RESUMO
Narrow-band resonances supported by a variety of periodic metallic or dielectric nanostructures have great potential applications in light sources, optical sensors, and switches or modulators. Here we report the switching of narrow-band lattice resonances in a mirror-backed two-dimensional array of dielectric nanopillars. The nanopillar is composed of a silica core and photochromic coating. By exposure to ultraviolet light, the photochromic molecules can be turned into a state that is highly absorptive around the wavelength of the lattice resonance. Because the lattice resonance has enhanced the near-fields concentrated on the tops of dielectric nanopillars, the absorptive coating can destroy this resonance. The absorptive state of the photochromic molecules can be recovered to a transparent state by exposure to visible light. We fabricate the device and characterize the change of reflection spectra to demonstrate the reversible switching of lattice resonances by exposure to ultraviolet and visible light alternately. An all-optical control of the narrow-band photoluminescence is further demonstrated by combining a fluorescent dye with the photochromic molecules.
RESUMO
BACKGROUND: Women are currently facing a tremendous threat of cervical cancer globally. Social media health campaigns have the potential to shape public health behaviors. This study explores the effects of cervical-cancer-related fear appeal messages with social cues on social media using the extended parallel processing model (EPPM). METHOD: We use a 2 (threat: present vs. absent) × 2 (efficacy: present vs. absent) × 2 (social cues: high vs. low) factorial experimental design to examine the effects of fear appeal messages with social cues on behavioral intention to receive the human papillomavirus (HPV) vaccination. RESULTS: There was a significant main effect of threat on the intention to receive HPV vaccination. Additionally, a significant three-way interactive effect among threat, efficacy, and social cues was detected. CONCLUSION: Women exposed to threat messages had a higher intention of HPV vaccination compared to those who were exposed to non-threat messages. Furthermore, with the low number of likes, women who were exposed to messages containing both threat and efficacy tended to have the highest intention of HPV vaccination. PRACTICE IMPLICATIONS: When conducting fear appeal campaigns on social media, the side effects of number of likes should be recognized. For vaccination promotion campaigns, the efficacy information should be more specific and audience-centered.
Assuntos
Infecções por Papillomavirus , Vacinas contra Papillomavirus , Mídias Sociais , Sinais (Psicologia) , Feminino , Humanos , Intenção , Infecções por Papillomavirus/prevenção & controle , Comunicação Persuasiva , VacinaçãoRESUMO
BACKGROUND: This study was designed to examine whether severe aortic regurgitation will affect the pharmacodynamics (PD) and pharmacokinetics (PK) of cisatracurium during anesthetic induction. METHODS: A total of 32 patients were divided into two groups: the AR group (n = 16) and the control group (n = 16). Arterial blood samples were drawn before and at 1, 2, 4, 6, 8, 10, 16 and 20 min after intravenous injection of 0.15 mg/kg cisatracurium. TOF tests were applied to determine the onset time of maximal muscle relaxation. The concentration of cisatracurium in plasma was determined by high-performance liquid chromatography. RESULTS: The onset time to maximal neuromuscular block was prolonged from 2.07 ± 0.08 min to 4.03 ± 0.14 min, which indicated that the PD responses to cisatracurium were significantly delayed in the AR group (P < 0.05) compared to the control group. A conventional two-compartment PK model showed a higher plasma concentration of cisatracurium among the AR group with markedly reduced intercompartment transfer rate (K12 = 0.19 ± 0.02 and K21 = 0.11 ± 0.01 in the AR group vs. K12=0.26 ± 0.01 and K21 = 0.19 ± 0.01 in the control group, P < 0.01) compared to the control group. CONCLUSION: Backward blood flow during diastole in severe AR impaired distribution of cisatracurium from the central compartment to the peripheral compartment, which accounted for the lagged PD responses. Findings in this study underlie the importance of muscular blockade monitoring among patients with severe aortic regurgitation during anesthetic induction. REGISTRATION: Name of the registry: Abnormal Cisatracurium Pharmacodynamics and Pharmacokinetics among Patients with Severe Aortic Regurgitation during Anesthetic Induction. TRIAL REGISTRATION NUMBER: ChiCTR1800019654. Date of registration: November 20th 2018.
