic pollutants via inhalation were estimated for waste processing workers and urban residents. This study shall provide preliminary data on the environmental occurrence, potential emission sources, and effects of multiple classes of organic pollutants in urban and waste processing areas in northern Vietnam.


Assuntos
Poluentes Atmosféricos/análise , Exposição por Inalação/análise , Exposição Ocupacional/análise , Compostos Orgânicos/análise , Instalações de Eliminação de Resíduos , Alcanos/análise , Cidades , Monitoramento Ambiental , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Praguicidas/análise , Plastificantes/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Reciclagem , Medição de Risco , Vietnã
5.
PLoS Comput Biol ; 13(5): e1005531, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28475588

RESUMO

Synonymous rare codons are considered to be sub-optimal for gene expression because they are translated more slowly than common codons. Yet surprisingly, many protein coding sequences include large clusters of synonymous rare codons. Rare codons at the 5' terminus of coding sequences have been shown to increase translational efficiency. Although a general functional role for synonymous rare codons farther within coding sequences has not yet been established, several recent reports have identified rare-to-common synonymous codon substitutions that impair folding of the encoded protein. Here we test the hypothesis that although the usage frequencies of synonymous codons change from organism to organism, codon rarity will be conserved at specific positions in a set of homologous coding sequences, for example to tune translation rate without altering a protein sequence. Such conservation of rarity-rather than specific codon identity-could coordinate co-translational folding of the encoded protein. We demonstrate that many rare codon cluster positions are indeed conserved within homologous coding sequences across diverse eukaryotic, bacterial, and archaeal species, suggesting they result from positive selection and have a functional role. Most conserved rare codon clusters occur within rather than between conserved protein domains, challenging the view that their primary function is to facilitate co-translational folding after synthesis of an autonomous structural unit. Instead, many conserved rare codon clusters separate smaller protein structural motifs within structural domains. These smaller motifs typically fold faster than an entire domain, on a time scale more consistent with translation rate modulation by synonymous codon usage. While proteins with conserved rare codon clusters are structurally and functionally diverse, they are enriched in functions associated with organism growth and development, suggesting an important role for synonymous codon usage in organism physiology. The identification of conserved rare codon clusters advances our understanding of distinct, functional roles for otherwise synonymous codons and enables experimental testing of the impact of synonymous codon usage on the production of functional proteins.


Assuntos
Sequência de Aminoácidos/genética , Códon/genética , Sequência Conservada/genética , Fases de Leitura Aberta/genética , RNA Mensageiro/genética , Biologia Computacional , Modelos Moleculares , RNA Mensageiro/metabolismo
6.
Org Lett ; 26(9): 1891-1895, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38408024

RESUMO

Pseudocyclic arylbenziodoxaboroles are unique aryne precursors under neutral aqueous conditions that selectively react with organic sulfides, forming the corresponding sulfonium salts. This reaction is compatible with various substituents (alkyl, halogen, CN, NO2, CHO, and cyclopropyl) in the aromatic ring or alkyl group of the sulfide. Similar reactions of sulfoxides afford o-hydroxy-substituted sulfonium salts. The structures of key products were confirmed by X-ray analysis.

7.
ACS Omega ; 8(31): 28733-28748, 2023 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-37576624

RESUMO

Improving lipophilicity for drugs to penetrate the lipid membrane and decreasing bacterial and fungal coinfections for patients with cancer pose challenges in the drug development process. Here, a series of new N-alkylated-2-(substituted phenyl)-1H-benzimidazole derivatives were synthesized and characterized by 1H and 13C NMR, FTIR, and HRMS spectrum analyses to address these difficulties. All the compounds were evaluated for their antiproliferative, antibacterial, and antifungal activities. Results indicated that compound 2g exhibited the best antiproliferative activity against the MDA-MB-231 cell line and also displayed significant inhibition at minimal inhibitory concentration (MIC) values of 8, 4, and 4 µg mL-1 against Streptococcus faecalis, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus compared with amikacin. The antifungal data of compounds 1b, 1c, 2e, and 2g revealed their moderate activities toward Candida albicans and Aspergillus niger, with MIC values of 64 µg mL-1 for both strains. Finally, the molecular docking study found that 2g interacted with crucial amino acids in the binding site of complex dihydrofolate reductase with nicotinamide adenine dinucleotide phosphate.

