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1.
Sensors (Basel) ; 21(19)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34640758

RESUMO

An intriguing challenge in the human-robot interaction field is the prospect of endowing robots with emotional intelligence to make the interaction more genuine, intuitive, and natural. A crucial aspect in achieving this goal is the robot's capability to infer and interpret human emotions. Thanks to its design and open programming platform, the NAO humanoid robot is one of the most widely used agents for human interaction. As with person-to-person communication, facial expressions are the privileged channel for recognizing the interlocutor's emotional expressions. Although NAO is equipped with a facial expression recognition module, specific use cases may require additional features and affective computing capabilities that are not currently available. This study proposes a highly accurate convolutional-neural-network-based facial expression recognition model that is able to further enhance the NAO robot' awareness of human facial expressions and provide the robot with an interlocutor's arousal level detection capability. Indeed, the model tested during human-robot interactions was 91% and 90% accurate in recognizing happy and sad facial expressions, respectively; 75% accurate in recognizing surprised and scared expressions; and less accurate in recognizing neutral and angry expressions. Finally, the model was successfully integrated into the NAO SDK, thus allowing for high-performing facial expression classification with an inference time of 0.34 ± 0.04 s.


Assuntos
Reconhecimento Facial , Robótica , Aminoacridinas , Emoções , Expressão Facial , Humanos
2.
Asia Pac J Public Health ; 33(8): 914-922, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34467767

RESUMO

This study aims to test the psychometric properties of the Malay, English, and Chinese 9-Item Shared Decision Making Questionnaire (SDM-Q-9) in breast cancer patients making treatment decisions. The original German SDM-Q-9 was translated to Malay using the back-translation method. A total of 222 newly diagnosed breast cancer patients making treatment decisions were sampled conveniently from three breast clinics between August 2015 and February 2016. A total of 66 patients answered the SDM-Q-9 in Malay, 87 in English, and 69 in Chinese. Data were analyzed using SPSS and AMOS software. SDM-Q-9 demonstrated good reliability in the three translations. All the items correlated well except for Item 1 in English. The factor loadings were within acceptable range except for Item 1 in Malay, Items 1 and 2 in English, and Items 7 and 9 in Chinese SDM-Q-9. However, no items were deleted in accordance with experts' opinions and the previous SDM-Q-9 validation studies. The Malay, English, and Chinese SDM-Q-9 demonstrated good reliability and validity.


Assuntos
Neoplasias da Mama , Tomada de Decisão Compartilhada , Aminoacridinas , Neoplasias da Mama/terapia , China , Tomada de Decisões , Feminino , Humanos , Malásia , Reprodutibilidade dos Testes , Inquéritos e Questionários
3.
J Biomed Inform ; 118: 103797, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33933653

RESUMO

The use of humanoid robots as assistants in therapy processes is not new. Several projects in the past several years have achieved promising results when combining human-robot interaction with standard techniques. Moreover, there are multiple screening systems for autism; one of the most used systems is the Quantitative Checklist for Autism in Toddlers (Q-CHAT-10), which includes ten questions to be answered by the parents or caregivers of a child. We present Q-CHAT-NAO, an observation-based autism screening system supported by a NAO robot. It includes the six questions of the Q-CHAT-10 that can be adapted to work in a robotic context; unlike the original system, it obtains information from the toddler instead of from an indirect source. The detection results obtained after applying machine learning models to the six questions in the Autistic Spectrum Disorder Screening Data for Toddlers dataset were almost equivalent to those of the original version with ten questions. These findings indicate that the Q-CHAT-NAO could be a screening option that would exploit all the benefits related to human-robot interaction.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Procedimentos Cirúrgicos Robóticos , Robótica , Aminoacridinas , Transtorno Autístico/diagnóstico , Pré-Escolar , Humanos , Programas de Rastreamento , Inquéritos e Questionários
5.
Bioorg Med Chem ; 40: 116191, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33965841