Assuntos
Insuficiência da Valva Aórtica/fisiopatologia , Atracúrio/análogos & derivados , Bloqueadores Neuromusculares/farmacologia , Insuficiência da Valva Aórtica/sangue , Atracúrio/sangue , Atracúrio/farmacocinética , Atracúrio/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Bloqueadores Neuromusculares/sangue , Bloqueadores Neuromusculares/farmacocinéticaRESUMO
Chemical analysis of an Australian marine sediment-derived Aspergillus sp. (CMB-M081F) yielded the new diketomorpholine (DKM) shornephine A (1) together with two known and one new diketopiperazine (DKP), 15b-ß-hydroxy-5-N-acetyladreemin (2), 5-N-acetyladreemin (3), and 15b-ß-methoxy-5-N-acetyladreemin (4), respectively. Structure elucidation of 1-4 was achieved by detailed spectroscopic analysis, supported by chemical degradation and derivatization, and biosynthetic considerations. The DKM (1) underwent a facile (auto) acid-mediated methanolysis to yield seco-shornephine A methyl ester (1a). Our mechanistic explanation of this transformation prompted us to demonstrate that the acid-labile and solvolytically unstable DKM scaffold can be stabilized by N-alkylation. Furthermore, we demonstrate that at 20 µM shornephine A (1) is a noncytotoxic inhibitor of P-glycoprotein-mediated drug efflux in multidrug-resistant human colon cancer cells.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Dicetopiperazinas/química , Dicetopiperazinas/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Morfolinas/química , Morfolinas/farmacologia , Animais , Aspergillus , Austrália , Linhagem Celular Tumoral , Dicetopiperazinas/isolamento & purificação , Humanos , Biologia Marinha , Estrutura MolecularRESUMO
ATP binding cassette (ABC) transporters, such as P-gp, BCRP and MRP1, can increase efflux of clinical chemotherapeutic agents and lead to multi-drug resistance (MDR) in cancer cells. While the discovery and development of clinically useful inhibitors has proved elusive to date, this molecular target nevertheless remains a promising strategy for addressing and potentially overcoming MDR. In a search for new classes of inhibitor, we used fluorescent accumulation and efflux assays supported by cell flow cytometry and MDR reversal assays, against a panel of sensitive and MDR human cancer cell lines, to evaluate the marine sponge co-metabolites 1-12 as inhibitors of P-gp, BCRP or MRP1 initiated MDR. These studies identified and characterized lamellarin O (11) as a selective inhibitor of BCRP mediated drug efflux. A structure-activity relationship analysis inclusive of the natural products 1-12 and the synthetic analogues 13-19, supported by in silico docking studies, revealed key structural requirements for the lamellarin O (11) BCRP inhibitory pharmacophore.
Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Cumarínicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Isoquinolinas/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Poríferos/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/fisiologia , Animais , Austrália , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos , Fluoresceínas/metabolismo , Humanos , Mitoxantrona/metabolismo , Simulação de Acoplamento Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/fisiologia , Proteínas de Neoplasias/fisiologia , Relação Estrutura-AtividadeRESUMO
An extract of the Great Australian Bight marine sponge Callyspongia sp. (CMB-01152) displayed inhibitory activity against the neurodegenerative disease kinase targets casein kinase 1 (CK1), cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 (GSK3ß). Chemical investigation, employing HPLC-DAD-MS single ion extraction protocols, facilitated identification of the new bromopyrrole alkaloids, callyspongisines A-D (1-4), and two known co-metabolites, hymenialdisine (5) and 2-bromoaldisine (6). Structure elucidation of 1-6 was supported by detailed spectroscopic analysis and chemical interconversion, as well as biosynthetic and synthetic considerations. Callyspongisine A (1) is only the second reported example of a natural imino-oxazoline, and the first to feature a spiro heterocyclic framework, while callyspongisines B-D (2-4) were speculated to be storage and handling artefacts of 1. The kinase inhibitory activity detected in Callyspongia sp. (CMB-01152) was attributed to 5.