8.
ACS Omega ; 8(42): 39203-39216, 2023 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-37901519

RESUMO

Cannabis sativa L. produces a wide variety of volatile secondary metabolites that contribute to its unique aroma. The major volatile constituents include monoterpenes, sesquiterpenes, and their oxygenated derivates. In particular, the compounds ß-myrcene, D-(+)-limonene, ß-caryophyllene, and terpinolene are often found in greatest amounts, which has led to their use in chemotaxonomic classification schemes and legal Cannabis sativa L. product labeling. While these compounds contribute to the characteristic aroma of Cannabis sativa L. and may help differentiate varieties on a broad level, their importance in producing specific aromas is not well understood. Here, we show that across Cannabis sativa L. varieties with divergent aromas, terpene expression remains remarkably similar, indicating their benign contribution to these unique, specific scents. Instead, we found that many minor, nonterpenoid compounds correlate strongly with nonprototypical sweet or savory aromas produced by Cannabis sativa L. Coupling sensory studies to our chemical analysis, we derive correlations between groups of compounds, or in some cases, individual compounds, that produce many of these diverse scents. In particular, we identified a new class of volatile sulfur compounds (VSCs) containing the 3-mercaptohexyl functional group responsible for the distinct citrus aromas in certain varieties and skatole (3-methylindole) as the key source of the chemical aroma in others. Our results provide not only a rich understanding of the chemistry of Cannabis sativa L. but also highlight how the importance of terpenes in the context of the aroma of Cannabis sativa L. has been overemphasized.

9.
Environ Technol ; 42(8): 1292-1301, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31496447

RESUMO

In this work, we reported synthesis of a novel magnetically separable g-C3N4/Zn doped Fe3O4 composite (g-CN/ZnFe) by a simple polyol thermal method. The characteristics of the as-prepared composite was checked by XRD, SEM, TEM, XPS, PL technologies. The optimized weight ratio of g-C3N4 and Zn doped Fe3O4 was investigated. In addition, the photocatalytic activities of the composite products were checked by degradation of Cephalexin (CEX) under visible light. The results showed that g-CN/ZnFe composite with an added 20% g-C3N4 exhibited the highest photocatalytic activity for cephalexin under visible light irradiation. The improved photocatalytic activity of 20% g-CN/ZnFe can be ascribed to the low combination rate of photoinduced electron/hole pairs. Especially, g-CN/ZnFe can be recovered easily by using an external magnetic field and has the high stability after six runs. These properties of the g-CN/ZnFe as-prepared composite could be a promising photocatalyst for the degradation of pharmaceutical contaminants.


Assuntos
Cefalexina , Luz , Catálise , Zinco
10.
Front Physiol ; 12: 658518, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34366878

