RESUMO
Hyaluronic acid (HA), a major component of skin extracellular matrix, provides an excellent framework for hemostatic design; however, there still lacks HA materials tailored with superior mechanical properties to address non-compressible hemorrhages. Here, we present a solvent-free thermal approach for constructing a shape-memory HA sponge for this application. Following facile thermal incubation around 130 °C, HA underwent cross-linking via esterification with poly(acrylic acid) within the sponge pre-shaped through a prior freeze-drying process. The resulting sponge system exhibited extensively interconnected macropores with a high fluid absorption capacity, excellent shape-memory property, and robust mechanical elasticity. When introduced to whole blood in vitro, the HA sponges demonstrated remarkable hemostatic properties, yielding a shorter coagulation time and lower blood clotting index compared to the commercial gelatin sponge (GS). Furthermore, in vivo hemostatic studies involving two non-compressible hemorrhage models (rat liver volume defect injury or femoral artery injury) achieved a significant reduction of approximately 64% (or 56%) and 73% (or 70%) in bleeding time and blood loss, respectively, which also outperformed GS. Additionally, comprehensive in vitro and in vivo evaluations suggested the good biocompatibility and biodegradability of HA sponges. This study highlights the substantial potential for utilizing the designed HA sponges in massive bleeding management.
Assuntos
Hemorragia , Ácido Hialurônico , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Animais , Hemorragia/tratamento farmacológico , Ratos , Hemostáticos/química , Hemostáticos/farmacologia , Temperatura , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Masculino , Porosidade , Ratos Sprague-DawleyRESUMO
Toll-like receptor (TLR) agonists can act as immune stimulants alone or as part of alum or oil formulations. Humoral and cellular immune responses were utilized to assess quantitative and qualitative immune response enhancement by TLR agonists using recombinant protective antigen (rPA) of B. anthracis as a model antigen. To rPA, combined with aluminum hydroxide (Alhydrogel; Al(OH)3) or squalene (AddaVax™), was added one of 7 TLR agonists: TLR2 agonist Pam3CysSK4 (PamS), TLR3 agonist double stranded polyinosinic:polycytidylic acid (PolyIC), TLR4 agonists Monophosphoryl lipid A (MPLA) or glucopyranosyl lipid A (GLA), TLR7-8 agonists 3M-052 or Resiquimod (Resiq), or TLR9 agonist CPG 7909 (CPG). CD-1 or BALB/c mice received two intraperitoneal or intramuscular immunizations 14 days apart, followed by serum or spleen sampling 14 days later. All TLR agonists except PamS induced high levels of B. anthracis lethal toxin-neutralizing antibodies and immunoglobulin G (IgG) anti-PA. Some responses were >100-fold higher than those without a TLR agonist, and IP delivery (0.5 mL) induced higher TLR-mediated antibody response increases compared to IM delivery (0.05 mL). TLR7-8 and TLR9 agonists induced profound shifts of IgG anti-PA response to IgG2a or IgG2b. Compared to the 14-day immunization schedule, use of a shortened immunization schedule of only 7 days between prime and boost found that TLR9 agonist CPG in a squalene formulation maintained higher interferon-γ-positive cells than TLR4 agonist GLA. Variability in antibody responses was lower in BALB/c mice than CD-1 mice but antibody responses were higher in CD-1 mice. Lower serum 50% effective concentration (EC50) values were found for rPA-agonist formulations and squalene formulations compared to Al(OH)3 formulations. Lower EC50 values also were associated with low frequency detection of linear peptide epitopes. In summary, TLR agonists elicited cellular immune responses and markedly boosted humoral responses.
Assuntos
Bacillus anthracis , Adjuvantes Imunológicos , Hidróxido de Alumínio , Animais , Antígenos , Imunoglobulina G , Camundongos , Camundongos Endogâmicos BALB C , Esqualeno , Receptor 2 Toll-Like , Receptor 4 Toll-Like/agonistas , Receptor 7 Toll-Like/agonistas , Receptor Toll-Like 9/agonistasRESUMO
Influenza hemagglutinin (HA) is considered a major protective antigen of seasonal influenza vaccine but antigenic drift of HA necessitates annual immunizations using new circulating HA versions. Low variation found within conserved non-HA influenza virus (INFV) antigens may maintain protection with less frequent immunizations. Conserved antigens of influenza A virus (INFV A) that can generate cross protection against multiple INFV strains were evaluated in BALB/c mice using modified Vaccinia virus Ankara (MVA)-vectored vaccines that expressed INFV A antigens hemagglutinin (HA), matrix protein 1 (M1), nucleoprotein (NP), matrix protein 2 (M2), repeats of the external portion of M2 (M2e) or as tandem repeats (METR), and M2e with transmembrane region and cytoplasmic loop (M2eTML). Protection by combinations of non-HA antigens was equivalent to that of subtype-matched HA. Combinations of NP and forms of M2e generated serum antibody responses and protected mice against lethal INFV A challenge using PR8, pandemic H1N1 A/Mexico/4108/2009 (pH1N1) or H5N1 A/Vietnam/1203/2004 (H5N1) viruses, as demonstrated by reduced lung viral burden and protection against weight loss. The highest levels of protection were obtained with NP and M2e antigens delivered as MVA inserts, resulting in broadly protective immunity in mice and enhancement of previous natural immunity to INFV A.