Assuntos
Callyspongia/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Animais , Austrália , Relação Dose-Resposta a Droga , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
High intrinsic or acquired expression of membrane spanning, adenosine triphosphate binding cassette (ABC) transporter proteins, such as P-glycoprotein (P-gp), in cancers represents a major impediment to chemotherapy, with accelerated drug efflux leading to multi-drug resistance (MDR). Although ABC transporter inhibitors offer the prospect of reversing the MDR phenotype, no inhibitors have advanced to the clinic. We employed a range of intracellular fluorescence and radio-ligand accumulation and efflux assays, together with cytotoxicity and MDR reversal assays, as well as flow cytometry, fluorescence microscopy and radioimmunoprecipitation, to discover and evaluate new P-gp inhibitors from a unique library of southern Australian and Antarctic marine natural products. This study successfully characterized two rare bromoditerpenes, parguerenes I and II, sourced from a southern Australian collection of the red alga Laurencia filiformis, as P-gp inhibitors. We determined that the parguerenes were non-cytotoxic, dose-dependent inhibitors of P-gp mediated drug efflux, that modify the extracellular antibody binding epitope of P-gp in a manner that differs markedly from that of the known inhibitors verapamil and cyclosporine A. We confirmed that parguerenes were capable of reversing P-gp mediated vinblastine, doxorubicin and paclitaxel MDR, that inhibitory properties span both P-gp and multidrug resistant protein 1 (MRP1), but do not extend to breast cancer resistance protein (BCRP), and that parguerene II is superior (more potent) to verapamil. Our investigations validate the proposition that marine natural products can deliver new ABC transporter inhibitor scaffolds, with structure characteristics fundamentally different from existing inhibitor classes.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Diterpenos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Laurencia/química , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Cisplatino/farmacologia , Diterpenos/química , Diterpenos/isolamento & purificação , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Fluoresceínas/metabolismo , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Paclitaxel/metabolismo , Vimblastina/farmacologiaRESUMO
Screening a library of Southern Australian and Antarctic marine invertebrates and algae for inhibitors of neurodegenerative disease kinase targets casein kinase 1 (CK1δ), cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3ß (GSK3ß) identified a Western Australian Didemnum species (CMB-02127) as a high-priority specimen. Chemical fractionation returned the known aromatic alkaloids ningalins B-D as the major metabolites, together with six minor metabolites, the new ningalins E-G and the known hexacyclic pyrrole alkaloids lamellarins Z, G and A6. All structures were assigned by detailed spectroscopic analysis and literature comparisons, and the structural assignments were supported by biosynthetic considerations. The ningalins showed potent and broad inhibition across the three kinases, while the lamellarins were generally more selective for CDK5. Docking studies using published X-ray crystal structures of CDK5 revealed both scaffolds target the ATP binding pocket.
Assuntos
Carbazóis/química , Catecóis/química , Cumarínicos/química , Inibidores de Proteínas Quinases/química , Pirróis/química , Urocordados/metabolismo , Animais , Austrália , Sítios de Ligação , Carbazóis/uso terapêutico , Carbazóis/toxicidade , Caseína Quinase Idelta/antagonistas & inibidores , Caseína Quinase Idelta/metabolismo , Catecóis/uso terapêutico , Catecóis/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Cumarínicos/uso terapêutico , Cumarínicos/toxicidade , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Quinase 5 Dependente de Ciclina/metabolismo , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Doenças Neurodegenerativas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/toxicidade , Estrutura Terciária de Proteína , Pirróis/uso terapêutico , Pirróis/toxicidade , Urocordados/químicaRESUMO
Chemical analysis of a Didemnum sp. (CMB-01656) collected during scientific Scuba operations off Wasp Island, New South Wales, yielded five new lamellarins A1 (1), A2 (2), A3 (3), A4 (4) and A5 (5) and eight known lamellarins C (6), E (7), K (8), M (9), S (10), T (11), X (12) and χ (13). Analysis of a second Didemnum sp. (CMB-02127) collected during scientific trawling operations along the Northern Rottnest Shelf, Western Australia, yielded the new lamellarin A6 (14) and two known lamellarins G (15) and Z (16). Structures were assigned to 1-16 on the basis of detailed spectroscopic analysis with comparison to literature data and authentic samples. Access to this unique library of natural lamellarins (1-16) provided a rare opportunity for structure-activity relationship (SAR) investigations, probing interactions between lamellarins and the ABC transporter efflux pump P-glycoprotein (P-gp) with a view to reversing multidrug resistance in a human colon cancer cell line (SW620 Ad300). These SAR studies, which were expanded to include the permethylated lamellarin derivative (17) and a series of lamellarin-inspired synthetic coumarins (19-24) and isoquinolines (25-26), successfully revealed 17 as a promising new non-cytotoxic P-gp inhibitor pharmacophore.