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1.
Nat Prod Res ; 34(2): 261-268, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30580613

RESUMO

A new [7.7]paracyclophane (1), together with eight known compounds (2-9), were isolated from a MeOH extract of the sea snail Planaxis sulcatus (Born, 1780). Their structures were elucidated by HR-ESI-MS and NMR techniques as well as comparison with those reported in literatures. The absolute configuration of metabolite 1 was determined using ECD spectroscopy. Among nine compounds, 1 exhibited significant cytotoxicity toward all eight cancer cells tested with IC50 values between 1.81 and 3.80 µg/mL.[Figure: see text].


Assuntos
Hidrocarbonetos Aromáticos com Pontes/isolamento & purificação , Citotoxinas/isolamento & purificação , Caramujos/química , Animais , Organismos Aquáticos , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Linhagem Celular Tumoral , Citotoxinas/farmacologia , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética/métodos , Estrutura Molecular , Caramujos/patogenicidade , Vietnã
2.
Toxicol Lett ; 320: 64-72, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31794810

RESUMO

Oxime-based acetylcholinesterase reactivators (briefly oximes) regenerate organophosphate-inactivated acetylcholinesterase and restore its function. Poor blood-brain-barrier passage and fast elimination from blood limit their actual use in treatment of patients exposed to organophosphates. Previous in vitro results implicated further testing of cucurbit[7]uril as a delivery vehicle for bisquaternary oximes. The present paper focuses on cell toxicity, in vivo safety and influence of cucurbit[7]uril on oxime pharmacokinetics and pharmacodynamics. Neither the K027 nor the complex caused any cell toxicity, changes in blood biochemistry or hepato- or nephrotoxicity in tested concentrations. The encapsulation of K027 increased and accelerated the blood-brain-barrier penetration. The peripheral oxime exposure also increased, supporting the suggestion that cucurbit[7]uril protects the circulating oxime from rapid renal clearance. Contrary to the comparable in vitro reactivation power of K027 and the encapsulated K027, we failed to confirm this in vivo. In theory, this might result from the non-specific binding of molecules to the cucurbit[7]uril or the interaction of K027 with cucurbit[7]uril being too strong for acetylcholinesterase reactivation. Precise explanation requires additional in silico, in vitro and also in vivo experiments.


Assuntos
Acetilcolinesterase/sangue , Acetilcolinesterase/metabolismo , Encéfalo/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/farmacocinética , Reativadores da Colinesterase/farmacocinética , Eritrócitos/efeitos dos fármacos , Imidazóis/farmacocinética , Oximas/farmacocinética , Compostos de Piridínio/farmacocinética , Células A549 , Animais , Encéfalo/enzimologia , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Reativadores da Colinesterase/administração & dosagem , Reativadores da Colinesterase/toxicidade , Relação Dose-Resposta a Droga , Eritrócitos/enzimologia , Feminino , Proteínas Ligadas por GPI/sangue , Proteínas Ligadas por GPI/metabolismo , Células Hep G2 , Humanos , Imidazóis/administração & dosagem , Imidazóis/toxicidade , Injeções Intramusculares , Masculino , Dose Máxima Tolerável , Camundongos Endogâmicos ICR , Oximas/administração & dosagem , Oximas/toxicidade , Compostos de Piridínio/administração & dosagem , Compostos de Piridínio/toxicidade , Medição de Risco , Distribuição Tecidual
4.
Acta Crystallogr C Struct Chem ; 74(Pt 11): 1413-1419, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30398196