RESUMO

Cisplatin analogues with an attached DNA-binding moiety represent a potentially effective class of DNA-damaging anti-tumour agents because they possess higher affinities for DNA and different DNA damage profiles compared with cisplatin. In this study, the interaction of four 9-aminoacridine carboxamide Pt complexes with purified DNA was investigated: firstly, using a fluorescent intercalator displacement (FID) assay with ethidium bromide; and secondly, with a DNA unwinding assay. The relative capacity of these compounds to perturb the fluorescence induced by DNA-bound ethidium bromide at clinically relevant drug concentrations was assessed over a 24-h period using an FID assay. All analogues were found to reduce the level of ethidium bromide-induced fluorescence in a concentration-dependent manner from the earliest time point of 10 min onwards. Cisplatin, however, showed a markedly slower reduction in ethidium bromide-induced fluorescence from 2 h onwards, producing a similar level of fluorescence reduction as that produced by the analogues from 6 h onwards. These results suggest that the altered DNA-binding modes of the DNA-targeted analogues confer a more efficient mechanism for DNA binding compared with cisplatin. Relative DNA binding coefficients were also determined for each of the compounds studied. With the DNA unwinding assay, an unwinding angle can be calculated from the coalescence point of plasmids in an agarose gel. It was found that all 9-aminoacridine carboxamide analogues had a greater unwinding angle compared with cisplatin. The knowledge obtained from these two assays has helped to further characterise the cisplatin analogues and could facilitate the development of more effective anti-tumour agents.


Assuntos
Aminoacridinas/farmacologia , Antineoplásicos/farmacologia , DNA/efeitos dos fármacos , Compostos Organoplatínicos/farmacologia , Aminoacridinas/química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , DNA/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Compostos Organoplatínicos/química , Plasmídeos , Relação Estrutura-Atividade
6.
Food Funct ; 12(3): 1232-1240, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33433545

RESUMO

The effects of potato and traditional staple foods (corn, wheat and rice) on physiology and gut microbiota were investigated by feeding ICR mice for 12 months. Compared with traditional staple foods, potato significantly improved the food and water intake and survival rate, and inhibited the swelling of viscera of mice, accompanied by a decreased white blood cell count and urine bilirubin content. Furthermore, potato significantly increased the relative abundance of Bacteroides and Faecalibacterium, which are short-chain fatty acid producing bacteria and play very important roles in the maintenance of human health. Meanwhile, potato significantly decreased the relative abundance of spoilage bacteria Pseudomonas and Thiobacillus. Analysis of putative metagenomes indicated that the potato diet upregulated the gene abundance of glycan biosynthesis and metabolism, digestive system and immune system. These findings indicated that potato has the potential to be an excellent substitute for traditional staple foods owing to its good physiological function and favorable gut microbiota modulation.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Oryza , Solanum tuberosum , Triticum , Zea mays , Aminoacridinas , Ração Animal , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Peso Corporal , Dieta , Ingestão de Líquidos , Ingestão de Alimentos , Camundongos , Compostos de Mostarda Nitrogenada , Distribuição Aleatória
7.
Mol Vis ; 26: 722-730, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33209015

RESUMO

Purpose: Central serous chorioretinopathy (CSCR) has been associated with oxidative stress-related risk factors. The objective of this study was to optimize an analytical method for evaluating the oxidative stress biomarker malondialdehyde (MDA) in human tears and determine its level in the tears of patients with CSCR. Methods: In this pilot study, tear samples were obtained from 34 healthy donors and 31 treatment-naïve CSCR male patients (eight with acute CSCR and 23 with chronic CSCR). Two analytical methods based on high-performance liquid chromatography followed by fluorescence detection were evaluated, with either 2-thiobarbituric derivative (TBA) or 2-aminoacridone (2-AA). Activity of CSCR was defined by the serous retinal detachment (SRD) height, which was measured by two independent observers on spectral-domain optical coherence tomography. Results: The 2-AA method showed higher sensitivity and precision compared to the TBA method. When the 2-AA method was applied to tears from healthy donors, the levels of MDA were statistically significantly higher in men compared to women (mean ± standard deviation, SD: 9,914 nM ± 6,126 versus 4,635 nM ± 1,173, p = 0.006). No difference was found in tear MDA levels between male patients with CSCR and age-matched control men (p = 0.17). However, MDA levels were statistically significantly higher in acute compared to chronic CSCR cases (mean ± SD: 12,295 nM ± 8,495 versus 6,790 ± 3,969 nM, p = 0.03). Additionally, there was a correlation between MDA levels and RPE leakage, quantified by the height of the serous retinal detachment (p = 0.02, r = 0.40). Conclusions: Levels of MDA in tears, measured with an optimized analytical method, correlate with RPE leakage in CSCR.