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Alcaloides/química , Alcaloides/farmacologia , Neoplasias do Colo/tratamento farmacológico , Cumarínicos/química , Cumarínicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Urocordados/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Alcaloides/isolamento & purificação , Animais , Antineoplásicos/farmacologia , Austrália , Linhagem Celular Tumoral , Cumarínicos/isolamento & purificação , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/isolamento & purificação , Humanos , Isoquinolinas/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
Fractionation of a southern Australian marine sponge, Ianthella sp., yielded sixteen metabolites including a new class of pyrrolidone, ianthellidones A-F (1-6), a new class of furanone, ianthellidones G-H (7-8), new and known lamellarins, lamellarins O1 (9), O2 (10), O (11) and Q (12), plus the known 4-hydroxybenzaldehyde (13), 4-hydroxybenzoic acid (14), 4-methoxybenzoic acid (15) and ethyl 4-hydroxybenzoate (16). Structures for all Ianthella metabolites were determined by detailed spectroscopic analysis, supported by a plausible biosynthetic relationship. The ianthellidones were non-cytotoxic towards two human colon cancer cell lines (SW620 and SW620 Ad300), as well as Gram +ve and Gram -ve bacteria, and a fungus. Ianthellidone F (6) and lamellarins O2 (10) and O (11) displayed modest BACE inhibitory properties (IC(50) > 10 µM), while lamellarin O1 (9) was more potent (IC(50) < 10 µM). Lamellarin O (11) exhibited modest cytotoxicity towards SW620 and SW620 Ad300 cell lines (IC(50) > 22 µM), was an inhibitor of the multi-drug resistance efflux pump P-glycoprotein, and displayed selective growth inhibitory activity against the Gram +ve bacterium Bacillus subtilis (ATCC 6633) (IC(50) 2.5 µM).
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Furanos/química , Poríferos/química , Inibidores de Proteases/química , Pirróis/química , Pirrolidinonas/química , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Furanos/farmacologia , Humanos , Estrutura Molecular , Inibidores de Proteases/farmacologia , Pirróis/farmacologia , Pirrolidinonas/farmacologia , Relação Estrutura-AtividadeRESUMO
An Australian marine sediment-derived isolate, Nocardiopsis sp. (CMB-M0232), yielded a new class of prenylated diketopiperazine, indicative of the action of a uniquely regioselective diketopiperazine indole prenyltransferase. The bridged scaffold of nocardioazine A proved to be a noncytotoxic inhibitor of the membrane protein efflux pump P-glycoprotein, reversing doxorubicin resistance in a multidrug resistant colon cancer cell.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Actinomycetales/química , Dicetopiperazinas/isolamento & purificação , Dicetopiperazinas/farmacologia , Dimetilaliltranstransferase/metabolismo , Austrália , Dicetopiperazinas/química , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Biologia Marinha , Modelos MolecularesRESUMO
Multidrug resistance protein 7 (MRP7; ABCC10) is an ABC transporter that confers resistance to anticancer agents such as the taxanes. We previously reported that several inhibitors of P-gp and MRP1 were able to inhibit the in vitro transport of E(2)17betaG by MRP7 in membrane vesicles transport assays. However, compounds that are able to reverse MRP7-mediated cellular resistance have not been identified. In this study, we examined the effects of cepharanthine (6',12'-dimethoxy-2,2'-dimethyl-6,7-[methylenebis(oxy)]oxyacanthan), an herbal extract isolated from Stephania cepharantha Hayata, to reverse paclitaxel resistance in MRP7-transfected HEK293 cells. Cepharanthine, at 2microM, completely reversed paclitaxel resistance in MRP7-transfected cells. In contrast, the effect of cepharanthine on the parental transfected cells was significantly less than that on the MRP7-transfected cells. In addition, cepharanthine significantly increased the accumulation of paclitaxel in MRP7-transfected cells almost to the level of control cells in the absence of cepharanthine. The efflux of paclitaxel from MRP7-transfected cells was also significantly inhibited by cepharanthine. The ability of cepharanthine to inhibit MRP7 was analyzed in membrane vesicle assays using E(2)17betaG, an established substrate of MRP7, as a probe. E(2)17betaG transport was competitively inhibited by cepharanthine with a K(i) value of 4.86microM. These findings indicate that cepharanthine reverses MRP7-mediated resistance to paclitaxel in a competitive manner.