RESUMO

3,5-Bis[(1H-tetrazol-5-yl)methyl]-4H-1,2,4-triazol-4-amine (H2L) associates under deprotonation with CuSO4 in aqueous medium to form a new waisted barrel-shaped M6L4 cluster, namely hexaaquatetrakis{µ4-3,5-bis[(1H-tetrazol-5-yl)methyl]-4H-1,2,4-triazol-4-amine}-µ4-sulfato-hexacopper(II) sulfate hydrate, [Cu6(SO4)(C6H6N12)4(H2O)6]SO4·nH2O (n = ∼23) (1). Cluster 1 resembles concave cucurbit[6]uril and has one disordered sulfate anion trapped inside the cage, which additionally stabilizes the Cu6 unit. The CuII ions have either a square-pyramidal or a distorted octahedral geometry. The equatorial positions are filled by N atoms from the L2- ligand, while the axial positions are occupied by coordinated water molecules and O atoms of the sulfate counter-ion. In the solid state, the Cu6 clusters are connected through a large number of hydrogen bonds formed by uncoordinated water molecules and an additional sulfate anion. The compound shows good antimicrobial activity against E. coli tested with the Kirby Bauer approach. In addition, the cell viability towards HeLa and L-929 cells was studied.


Assuntos
Antibacterianos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Complexos de Coordenação/farmacologia , Tetrazóis/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/toxicidade , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Cobre/química , Cristalografia por Raios X , Escherichia coli/efeitos dos fármacos , Células HeLa , Humanos , Ligação de Hidrogênio , Ligantes , Camundongos , Estrutura Molecular , Tetrazóis/síntese química , Tetrazóis/química , Tetrazóis/toxicidade , Água/química
8.
Cancer Treat Res Commun ; 15: 1-6, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30207281

RESUMO

MICROABSTRACT: Women treated with chest radiation for Hodgkin lymphoma (HL) have significantly higher risk of developing breast cancer, and little is known about how these patients tolerate chemotherapy for breast cancer. This small retrospective study identified 15 patients, noting that these patients tolerate proposed chemotherapy regimens for breast cancer in rates similar to those without prior HL and therapeutic radiation. PURPOSE: Women treated for Hodgkin lymphoma (HL) with chest radiation have significantly higher risk of developing breast cancer, and little is known about how these patients tolerate chemotherapy for breast cancer. METHODS: Women with breast cancer diagnosed from 1986-2015 after radiation for HL were identified from hospitals and clinics in St. Paul and Minneapolis, Minnesota. Patient, tumor and treatment characteristics, and clinical outcomes were abstracted from medical records and summarized using descriptive statistics. Chemotherapy was defined as tolerated if all scheduled doses and cycles were completed without deviation from the initial plan, with lack of grade 3 or higher toxicity attributable to chemotherapy in categories including blood, cardiac, gastrointestinal, fatigue and pain. RESULTS: Forty-two patients with breast cancer and prior radiation for HL were identified, 15 of which received chemotherapy for breast cancer. We noted 75% tolerability of taxane-based and 100% tolerability of anthracycline-based chemotherapy, suggesting that most patients with prior radiation for HL tolerate chemotherapy for breast cancer. A subset of patients (N = 7) in this study were also treated with chemotherapy for HL prior to breast cancer diagnosis, and 86% (6 of 7) also tolerated chemotherapy for breast cancer. CONCLUSIONS: Treatment of breast cancer is strongly influenced by prior treatment of HL. Although this study was small and did not meet statistical significance, the data suggest that these patients tolerate proposed chemotherapy regimens for breast cancer in rates similar to those without prior HL and therapeutic radiation. Larger studies comparing specific chemotherapy dosing schedules are needed to address this complicated population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Neoplasias da Mama/tratamento farmacológico , Doença de Hodgkin/radioterapia , Neoplasias Induzidas por Radiação/tratamento farmacológico , Segunda Neoplasia Primária/tratamento farmacológico , Adulto , Antraciclinas/administração & dosagem , Antraciclinas/uso terapêutico , Antraciclinas/toxicidade , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Neoplasias da Mama/etiologia , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Sobreviventes de Câncer/estatística & dados numéricos , Estudos de Coortes , Feminino , Humanos , Minnesota , Neoplasias Induzidas por Radiação/etiologia , Segunda Neoplasia Primária/etiologia , Projetos Piloto , Radioterapia/efeitos adversos , Estudos Retrospectivos , Taxoides/administração & dosagem , Taxoides/uso terapêutico , Taxoides/toxicidade
10.
Chem Commun (Camb) ; 54(31): 3851-3854, 2018 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-29594291