Assuntos
Coriorretinopatia Serosa Central/metabolismo , Coriorretinopatia Serosa Central/patologia , Malondialdeído/metabolismo , Estresse Oxidativo , Lágrimas/metabolismo , Adulto , Aminoacridinas/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Coriorretinopatia Serosa Central/complicações , Coriorretinopatia Serosa Central/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Descolamento Retiniano/complicações , Descolamento Retiniano/diagnóstico por imagem , Tiobarbitúricos/metabolismo , Tomografia de Coerência Óptica
8.
Int J Mol Sci ; 21(11)2020 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-32486425

RESUMO

Activity modulation of drug metabolism enzymes can change the biotransformation of chemotherapeutics and cellular responses induced by them. As a result, drug-drug interactions can be modified. Acridinone derivatives, represented here by C-1305 and C-1311, are potent anticancer drugs. Previous studies in non-cellular systems showed that they are mechanism-based inhibitors of cytochrome P4503A4 and undergo glucuronidation via UDP-glucuronosyltranspherase 1A10 isoenzyme (UGT1A10). Therefore, we investigated the potency of these compounds to modulate P4503A4 and UGT1A10 activity in breast MCF-7 and colon HCT116 cancer cells and their influence on cytotoxicity and cellular response in cells with different expression levels of studied isoenzymes. We show that C-1305 and C-1311 are inducers of not only P4503A4 but also UGT1A10 activity. MCF-7 and HCT116 cells with high P4503A4 activity are more sensitive to acridinone derivatives and undergo apoptosis/necrosis to a greater extent. UGT1A10 was demonstrated to be responsible for C-1305 and C-1311 glucuronidation in cancer cells and glucuronide products were excreted outside the cell very fast. Finally, we show that glucuronidation of C-1305 antitumor agent enhances its pro-apoptotic properties in HCT116 cells, while the cytotoxicity and cellular response induced by C-1311 did not change after drug glucuronidation in both cell lines.


Assuntos
Acridinas/farmacologia , Aminoacridinas/farmacologia , Antineoplásicos/farmacologia , Citocromo P-450 CYP3A/metabolismo , Glucuronosiltransferase/metabolismo , Triazóis/farmacologia , Apoptose , Biotransformação , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Glucuronídeos/metabolismo , Células HCT116 , Humanos , Isoenzimas , Células MCF-7 , Potencial da Membrana Mitocondrial , Necrose , Especificidade por Substrato
9.
Food Funct ; 11(5): 3895-3903, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32407431

RESUMO

Semen Ziziphus jujube (SZJ) has been widely consumed because it is recognized as edible in China to treat insomnia disorders. However, the underlying mechanisms and potential therapeutic targets remain obscure. SZJ-I and SZJ-II with a saponin content of 52.10% and 75.20%, respectively, were extracted from SZJ. LC-MS analysis presented quite different chemical profiles of SZJ-I and SZJ-II. Mice with p-chlorophenylalanine (PCPA)-induced insomnia were used to comparatively and systematically test the sedative-hypnotic activities of SZJ-I and SZJ-II. In vivo behavioral tests revealed that SZJ-I and SZJ-II significantly shortened the immobility time and potentiated sodium pentobarbital-induced sleep. SZJ-II with a higher saponin content showed greater potency than SZJ-I. SZJ-I and SZJ-II also protected against PCPA-triggered neuropathological damages in the brain. Concentrations of 5-hydroxytryptamine (5-HT), dopamine (DA), noradrenaline (NE), glutamate (Glu), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), nitric oxide (NO) and prostaglandin D2 (PGD2) in plasma were significantly affected by SZJ-I and SZJ-II application. SZJ-I and SZJ-II also exhibited differential modulation of 5-hydroxytryptamine 1A (5-HT1A), 5-hydroxytryptamine 2A (5-HT2A), GABAA receptor α2 (GABAARα2), GABAA receptor α3 (GABAARα3), glutamic acid decarboxylase (GAD) 65/67, IL-6 and IL-1ß expression in the hypothalamus and hippocampus. SZJ-I and SZJ-II might exert excellent sedative-hypnotic effects through multiple mechanisms that worked simultaneously. SZJ-I and especially SZJ-II are promising candidates for relieving insomnia.