Assuntos
Benzilisoquinolinas/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/fisiologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/fisiologia , Antineoplásicos Fitogênicos/farmacologia , Benzilisoquinolinas/química , Transporte Biológico Ativo/efeitos dos fármacos , Transporte Biológico Ativo/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Paclitaxel/metabolismo , Paclitaxel/farmacologiaRESUMO
The transporter associated with antigen processing (TAP) and the major histocompatibility complex class I (MHC-I), two important components of the MHC-I antigen presentation pathway, are often deficient in tumor cells. The restoration of their expression has been shown to restore the antigenicity and immunogenicity of tumor cells. However, it is unclear whether TAP and MHC-I expression in tumor cells can affect the induction phase of the T cell response. To address this issue, we expressed viral antigens in tumors that are either deficient or proficient in TAP and MHC-I expression. The relative efficiency of direct immunization or immunization through cross-presentation in promoting adaptive T cell responses was compared. The results demonstrated that stimulation of animals with TAP and MHC-I proficient tumor cells generated antigen specific T cells with greater killing activities than those of TAP and MHC-I deficient tumor cells. This discrepancy was traced to differences in the ability of dendritic cells (DCs) to access and sample different antigen reservoirs in TAP and MHC-I proficient versus deficient cells and thereby stimulate adaptive immune responses through the process of cross-presentation. In addition, our data suggest that the increased activity of T cells is caused by the enhanced DC uptake and utilization of MHC-I/peptide complexes from the proficient cells as an additional source of processed antigen. Furthermore, we demonstrate that immune-escape and metastasis are promoted in the absence of this DC 'arming' mechanism. Physiologically, this novel form of DC antigen sampling resembles trogocytosis, and acts to enhance T cell priming and increase the efficacy of adaptive immune responses against tumors and infectious pathogens.
Assuntos
Células Dendríticas/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Infecções/imunologia , Complexo Principal de Histocompatibilidade , Neoplasias/imunologia , Linfócitos T/imunologia , Adaptação Biológica/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Apresentação Cruzada/imunologia , Raios gama , Antígenos de Histocompatibilidade Classe I/efeitos da radiação , Humanos , Camundongos , Linfócitos T/efeitos da radiação , Linfócitos T Citotóxicos/imunologiaRESUMO
To investigate the mechanism of cellular resistance to 6-MP, we established a 6-MP resistant cell line (CEM-MP5) by stepwise selection of the human T-lymphoblastic leukemia cell line (CEM). CEM-MP5 cells were about 100-fold resistant to 6-MP compared with parental CEM cells. Western blot analysis demonstrated that multidrug resistant protein 4 (MRP4) was increased in CEM-MP5 cells, whereas the levels of the nucleoside transporters hENT1, hCNT2 and hCNT3 were decreased compared with those of parental CEM cells. Consistent with the operation of an efflux pump, accumulation of [14C]6-MP and/or its metabolites was reduced, and ATP-dependent efflux was increased in CEM-MP5 cells. Taken together these results showed that up-regulation of MRP4 and down-regulation of influx transporters played a major role in 6-MP resistance of CEM-MP5 cells.