RESUMO

An efficient surface modification for upconversion nanoparticles (UCNPs) is reported via supramolecular host-guest self-assembly. Cucurbit[7]uril (CB) can provide a hydrophilic surface and cavities for most biomolecules. High biological efficiency, activity and versatility of the approach enable UCNPs to be significantly applied in bio-imaging, early disease detection, and bio-sensing.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Imidazóis/química , Nanopartículas Metálicas/química , Adamantano/análogos & derivados , Adamantano/química , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Caderinas/química , Európio/química , Fluoretos/química , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Imidazóis/toxicidade , Imunoglobulina G/química , Ligantes , Nanopartículas Metálicas/toxicidade , Tamanho da Partícula , Itérbio/química , Ítrio/química
11.
Biomater Sci ; 6(5): 1031-1039, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29557458

RESUMO

Due to its outstanding capability to facilitate DNA condensation, transportation and endosomal escape, polyethylenimine (PEI) has been frequently studied for gene delivery. However, its molecular weight (M.W.) dependent transfection efficiency and cytotoxicity has severely limited its clinical application. To resolve this dilemma, a supramolecular strategy was developed for the first time, in which PEI with large M.W. (branched, 25 kDa) that has a satisfactory transfection efficiency, yet high non-specific cytotoxicity for gene delivery was wrapped with macrocyclic cucurbit[7]uril (CB[7]). The successful wrapping of the PEI by the macrocyclic CB[7] was proved by 1H NMR spectroscopy and supported by isothermal titration calorimetry (ITC). The plasmid DNA (pDNA) condensability of PEI was not affected by the supramolecular coating as evidenced from the agarose gel electrophoresis assay. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) results demonstrated that the particle size, zeta potential, and morphology of the self-assemblies of PEI/pDNA and PEI/CB[7]/pDNA were comparable. As a consequence of the supramolecular wrapping, the cytotoxicity of PEI was significantly constrained as demonstrated by MTT assay, apoptosis assay, and a hemolysis study. In particular, both the cellular uptake and the gene transfection efficiency results suggest that the supramolecular wrapping of PEI by CB[7] exhibits negligible effects on PEI, thus functioning as an effective non-viral gene delivery vector. This novel supramolecular-wrapping strategy provides new insights for facile alleviation of the non-specific toxicity of PEI and potentially other polycationic gene vectors without compromising their transfection efficiency.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Imidazóis/química , Polietilenoimina/química , Transfecção/métodos , Apoptose/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Linhagem Celular Tumoral , Células HEK293 , Hemólise/efeitos dos fármacos , Humanos , Imidazóis/toxicidade , Plasmídeos/genética , Polietilenoimina/toxicidade
12.
Epilepsia ; 59 Suppl 2: 220-227, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29453777