Assuntos
Hipnóticos e Sedativos/farmacologia , Extratos Vegetais/farmacologia , Saponinas/farmacologia , Sono/efeitos dos fármacos , Ziziphus/química , Aminoacridinas , Animais , Citocinas/genética , Citocinas/metabolismo , Diazepam/farmacologia , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônios/metabolismo , Hipnóticos e Sedativos/química , Masculino , Camundongos , Compostos de Mostarda Nitrogenada , Pentobarbital/farmacologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Saponinas/administração & dosagem , Saponinas/química
10.
Biophys J ; 117(6): 1101-1115, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31474304

RESUMO

Understanding local conformations of DNA at the level of individual nucleic acid bases and base pairs is important for elucidating molecular processes that depend on DNA sequence. Here, we apply linear absorption and circular dichroism measurements to the study of local DNA conformations, using the guanine base analog 6-methyl isoxanthopterin (6-MI) as a structural probe. We show that the spectroscopic properties of this probe can provide detailed information about the average local base and basepair conformations as a function of the surrounding DNA sequence. Based on these results we apply a simple theoretical model to calculate the circular dichroism spectra of 6-MI-substituted DNA constructs and show that our model can be used to extract information about how the local conformations of the 6-MI probe are influenced by the local base or basepair environment. We also use this probe to examine the pathway for the insertion (intercalation) of a tethered acridine ligand (9-amino-6-chloro methoxyacridine) into duplex DNA. We show that this model intercalator interacts with duplex DNA by a "displacement insertion intercalation" mechanism, whereby the acridine moiety is inserted into the DNA structure and displaces the base located opposite its attachment site. These findings suggest that site-specifically positioned base analog probes can be used to characterize the molecular and structural details of binding ligand effects on local base stacking and unstacking reactions in single- and double-stranded DNA and thus may help to define the molecular mechanisms of DNA-protein interactions that involve the site-specific intercalation of aromatic amino acid side chains into genomic DNA.


Assuntos
DNA/química , Substâncias Intercalantes/química , Sondas Moleculares/química , Conformação de Ácido Nucleico , Aminoacridinas/química , Sequência de Bases , Simulação por Computador , Eletricidade , Ligantes , Modelos Moleculares , Xantopterina/química
12.
J Pharm Biomed Anal ; 169: 269-278, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30884325

RESUMO

The metabolism of antitumor-active 5-diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311) has been investigated widely over the last decade but some aspects of molecular mechanisms of its metabolic transformation are still not explained. In the current work, we have reported a direct and rapid analytical tool for better prediction of C-1311 metabolism which is based on electrochemistry (EC) coupled on-line with electrospray ionization mass spectrometry (ESI-MS). Simulation of the oxidative phase I metabolism of the compound was achieved in a simple electrochemical thin-layer cell consisting of three electrodes (ROXY™, Antec Leyden, the Netherlands). We demonstrated that the formation of the products of N-dealkylation reactions can be easily simulated using purely instrumental approach. Newly reported products of oxidative transformations like hydroxylated or oxygenated derivatives become accessible. Structures of the electrochemically generated metabolites were elucidated on the basis of accurate mass ion data and tandem mass spectrometry experiments. In silico prediction of main sites of C-1311 metabolism was performed using MetaSite software. The compound was evaluated for cytochrome P450 1A2-, 3A4-, and 2D6-mediated reactions. The results obtained by EC were also compared and correlated with those of reported earlier for conventional in vitro enzymatic studies in the presence of liver microsomes and in the model peroxidase system. The in vitro experimental approach and the in silico metabolism findings showed a quite good agreement with the data from EC/ESI-MS analysis. Thus, we conclude here that the electrochemical technique provides the promising platform for the simple evaluation of drug metabolism and the reaction mechanism studies, giving first clues to the metabolic transformation of pharmaceuticals in the human body.