Assuntos
Anticorpos Antivirais/sangue , Vírus da Influenza A Subtipo H1N1/imunologia , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/imunologia , Proteínas do Nucleocapsídeo/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Proteínas da Matriz Viral/imunologia , Proteínas Viroporinas/imunologia , Animais , Antígenos Virais/imunologia , Proteção Cruzada , Feminino , Vetores Genéticos , Vírus da Influenza A Subtipo H1N1/patogenicidade , Virus da Influenza A Subtipo H5N1/patogenicidade , Vacinas contra Influenza/administração & dosagem , Camundongos Endogâmicos BALB C , Proteínas do Nucleocapsídeo/administração & dosagem , Infecções por Orthomyxoviridae/imunologia , Pandemias , Vacinação , Proteínas da Matriz Viral/administração & dosagem , Proteínas da Matriz Viral/genética , Proteínas Viroporinas/administração & dosagemRESUMO
With the rapid development of technology, information security has always been considered a major challenge. In this work, the excellent combination of persistent luminescence, photoluminescence, up-conversion luminescence, and thermo-luminescence in a particular material Zn4B6O13:Tb3+,Yb3+ synthesized via a solid-state reaction is reported, which can be used for the information encryption and anti-counterfeiting. Tb3+ ions were chosen as the emitting centers for multimodal emissions, and Yb3+ codoping can be used as electron traps and sensitizer to adjust trap distribution and efficient up-conversion luminescence in rare-earth-doped luminescent materials. Besides, the as-prepared luminescent materials exhibit high thermal stability and excellent water resistance. On the basis of these properties, the samples were used to print luminescent images through a screen printing process on the film and banknote. The luminescent image in a film is showing different patterns and on a banknote is showing green emissions under different stimulations. These multimodal emissions demonstrate that the as-prepared sample is suitable for advanced information encryption and anti-counterfeiting.
RESUMO
In this work, a layered melilite structure, CaLaAl3O7, was synthesized and observed to have obvious luminescence behaviors under the stimuli of ultraviolet light and rubbing, which were called photoluminescence and triboluminescence, respectively. Considering the wide bandgap of CaLaAl3O7 and its specific crystal structure, the observed luminescence should be attributed to intrinsic defects. Both the photoluminescence and triboluminescence of CaLaAl3O7 show a strong dependence on the synthesis atmosphere, suggesting that they should be related to the oxygen vacancy. It is attractive to find that the triboluminescence of CaLaAl3O7 shows a distinct spectral characteristic compared to its photoluminescence. Further computational results suggest that the applied mechanical stimuli on the CaLaAl3O7 cell could promote the formation of the vacancies of oxygen and calcium, responsible for the spectral differences.
RESUMO
Anticounterfeiting is a vitally important issue in modern society. At present, the most commonly used luminescent anticounterfeiting technique is based on static photoluminescence (PL), which is easily counterfeited by certain substitutes. In this work, we report for the first time a dynamic PL material, Na2CaGe2O6:Tb3+. Irradiated by a portable ultraviolet (254 nm) lamp, the PL color of the material due to Tb3+ changes from the initial red to yellow and, finally, green. The investigation reveals that the dynamic PL is due to the presence of appropriate traps and the cross-relaxation effect of Tb3+ in Na2CaGe2O6. By employing this unique dynamic PL material, high-level dynamic luminescent anticounterfeiting and encryption devices can be fabricated. The dynamic PL features of the devices are easily detected using a cheap portable lamp, and at present, it is impossible for the features to be faked by any substitutes. In a virtual military scenario, the results demonstrate that the encryption device is safe and that a spy will be detected. Accordingly, this dynamic PL material could inspire more ingenious security designs.
RESUMO
The development of luminescent materials for anticounterfeiting and encryption is of great importance. Herein, we develop a multistimuli-responsive luminescent material, Na2CaGe2O6:Pb2+/Er3+, and use it to print luminescent images. The photoluminescence and upconversion luminescence of these images show different patterns and colors under different stimuli. The photostimulated luminescence (PSL) of the printed images causes dynamic changes in appearance and is accordingly applied for dynamic multimodal anticounterfeiting on banknotes. The PSL of these luminescent images is also applied in a virtual war scenario to demonstrate that the dynamic PSL-encrypted information in the fabricated image is sufficiently safe even in extreme cases and that spies will be detected. These results can inspire us with more creative security designs based on this luminescent material.