RESUMO

Allopregnanolone (5α-pregnan-3α-ol-20-one) and its synthetic 3ß-methyl analog, ganaxolone, are positive allosteric modulators of synaptic and extrasynaptic γ-aminobutyric acid (GABA)A receptors that exhibit antiseizure activity in diverse animal seizure models, including models of status epilepticus (SE). The 2 neuroactive steroids are being investigated as treatments for SE, including as a treatment for SE induced by chemical threat agents. Intramuscular injection is the preferred route of administration in the prehospital treatment of SE. The objective of this study was to assess the efficacy of intramuscular allopregnanolone and ganaxolone in the treatment of SE induced by the chemical threat agent tetramethylenedisulfotetramine (TETS). The test agents were administered 40 minutes after the onset of SE when mice are refractory to treatment. Allopregnanolone and ganaxolone (each at 3 mg/kg) terminated SE in, respectively, 92% and 75% of animals, and prevented mortality in 85% and 50% of animals; the mean times to termination of behavioral seizures were, respectively, 172 ± 16 and 447 ± 52 seconds. In a separate series of experiments, mice were dosed with the neuroactive steroids by intramuscular injection, and plasma and brain levels were sampled at various time points following injection to estimate pharmacokinetic parameters. Plasma Cmax (maximum concentration) values for allopregnanolone and ganaxolone were 645 and 550 ng/mL, respectively. Brain exposure of both steroids was approximately 3-fold the plasma exposure. Two-compartment pharmacokinetic analysis revealed that the central compartment Vd (volume of distribution), CL (clearance), t½ (terminal half-life), and F (intramuscular bioavailability) values for allopregnanolone and ganaxolone were, respectively, 4.95 L/kg 12.88 L/kg/h,16 minutes, 97%, and 5.07 L/kg, 8.35 L/kg/h, 25 minutes, 95%. Allopregnanolone and ganaxolone are effective in the treatment of TETS-induced SE when administered by the intramuscular route. Allopregnanolone is more rapidly acting and modestly more effective, possibly because it has greater potency on GABAA receptors.


Assuntos
Anticonvulsivantes/administração & dosagem , Injeções Intramusculares/métodos , Pregnanolona/análogos & derivados , Pregnanolona/administração & dosagem , Estado Epiléptico/tratamento farmacológico , Animais , Anticonvulsivantes/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Convulsivantes/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estudos Longitudinais , Masculino , Camundongos , Pregnanolona/farmacocinética , Estado Epiléptico/etiologia , Fatores de Tempo
13.
Dev Neurobiol ; 78(4): 403-416, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29411537

RESUMO

Tetramethylenedisulfotetramine (TMDT) is a synthetic neurotoxic rodenticide considered a chemical threat agent. Symptoms of intoxication include seizures leading to status epilepticus and death. While children and women have been often the victims, no studies exist investigating the neurotoxic effects of TMDT in developing individuals or females. Thus, we performed such an investigation in developing Sprague-Dawley rats of both sexes in order to identify potential age- or sex-dependent vulnerability to TMDT exposure. Subcutaneous injection was chosen as the preferred route of TMDT exposure. EEG recordings confirmed the seizure activity observed in both postnatal day 15 (P15) and adult rats. Additionally, P15 rats displayed greater sensitivity to TMDT than postnanatal day 25 or adult animals. Seizures were generally more severe in females compared to males. Barrel rotations accompanied convulsions in P25 and adult, but sparsely in P15 rats. Adults developed barrel rolling less frequently than P25 population. Neuronal cell death was not present in 24-h TMDT survivors at any age or sex tested. A seizure rechallenge with flurothyl 7 days following TMDT exposure demonstrated longer latencies to the first clonic seizure but a faster progression into the tonic-clonic seizure in P15 and adult survivors as compared to their vehicle-injected counterparts. In conclusion, the youngest age group represents the most vulnerable population to the TMDT-induced toxidrome. Females appear to be more vulnerable than males. TMDT exposure promotes seizure spread and progression in survivors. These findings will help to establish sex- and age-specific treatment strategies for TMDT-exposed individuals. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 403-416, 2018.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/fisiopatologia , Caracteres Sexuais , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Morte Celular , Relação Dose-Resposta a Droga , Eletroencefalografia , Feminino , Ácido Caínico , Masculino , Degeneração Neural/etiologia , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Neurônios/patologia , Neurônios/fisiologia , Síndromes Neurotóxicas/patologia , Distribuição Aleatória , Ratos Sprague-Dawley , Convulsões/etiologia , Convulsões/patologia , Convulsões/fisiopatologia
14.
Neurotoxicology ; 63: 21-32, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28855111