Assuntos
Aminoacridinas/metabolismo , Antineoplásicos/metabolismo , Fenômenos Bioquímicos/fisiologia , Simulação por Computador , Sistema Enzimático do Citocromo P-450/metabolismo , Técnicas Eletroquímicas/métodos , Eletroquímica/métodos , Eletrodos , Humanos , Inativação Metabólica/fisiologia , Microssomos Hepáticos/metabolismo , Oxirredução , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos
13.
Annu Int Conf IEEE Eng Med Biol Soc ; 2019: 1641-1644, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31946211

RESUMO

Socially assistive robots have shown potential benefits in therapy of child and elderly patients with social and cognitive deficits. In particular, for autistic children, humanoid robots could enhance engagement and attention, thanks to their simplified toy-like appearance and the reduced set of possible movements and expressions. The recent focus on autism-related motor impairments has increased the interest on developing new robotic tools aimed at improving not only the social capabilities but also the motor skills of autistic children. To this purpose, we have designed two embodied mirroring setups using the NAO humanoid robot. Two different tracking systems were used and compared: Inertial Measurement Units and the Microsoft Kinect, a marker-less vision based system. Both platforms were able to mirror upper limb basic movements of two healthy subjects, an adult and a child. However, despite the lower accuracy, the Kinect-based setup was chosen as the best candidate for embodied mirroring in autism treatment, thanks to the lower intrusiveness and reduced setup time. A prototype of an interactive mirroring game was developed and successfully tested with the Kinect-based platform, paving the way to the development of a versatile and powerful tool for clinical use with autistic children.


Assuntos
Transtorno Autístico , Robótica , Aminoacridinas , Criança , Humanos , Movimento , Extremidade Superior
14.
J Biotechnol ; 281: 99-105, 2018 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-29981447

RESUMO

Channelrhodopsins (ChRs) are a group of membrane proteins that allow cation flux across the cellular membrane when stimulated by light. They have been emerged as important tools in optogenetics where light is used to trigger a change in the membrane potential of live cells which induces downstream physiological cascades. There is also increased interest in their applications for generating light-responsive biomaterials. Here we have used a two-step screening protocol to develop a Pichia pastoris strain that produces superior yields of an enhance variant of CaChR2 (from Chlamydomonas reinhardtii), called ChIEF. We have also studied the effect of the co-factor, namely all-trans retinal (ATR), on the recombinant overexpression, folding, and function of the protein. We found that both ChIEF-mCitrine and CaChR2 can be overexpressed and properly trafficked to the plasma membrane in yeast regardless of the presence of the ATR. The purified protein was reconstituted into large unilamellar lipid vesicle using the detergent-assisted method. Using 9-amino-6-chloro-2-methoxyacridine (ACMA) as the fluorescent proton indicator, we have developed a flux assay to verify the light-activated proton flux in the ChIEF-mCitrine vesicles. Hence such vesicles are effectively light-responsive nano-compartments. The results presented in this work lays foundations for creating bio-mimetic materials with a light-responsive function using channelrhodopsins.