RESUMO

BACKGROUND: Ciliary defects cause heterogenous phenotypes related to mutation burden which lead to impaired development. A previously reported homozygous deletion in the Man1a2 gene causes lethal respiratory failure in newborn pups and decreased lung ciliation compared with wild type (WT) pups. The effects of heterozygous mutation, and the potential for rescue are not known. PURPOSE: We hypothesized that survival and lung ciliation, (a) would decrease progressively in Man1a2 +/- heterozygous and Man1a2 -/- null newborn pups compared with WT, and (b) could be enhanced by gestational treatment with N-Acetyl-cysteine (NAC), an antioxidant. METHODS: Man1a2+/- adult mice were fed NAC or placebo from a week before breeding through gestation. Survival of newborn pups was monitored for 24 h. Lungs, liver and tails were harvested for morphology, genotyping, and transcriptional profiling. RESULTS: Survival (p = 0.0001, Kaplan-Meier) and percent lung ciliation (p = 0.0001, ANOVA) measured by frequency of Arl13b+ respiratory epithelial cells decreased progressively, as hypothesized. Compared with placebo, gestational NAC treatment enhanced (a) lung ciliation in pups with each genotype, (b) survival in heterozygous pups (p = 0.017) but not in WT or null pups. Whole transcriptome of lung but not liver demonstrated patterns of up- and down-regulated genes that were identical in living heterozygous and WT pups, and completely opposite to those in dead heterozygous and null pups. Systems biology analysis enabled reconstruction of protein interaction networks that yielded functionally relevant modules and their interactions. In these networks, the mutant Man1a2 enzyme contributes to abnormal synthesis of proteins essential for lung development. The associated unfolded protein, hypoxic and oxidative stress responses can be mitigated with NAC. Comparisons with the developing human fetal lung transcriptome show that NAC likely restores normal vascular and epithelial tube morphogenesis in Man1a2 mutant mice. CONCLUSION: Survival and lung ciliation in the Man1a2 mutant mouse, and its improvement with N-Acetyl cysteine is genotype-dependent. NAC-mediated rescue depends on the central role for oxidative and hypoxic stress in regulating ciliary function and organogenesis during development.

11.
Front Neurorobot ; 14: 619350, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33536891

RESUMO

This study presents an online tuning proportional-integral-derivative (PID) controller using a multilayer fuzzy neural network design for quadcopter attitude control. PID controllers are simple but effective control methods. However, finding the suitable gain of a model-based controller is relatively complicated and time-consuming because it depends on external disturbances and the dynamic modeling of plants. Therefore, the development of a method for online tuning of quadcopter PID parameters may save time and effort, and better control performance can be achieved. In our controller design, a multilayer structure was provided to improve the learning ability and flexibility of a fuzzy neural network. Adaptation laws to update network parameters online were derived using the gradient descent method. Also, a Lyapunov analysis was provided to guarantee system stability. Finally, simulations concerning quadcopter attitude control were performed using a Gazebo robotics simulator in addition to a robot operating system (ROS), and their results were demonstrated.

12.
Cell Rep ; 30(8): 2758-2775.e6, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32101750

RESUMO

Nuclear factor κB (NF-κB) RelA is the potent transcriptional activator of inflammatory response genes. We stringently defined a list of direct RelA target genes by integrating physical (chromatin immunoprecipitation sequencing [ChIP-seq]) and functional (RNA sequencing [RNA-seq] in knockouts) datasets. We then dissected each gene's regulatory strategy by testing RelA variants in a primary-cell genetic-complementation assay. All endogenous target genes require RelA to make DNA-base-specific contacts, and none are activatable by the DNA binding domain alone. However, endogenous target genes differ widely in how they employ the two transactivation domains. Through model-aided analysis of the dynamic time-course data, we reveal the gene-specific synergy and redundancy of TA1 and TA2. Given that post-translational modifications control TA1 activity and intrinsic affinity for coactivators determines TA2 activity, the differential TA logics suggests context-dependent versus context-independent control of endogenous RelA-target genes. Although some inflammatory initiators appear to require co-stimulatory TA1 activation, inflammatory resolvers are a part of the NF-κB RelA core response.


Assuntos
Inflamação/genética , Fator de Transcrição RelA/metabolismo , Ativação Transcricional/genética , Animais , Sequência de Bases , Embrião de Mamíferos/citologia , Fibroblastos/metabolismo , Lógica , Camundongos Endogâmicos C57BL , Modelos Biológicos , Domínios Proteicos , Fator de Necrose Tumoral alfa
13.
Chemosphere ; 247: 125991, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32069737