RESUMO

Tetramethylenedisulfotetramine (tetramine, or TETS) is a highly toxic rodenticide that has been responsible for over 14,000 accidental and intentional poisonings worldwide. Although the vast majority of TETS poisonings involved tainted food or drink, the laboratory in vivo studies of TETS intoxication used intraperitoneal injection or gavage for TETS exposure. Seeking to develop and characterize a more realistic model of TETS intoxication in the present study, rats were trained to rapidly and voluntarily consume a poisoned food morsel. Initially, the overt toxic effects of TETS consumption across a large range of doses were characterized, then a focused range of doses was selected for more intensive behavioral evaluation (in operant test chambers providing a variable-interval schedule of food reinforcement). The onset of intoxication following voluntary oral consumption of TETS was rapid, and clear dose-dependent response-rate suppression was observed across multiple performance measures within the operant-chamber environment. At most doses, recovery of operant performance did not occur within 30h. Food consumption and body weight changes were also dose dependent and corroborated the behavioral measures of intoxication. This voluntary oral-poisoning method with concomitant operant-behavioral assessment shows promise for future studies of TETS (and other toxic chemicals of interest) and may be extremely valuable in characterizing treatment outcomes.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/toxicidade , Condicionamento Operante/efeitos dos fármacos , Transtornos Mentais/induzido quimicamente , Neurotoxinas/toxicidade , Administração Oral , Animais , Escala de Avaliação Comportamental , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Alimentar/efeitos dos fármacos , Dose Letal Mediana , Masculino , Transtornos Mentais/mortalidade , Ratos , Ratos Sprague-Dawley , Esquema de Reforço , Estatísticas não Paramétricas , Fatores de Tempo
15.
Chem Commun (Camb) ; 53(62): 8739-8742, 2017 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-28726866

RESUMO

An acyclic cucurbit[n]uril (CB[n]) conjugated dextran is developed as a new biomaterial for drug delivery and bioimaging. This biomaterial retains the host-guest recognition properties of acyclic CB[n]s. It is able to directly encapsulate anti-tumor drugs 5-fluorouracil and temozolomide. This polymeric material can form a supramolecular assembly with polyethyleneimine (PEI). Although there is no conventional chromophore in these supramolecular systems, they exhibit aggregation-induced emission (AIE) in water with a quantum yield of 10%. This supramolecular assembly is used for bioimaging in vitro with good biocompatibility.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Dextranos/química , Portadores de Fármacos/química , Imidazóis/química , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Dacarbazina/análogos & derivados , Dacarbazina/química , Dextranos/síntese química , Dextranos/toxicidade , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Etilenodiaminas/química , Fluoruracila/química , Células HeLa , Humanos , Imidazóis/síntese química , Imidazóis/toxicidade , Substâncias Luminescentes/síntese química , Substâncias Luminescentes/química , Substâncias Luminescentes/toxicidade , Microscopia Confocal , Nanopartículas/química , Nanopartículas/toxicidade , Tamanho da Partícula , Polietilenoimina/química , Temozolomida
16.
Food Chem Toxicol ; 108(Pt B): 510-518, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28082230

RESUMO

Hemimethyl-substituted cucurbit[7]uril (HMeCB[7]), a derivative of cucurbit[7]uril (CB[7]) with nearly identical host-guest complexation properties to that of the parent, has significant potential in biomedical sciences due to its superior solubility in water. Its toxicity profile has been investigated in this work, including its developmental and organ-specific toxicities, with both in vivo zebrafish models and a relevant in vitro cellular model. These results demonstrated that HMeCB[7] has negligible developmental toxicity at concentrations up to 3.2 mM and very moderate cardiotoxicity and hepatotoxicity at concentrations of ≥0.8 mM, and is thus generally less toxic than the parent CB[7]. Our results suggest that HMeCB[7] may be a promising candidate of excipient in medicinal and pharmaceutical research fields.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Imidazóis/química , Imidazóis/toxicidade , Animais , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas , Embrião não Mamífero/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/embriologia , Hepatócitos/efeitos dos fármacos , Humanos , Modelos Moleculares , Estereoisomerismo , Peixe-Zebra/embriologia
17.
Brain Imaging Behav ; 11(6): 1652-1663, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27766586