Assuntos
Channelrhodopsins , Pichia , Proteínas Recombinantes de Fusão , Aminoacridinas , Proteínas de Bactérias , Bioensaio , Channelrhodopsins/química , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Chlamydomonas reinhardtii , Fluorescência , Corantes Fluorescentes , Proteínas Luminescentes , Pichia/efeitos dos fármacos , Pichia/genética , Pichia/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Vitamina A/farmacologia
16.
Arthritis Rheumatol ; 70(11): 1807-1819, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29781188

RESUMO

OBJECTIVE: Type I interferon (IFN) is strongly implicated in the pathogenesis of systemic lupus erythematosus (SLE) as well as rare monogenic interferonopathies such as Aicardi-Goutières syndrome (AGS), a disease attributed to mutations in the DNA exonuclease TREX1. The DNA-activated type I IFN pathway cyclic GMP-AMP (cGAMP) synthase (cGAS) is linked to subsets of AGS and lupus. This study was undertaken to identify inhibitors of the DNA-cGAS interaction, and to test the lead candidate drug, X6, in a mouse model of AGS. METHODS: Trex1-/- mice were treated orally from birth with either X6 or hydroxychloroquine (HCQ) for 8 weeks. Expression of IFN-stimulated genes (ISGs) was quantified by quantitative polymerase chain reaction. Multiple reaction monitoring by ultra-performance liquid chromatography coupled with tandem mass spectrometry was used to quantify the production of cGAMP and X6 drug concentrations in the serum and heart tissue of Trex1-/- mice. RESULTS: On the basis of the efficacy-to-toxicity ratio established in vitro, drug X6 was selected as the lead candidate for treatment of Trex1-/- mice. X6 was significantly more effective than HCQ in attenuating ISG expression in mouse spleens (P < 0.01 for Isg15 and Isg20) and hearts (P < 0.05 for Isg15, Mx1, and Ifnb, and P < 0.01 for Cxcl10), and in reducing the production of cGAMP in mouse heart tissue (P < 0.05), thus demonstrating target engagement by the X6 compound. Of note, X6 was also more effective than HCQ in reducing ISG expression in vitro (P < 0.05 for IFI27 and MX1, and P < 0.01 for IFI44L and PKR) in human peripheral blood mononuclear cells from patients with SLE. CONCLUSION: This study demonstrates that X6 is superior to HCQ for the treatment of an experimental autoimmune myocarditis mediated in vivo by the cGAS/stimulator of IFN genes (cGAS/STING) pathway. The findings suggest that drug X6 could be developed as a novel treatment for AGS and/or lupus to inhibit activation of the cGAS/STING pathway.


Assuntos
Aminoacridinas/farmacologia , Antimaláricos/farmacologia , Exodesoxirribonucleases/genética , Coração/efeitos dos fármacos , Interferon beta/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Nucleotidiltransferases/efeitos dos fármacos , Fosfoproteínas/genética , Animais , Quimiocina CXCL10/efeitos dos fármacos , Quimiocina CXCL10/genética , Cromatografia Líquida , Citocinas/efeitos dos fármacos , Citocinas/genética , Humanos , Hidroxicloroquina/farmacologia , Técnicas In Vitro , Interferon beta/genética , Interferon beta/metabolismo , Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico , Camundongos , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia , Proteínas de Resistência a Myxovirus/efeitos dos fármacos , Proteínas de Resistência a Myxovirus/genética , Nucleotidiltransferases/antagonistas & inibidores , Nucleotidiltransferases/genética , Tamanho do Órgão , Reação em Cadeia da Polimerase , Baço/efeitos dos fármacos , Baço/patologia , Espectrometria de Massas em Tandem , Ubiquitinas/efeitos dos fármacos , Ubiquitinas/genética
17.
Pharmacol Rep ; 70(3): 470-475, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29649683

RESUMO

BACKGROUND: Among the studied antitumor acridinone derivatives developed in our laboratory, 5-dimethylaminopropylamino-8-hydroxytriazoloacridinone (C-1305) and 5-diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311) exhibited cytotoxic and antitumor properties against several cancer types and were selected to be evaluated in preclinical and early-phase clinical trials. In the present work, we investigated the impact of C-1305 and C-1311 on UDP-glucuronosyltransferase (UGT) activity. METHODS: Enzyme activity modulation was studied using HPLC by analyzing standard UGT substrate metabolism in the presence and absence of antitumor drugs. The investigations were performed in two model systems: (i) under noncellular conditions, including human liver microsomes (HLM) and recombinant UGT1A1, 1A9 and 1A10 isoenzymes and (ii) in tumor cells. RESULTS: There was observed a slight impact of studied drugs on enzyme activity. Only UGT1A1 action was altered by both compounds. The modulatory effects of UGT activity in cellular systems depended on the tumor cell type. In the case of HepG2, C-1305 and C-1311 strongly induced UGT activity, particularly for C-1311, at concentrations significantly lower than the EC50. This effect contradicted irinotecan mediated UGT inhibition. HT29 colon tumor cells were less sensitive than HepG2 to enzyme modulation in the presence of the studied compounds, particularly C-1305, where enzymatic inhibition similar to that of irinotecan was observed. CONCLUSIONS: The results demonstrated that UGT activity modulation should be expected in the case of antitumor therapy with C-1305 or/and C-1311. Analysis of the results indicated that these modulations would occur via cellular regulatory pathways not by direct drug-enzyme interactions.