RESUMO

Polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), hexabromobiphenyl (BB-153), novel brominated flame retardants (NBFRs), and unsubstituted/methylated polycyclic aromatic hydrocarbons (PAHs/Me-PAHs) were simultaneously monitored in the air samples collected from Vietnamese urban and vehicular waste processing areas by using polyurethane foam-based passive air sampling (PUF-PAS) method. Concentrations (pg m-3) of organic pollutants decreased in the order: PAHs (median 29,000; range 5100-100,000) > Me-PAHs (6000; 1000-33,000) > PCBs (480; 170-1100) > PBDEs (11; 5.3-86) > NBFRs (0.20; n. d. - 51) > BB-153 (n.d.). The difference in total PCB and PBDE concentrations between the urban and waste processing air samples was not statistically significant. Meanwhile, levels of PAHs, Me-PAHs, benzo [a]pyrene equivalents (BaP-EQs), and toxic equivalents of dioxin-like PCBs (WHO-TEQs) were much higher in the waste processing sites. This is the first report on the abundance of mono- and di-CBs (notably CB-11) in the air from a developing country, suggesting their roles as emerging and ubiquitous air pollutants. Our results have indicated potential sources of specific organic pollutants such as dioxin-like PCBs, PAHs, and Me-PAHs from improper treatment of end-of-life vehicles and other vehicle related materials (e.g., waste oils and rubber tires), as well as current emission of PCBs and PBDEs in the urban area in Vietnam. Further atmospheric monitoring studies should be conducted in this developing country that cover both legacy and emerging contaminants with a focus on areas affected by rapid urbanization and informal waste processing activities.


Assuntos
Poluentes Atmosféricos/análise , Monitoramento Ambiental/métodos , Poliuretanos , Retardadores de Chama/análise , Éteres Difenil Halogenados/análise , Bifenilos Policlorados/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Urbanização , Vietnã , Gerenciamento de Resíduos
14.
Hosp Pediatr ; 8(9): 538-546, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30154081

RESUMO

BACKGROUND: Asthma and obesity are 2 common pediatric problems. Obesity is a known risk factor for asthma, and obese children with asthma have higher disease burden. However, little is known on how obesity in urban minority children, mainly Hispanic and African American children, impacts morbidity during pediatric asthma hospitalizations. METHODS: A retrospective chart review was conducted on children and adolescents age 2 to 18 years hospitalized at the Children's Hospital at Montefiore for an acute asthma exacerbation. We elucidated the association of overweight or obese status with severity of the exacerbation, quantified by length of stay (LOS) and need for intensive care management. Multivariate analysis was conducted to identify independent predictors of LOS. RESULTS: A total of 975 children met the inclusion criteria, of whom 55% were normal weight and 45% were overweight or obese. Sixty percent were Hispanic, and 37% were African American. The overall average LOS was 2.57 days (range: 0.67-12.92). Overweight or obese status was associated with a higher asthma severity at baseline (P = .021). Overweight or obese children had a longer average LOS compared with normal weight children (2.75 vs 2.39 days; P < .01) with more PICU stays (P = .006), even after adjustment for higher baseline asthma severity. The severity of the exacerbation did not differ by ethnicity. CONCLUSIONS: Obesity in children hospitalized for asthma is associated with more severe asthma exacerbations, longer LOS, and increased use of PICU level care, independent of their higher baseline disease severity and ethnicity.


Assuntos
Asma/epidemiologia , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Tempo de Internação/estatística & dados numéricos , Obesidade Infantil/epidemiologia , Negro ou Afro-Americano , Asma/fisiopatologia , Criança , Pré-Escolar , Comorbidade , Bases de Dados Factuais , Progressão da Doença , Etnicidade/estatística & dados numéricos , Feminino , Hispânico ou Latino/estatística & dados numéricos , Hospitalização , Hospitais Pediátricos , Humanos , Masculino , Morbidade , Análise Multivariada , Sobrepeso/epidemiologia , Estudos Retrospectivos , Índice de Gravidade de Doença , População Branca/estatística & dados numéricos
15.
J Nucl Med ; 46(3): 484-94, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15750163