RESUMO

Women with ovarian cancer often undergo chemotherapy involving multiple agents. However, little is known about treatment-related central neurotoxicity in this population. The goal of this cross-sectional study was to assess brain structure and function and neurocognitive abilities in patients with ovarian cancer following first-line chemotherapy. Eighteen patients with ovarian, peritoneal and fallopian tube cancer and eighteen healthy controls matched for gender, age and education participated in the study. The patients were evaluated 1-4 months following completion of first-line taxane/platinum chemotherapy. All participants underwent structural and functional magnetic resonance imaging (MRI), and completed neuropsychological tests of attention, memory and executive functions. Neuroimaging assessments included voxel-based morphometry (VBM) for measuring gray matter (GM) volume, and functional MRI (fMRI) during the N-back working memory task. The results of VBM showed that patients had significantly reduced GM volume compared to healthy controls in the right middle/superior frontal gyrus, and in the left supramarginal gyrus and left inferior parietal lobule. fMRI results indicated significantly decreased activation in patients relative to healthy controls in the left middle frontal gyrus and left inferior parietal lobule during the N-back task (1/2/3-back >0-back). There were no statistically significant differences between the two groups on the neuropsychological tests. This is the first study showing structural and functional alterations involving frontal and parietal regions in patients with ovarian cancer treated with first-line chemotherapy. These findings are congruent with studies involving women with breast cancer, and provide additional supporting evidence for central neurotoxicity associated with taxane/platinum chemotherapy.


Assuntos
Antineoplásicos/toxicidade , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Mapeamento Encefálico , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Estudos de Coortes , Estudos Transversais , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/efeitos dos fármacos , Substância Cinzenta/patologia , Substância Cinzenta/fisiopatologia , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Memória de Curto Prazo/fisiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tamanho do Órgão , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/fisiopatologia , Neoplasias Ovarianas/psicologia , Projetos Piloto , Compostos de Platina/uso terapêutico , Compostos de Platina/toxicidade , Dados Preliminares , Taxoides/uso terapêutico , Taxoides/toxicidade
18.
Curr Alzheimer Res ; 14(3): 317-326, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27784218

RESUMO

BACKGROUND: Alzheimer´s disease, a progressive and degenerative disorder of the brain, is the most common cause of dementia among the elderly. To face its multifactorial nature, the use of single compounds that can simultaneously modulate different targets involved in the neurodegenerative cascade has emerged as an interesting therapeutic approach. OBJECTIVE: This work investigated the ability of uleine, the major indole alkaloid purified from stem barks of the Brazilian medicinal plant Himatanthus lancifolius, to interact with crucial Alzheimer´s disease disruptive targets associated with two of its major neurodegenerative pathways: acetylcholinesterase and butyrylcholinesterase (cholinergic pathway) and ß-secretase and ß-amyloid peptide (amyloidogenic pathway). METHODS: Uleine's capacity to inhibit human acetylcholinesterase and butyrylcholinesterase enzymes was determined measuring the difference between reaction rates with and without uleine monitored at 412 nm using 5,5'- dithiobis-(2- nitrobenzoic acid) as colorimetric agent. FRET based assay was used to evaluate ß-secretase inhibition using DABCYL- Ser-Glu-Val-Asn-Leu-Asp-Ala-Glu-Phe-EDANS as substrate and ß-amyloid peptide spontaneous aggregation assay was performed using the thioflavin T spectroscopy assay. Cell viability and toxicity experiments with PC12 and SH-SY5Y cell lines were performed using the MTT colorimetric assay. RESULTS: Uleine demonstrated strong inhibitory activities for both cholinesterases (IC50 279.0±4.5 and 24.0±1.5 µM, respectively) and ß-secretase (IC50 180±22 nM). Above all, uleine significantly inhibited the self-aggregation of amyloid- ß peptide and was not toxic for PC12 or SH-SY5Y neuronal cells. CONCLUSION: These data show for the first time that the natural compound uleine has a novel, multieffective ability to decelerate or even inhibit the development of Alzheimer´s disease.