Assuntos
Acridinas/farmacologia , Aminoacridinas/farmacologia , Antineoplásicos/farmacologia , Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Triazóis/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Linhagem Celular Tumoral , Células HT29 , Células Hep G2 , Humanos , Irinotecano , Isoenzimas/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo
18.
Molecules ; 23(3)2018 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-29534488

RESUMO

Symptomatic treatment of myasthenia gravis is based on the use of peripherally-acting acetylcholinesterase (AChE) inhibitors that, in some cases, must be discontinued due to the occurrence of a number of side-effects. Thus, new AChE inhibitors are being developed and investigated for their potential use against this disease. Here, we have explored two alternative approaches to get access to peripherally-acting AChE inhibitors as new agents against myasthenia gravis, by structural modification of the brain permeable anti-Alzheimer AChE inhibitors tacrine, 6-chlorotacrine, and huprine Y. Both quaternization upon methylation of the quinoline nitrogen atom, and tethering of a triazole ring, with, in some cases, the additional incorporation of a polyphenol-like moiety, result in more polar compounds with higher inhibitory activity against human AChE (up to 190-fold) and butyrylcholinesterase (up to 40-fold) than pyridostigmine, the standard drug for symptomatic treatment of myasthenia gravis. The novel compounds are furthermore devoid of brain permeability, thereby emerging as interesting leads against myasthenia gravis.


Assuntos
Acetilcolinesterase/metabolismo , Aminoacridinas/síntese química , Aminoquinolinas/síntese química , Inibidores da Colinesterase/síntese química , Acetilcolinesterase/química , Aminoacridinas/química , Aminoacridinas/farmacologia , Aminoquinolinas/química , Aminoquinolinas/farmacologia , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Regulação para Baixo , Proteínas Ligadas por GPI/química , Proteínas Ligadas por GPI/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Modelos Moleculares , Estrutura Molecular , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/enzimologia , Relação Estrutura-Atividade , Tacrina/química
19.
Intern Med ; 57(7): 1045-1048, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29269681

RESUMO

A 60-year-old man developed pneumonia after undergoing autologous peripheral blood stem cell transplantation for diffuse large-B cell lymphoma. A urinary antigen test and sputum culture were both negative for Legionella pneumophila; however, a sputum sample that was examined by loop-mediated isothermal amplification (LAMP) was positive for Legionella spp. On admission, the results of blood culturing using a BACTEC system were negative for 7 days. However, L. pneumophila serogroup 5 was detected in a blood subculture using WYOα medium. The patient was successfully treated with a fluoroquinolone-based regimen. LAMP is useful for the diagnosis of Legionella spp.


Assuntos
Bacteriemia/genética , Fluoroquinolonas/uso terapêutico , Legionella pneumophila/classificação , Doença dos Legionários/diagnóstico , Doença dos Legionários/tratamento farmacológico , Técnicas de Amplificação de Ácido Nucleico , Pneumonia/diagnóstico , Aminoacridinas , Humanos , Linfoma/terapia , Masculino , Pessoa de Meia-Idade , Neutropenia/diagnóstico , Neutropenia/microbiologia , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Pneumonia/diagnóstico por imagem , Pneumonia/microbiologia , Sorogrupo , Escarro/microbiologia , Resultado do Tratamento
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