RESUMO

UNLABELLED: Brain kappa-opioid receptors (ORs) may be involved in several pathologic conditions, such as addiction, psychosis, and seizures. (+/-)-4-Methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine (GR89696) is a potent and selective kappa-OR agonist. The (-)-isomer, GR103545, is the active enantiomer of GR89696. The aim of this study was to characterize the potential of 11C-GR103545 to image kappa-OR in vivo with PET. METHODS: Brain uptake of 11C-GR103545 was studied in baboons under control conditions and after blockade by naloxone (1 mg/kg intravenously). Uptake of the racemic 11C-GR89696 and of the inactive enantiomer (+)-11C-GR89696 was also evaluated. Regional total distribution volumes were derived using the arterial input function and a 2-tissue-compartment model. RESULTS: 11C-GR103545 showed excellent brain penetration and uptake kinetics, with significant washout observed within the time frame of the PET experiment. Naloxone pretreatment did not affect cerebellar total distribution volume and reduced total distribution volume in other regions to a level comparable to that in the cerebellum. The regional pattern of 11C-GR103545 binding potential was consistent with the distribution of kappa-OR in primate brain, with highest levels observed in anterior cortical regions (prefrontal cortex and cingulate cortex) and striatum. In most regions, the specific-to-nonspecific equilibrium partition coefficient (V3'') ranged from 1 to 2, predicting reliable quantification. 11C-GR103545 V3'' values were approximately double the 11C-GR89696 V3'' values, whereas (+)-11C-GR89696 V3'' values were negligible, demonstrating the enantiomeric selectivity of the binding and the advantage of using the pure active enantiomer for PET studies. CONCLUSION: 11C-GR103545 is a promising PET radiotracer for imaging the kappa-OR.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Piperazinas/farmacocinética , Pirrolidinas/farmacocinética , Receptores Opioides kappa/metabolismo , Animais , Biomarcadores/metabolismo , Radioisótopos de Carbono/química , Radioisótopos de Carbono/farmacocinética , Aumento da Imagem/métodos , Marcação por Isótopo/métodos , Masculino , Taxa de Depuração Metabólica , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/metabolismo , Papio , Piperazinas/química , Tomografia por Emissão de Pósitrons/métodos , Pirrolidinas/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual
16.
J Mol Biol ; 427(17): 2748-56, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26191773

RESUMO

Whereas ubiquitin-dependent degrons have been characterized in some detail, how proteins may be targeted to ubiquitin-independent proteasomal degradation remains unclear. Here we show that IκBα contains an ubiquitin-independent degron whose activity is portable to heterologous proteins such as the globular protein GFP (green fluorescent protein) via a proteasome-dependent, ubiquitin-independent, non-lysosomal pathway. The ubiquitin-independent degradation signal resides in an 11-amino-acid sequence, which is not only sufficient but also required for IκBα's short half-life. Finally, we show that this degron's activity is regulated by the interaction with NFκB, which controls its solvent exposure, and we demonstrate that this regulation of the degron's activity is critical for IκBα's signaling functions.


Assuntos
Repetição de Anquirina/genética , Proteínas I-kappa B/metabolismo , Transdução de Sinais/genética , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Células 3T3 , Sequência de Aminoácidos , Animais , Linhagem Celular , Cloroquina/farmacologia , Cicloeximida/farmacologia , Proteínas de Ligação a DNA/metabolismo , Proteínas de Fluorescência Verde , Células HEK293 , Humanos , Lisossomos/metabolismo , Macrolídeos/farmacologia , Camundongos , Inibidor de NF-kappaB alfa , Proteólise , Ubiquitina/metabolismo
17.
Nat Commun ; 6: 7068, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25946967

RESUMO

The NFκB family of dimeric transcription factors regulate inflammatory and immune responses. While the dynamic control of NFκB dimer activity via the IκB-NFκB signalling module is well understood, there is little information on how specific dimer repertoires are generated from Rel family polypeptides. Here we report the iterative construction-guided by in vitro and in vivo experimentation-of a mathematical model of the Rel-NFκB generation module. Our study reveals that IκBß has essential functions within the Rel-NFκB generation module, specifically for the RelA:RelA homodimer, which controls a subset of NFκB target genes. Our findings revise the current dogma of the three classical, functionally related IκB proteins by distinguishing between a positive 'licensing' factor (IκBß) that contributes to determining the available NFκB dimer repertoire in a cell's steady state, and negative feedback regulators (IκBα and -ɛ) that determine the duration and dynamics of the cellular response to an inflammatory stimulus.