Assuntos
Alcaloides/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Alcaloides/toxicidade , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Biomarcadores/metabolismo , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/toxicidade , Células HEK293 , Humanos , Fármacos Neuroprotetores/toxicidade , Casca de Planta/química , Extratos Vegetais/farmacologia , Extratos Vegetais/toxicidade , Agregação Patológica de Proteínas/tratamento farmacológico , Agregação Patológica de Proteínas/metabolismo , Ratos
19.
Sci Rep ; 6: 37003, 2016 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-27841317

RESUMO

To better address the problem of drug resistance during cancer chemotherapy and explore the possibility of manipulating drug response phenotypes, we developed a network-based phenotype mapping approach (P-Map) to identify gene candidates that upon perturbed can alter sensitivity to drugs. We used basal transcriptomics data from a panel of human lymphoblastoid cell lines (LCL) to infer drug response networks (DRNs) that are responsible for conferring response phenotypes for anthracycline and taxane, two common anticancer agents use in clinics. We further tested selected gene candidates that interact with phenotypic differentially expressed genes (PDEGs), which are up-regulated genes in LCL for a given class of drug response phenotype in triple-negative breast cancer (TNBC) cells. Our results indicate that it is possible to manipulate a drug response phenotype, from resistant to sensitive or vice versa, by perturbing gene candidates in DRNs and suggest plausible mechanisms regulating directionality of drug response sensitivity. More important, the current work highlights a new way to formulate systems-based therapeutic design: supplementing therapeutics that aim to target disease culprits with phenotypic modulators capable of altering DRN properties with the goal to re-sensitize resistant phenotypes.


Assuntos
Antineoplásicos/toxicidade , Resistencia a Medicamentos Antineoplásicos/genética , Redes Reguladoras de Genes/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Algoritmos , Antraciclinas/toxicidade , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Linhagem Celular Tumoral , Humanos , Núcleosídeo-Difosfato Quinase/genética , Núcleosídeo-Difosfato Quinase/metabolismo , Fenótipo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/metabolismo , Taxoides/toxicidade
20.
Ann N Y Acad Sci ; 1378(1): 124-136, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27467073

RESUMO

Exposures to seizure-inducing chemical threat agents are a major public health concern. Of particular need is improved treatment to terminate convulsions and to prevent the long-term neurological sequelae in survivors. We are studying the organophosphorus cholinesterase inhibitor diisopropyl fluorophosphate (DFP) and the GABA receptor inhibitor tetramethylenedisulfotetramine (TETS), which arguably encompass the mechanistic spectrum of seizure-inducing chemical threats, with the goal of identifying therapeutic approaches with broad-spectrum efficacy. Research efforts have focused on developing translational models and translational diagnostic approaches, including (1) in vivo models of DFP- and TETS-induced seizures for studying neuropathological mechanisms and identifying treatment approaches; (2) in vivo imaging modalities for noninvasive longitudinal monitoring of neurological damage and response to therapeutic candidates; and (3) higher-throughput in vitro platforms for rapid screening of compounds to identify potential antiseizure and neuroprotective agents, as well as mechanistically relevant novel drug targets. This review summarizes our progress toward realizing these goals and discusses best practices and mechanistic insights derived from our modeling efforts.


Assuntos
Anticonvulsivantes/uso terapêutico , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Inibidores da Colinesterase/toxicidade , Isoflurofato/toxicidade , Convulsões/induzido quimicamente , Convulsões/terapia , Animais , Anticonvulsivantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Intoxicação por Organofosfatos/metabolismo , Intoxicação por Organofosfatos/terapia , Convulsões/metabolismo , Resultado do Tratamento
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