Assuntos
Proteínas I-kappa B/metabolismo , NF-kappa B/metabolismo , Multimerização Proteica , Fator de Transcrição RelA/metabolismo , Animais , Ligação Competitiva , Fenômenos Biofísicos , Cinética , Camundongos , Modelos Biológicos , Ligação Proteica , Isoformas de Proteínas/metabolismo , Transdução de Sinais
18.
J Health Care Poor Underserved ; 26(2 Suppl): 104-15, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25981092

RESUMO

The nail salon sector is booming, predominantly with Vietnamese immigrant workers who regularly handle nail care products containing harmful chemicals. Based on lessons learned from an ongoing randomized controlled trial, occupational interventions need to incorporate inputs from different stakeholders, including salon owners, workers, and customers as well as governmental regulatory agencies.


Assuntos
Indústria da Beleza , Promoção da Saúde , Doenças Profissionais/prevenção & controle , Exposição Ocupacional/prevenção & controle , Adulto , California/epidemiologia , Emigrantes e Imigrantes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional/efeitos adversos , Vietnã/etnologia
19.
Cell Rep ; 9(6): 2098-111, 2014 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-25497099

RESUMO

BAFF, an activator of the noncanonical NFκB pathway, provides critical survival signals during B cell maturation and contributes to B cell proliferation. We found that the NFκB family member RelB is required ex vivo for B cell maturation, but cRel is required for proliferation. Combined molecular network modeling and experimentation revealed Nfkb2 p100 as a pathway switch; at moderate p100 synthesis rates in maturing B cells, BAFF fully utilizes p100 to generate the RelB:p52 dimer, whereas at high synthesis rates, p100 assembles into multimeric IκBsome complexes, which BAFF neutralizes in order to potentiate cRel activity and B cell expansion. Indeed, moderation of p100 expression or disruption of IκBsome assembly circumvented the BAFF requirement for full B cell expansion. Our studies emphasize the importance of p100 in determining distinct NFκB network states during B cell biology, which causes BAFF to have context-dependent functional consequences.


Assuntos
Fator Ativador de Células B/metabolismo , Linfócitos B/metabolismo , Proliferação de Células , NF-kappa B/metabolismo , Transdução de Sinais , Animais , Fator Ativador de Células B/genética , Linfócitos B/citologia , Linfócitos B/fisiologia , Diferenciação Celular , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Camundongos , Modelos Biológicos , NF-kappa B/genética , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo
20.
J Hazard Mater ; 185(2-3): 653-61, 2011 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-20952129

RESUMO

We present a simple and efficient method for the fabrication of magnetic Fe(2)MO(4) (M:Fe and Mn) activated carbons (Fe(2)MO(4)/AC-H, M:Fe and Mn) by impregnating the activated carbon with simultaneous magnetic precursor and carbon modifying agent followed by calcination. The obtained samples were characterized by nitrogen adsorption isotherms, X-ray diffraction (XRD), scanning electron microscopy (SEM) and vibrating sample magnetometer (VSM), and the catalytic activity in heterogeneous Fenton oxidation of methyl orange (MO) was evaluated. The resulting Fe(2)MnO(4)/AC-H showed higher catalytic activity in the methyl orange oxidation than Fe(3)O(4)/AC-H. The effect of operational parameters (pH, catalyst loading H(2)O(2) dosage and initial MO concentration) on degradation performance of the oxidation process was investigated. Stability and reusability of selected catalyst were also tested.


Assuntos
Compostos Azo/química , Carbono/química , Compostos de Ferro/química , Magnetismo , Adsorção , Microscopia Eletrônica de Varredura , Nitrogênio/química , Oxirredução , Espectrofotometria Ultravioleta , Difração de Raios X
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