RESUMO
Calcium [Ca(II)] is a fundamental transducer of electrical activity in the central nervous system (CNS). Influx of Ca(II) into the cytosol is responsible for action potential initiation and propagation, and initiates interneuronal communication via release of neurotransmitters and activation of gene expression. Despite the importance of Ca(II) in physiology, it remains a challenge to visualize Ca(II) flux in the central nervous system (CNS) in vivo. To address these challenges, we have developed a new generation, Ca(II)-activated MRI contrast agent that utilizes ethyl esters to increase cell labeling and prevent extracellular divalent Ca(II) binding. Following labeling, the ethyl esters can be cleaved, thus allowing the agent to bind Ca(II), increasing relaxivity and resulting in enhanced positive MR image contrast. The ability of this probe to discriminate between extra- and intracellular Ca(II) may allow for spatiotemporal in vivo imaging of Ca(II) flux during seizures or ischemia where large Ca(II) fluxes (1-10 µM) can result in cell death.
Assuntos
Cálcio/análise , Meios de Contraste/metabolismo , Esterases/metabolismo , Imageamento por Ressonância Magnética , Animais , Cálcio/metabolismo , Linhagem Celular , Permeabilidade da Membrana Celular , Meios de Contraste/química , Meios de Contraste/farmacocinética , Espaço Extracelular/química , Espaço Extracelular/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Espaço Intracelular/química , Espaço Intracelular/metabolismo , Imageamento por Ressonância Magnética/métodos , CamundongosRESUMO
Porphyrazines (Pz), or tetraazaporphyrins, are being studied for their potential use in detection and treatment of cancer. Here, an amphiphilic Cu-Pz-Gd(III) conjugate has been prepared via azide-alkyne Huisgen cycloaddition or 'click' chemistry between an azide functionalized Pz and alkyne functionalized DOTA-Gd(III) analog for use as an MRI contrast agent. This agent, Cu-Pz-Gd(III), is synthesized in good yield and exhibits solution-phase ionic relaxivity (r1 = 11.5 mM(-1) s(-1)) that is approximately four times higher than that of a clinically used monomeric Gd(III) contrast agent, DOTA-Gd(III). Breast tumor cells (MDA-MB-231) associate with Cu-Pz-Gd(III) in vitro, where significant contrast enhancement (9.336 ± 0.335 contrast-to-noise ratio) is observed in phantom cell pellet MR images. This novel contrast agent was administered in vivo to an orthotopic breast tumor model in athymic nude mice and MR images were collected. The average T1 of tumor regions in mice treated with 50 mg kg(-1) Cu-Pz-Gd(III) decreased relative to saline-treated controls. Furthermore, the decrease in T1 was persistent relative to mice treated with the monomeric Gd(III) contrast agent. An ex vivo biodistribution study confirmed that Cu-Pz-Gd(III) accumulates in the tumors and is rapidly cleared, primarily through the kidneys. Differential accumulation and T1 enhancement by Cu-Pz-Gd(III) in the tumor's core relative to the periphery offer preliminary evidence that this agent would find application in the imaging of necrotic tissue.
Assuntos
Neoplasias da Mama/diagnóstico por imagem , Meios de Contraste , Gadolínio , Imageamento por Ressonância Magnética , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Meios de Contraste/química , Feminino , Gadolínio/química , Humanos , Camundongos , Porfirinas/química , RadiografiaRESUMO
After the manner in which coenzymes often participate in the binding of substrates in the active sites of enzymes, pillar[5]arene, a macrocycle containing five hydroquinone rings linked through their para positions by methylene bridges, modifies the binding properties of cucurbit[6]uril, such that the latter templates azide-alkyne cycloadditions that do not occur in the presence of only the cucurbit[6]uril, a macrocycle composed of six glycoluril residues doubly linked through their nitrogen atoms to each other by methylene groups. Here, we describe how a combination of pillar[5]arene and cucurbit[6]uril interacts cooperatively with bipyridinium dications substituted on their nitrogen atoms with 2-azidoethyl- to 5-azidopentyl moieties to afford, as a result of orthogonal templation, two [4]rotaxanes and one [5]rotaxane in >90% yields inside 2 h at 55 °C in acetonitrile. Since the hydroxyl groups on pillar[5]arene and the carbonyl groups on cucurbit[6]uril form hydrogen bonds readily, these two macrocycles work together in a cooperative fashion to the extent that the four conformational isomers of pillar[5]arene can be trapped on the dumbbell components of the [4]rotaxanes. In the case of the [5]rotaxane, it is possible to isolate a compound containing two pillar[5]arene rings with local C5 symmetries. In addition to fixing the stereochemistries of the pillar[5]arene rings, the regiochemistries associated with the 1,3-dipolar cycloadditions have been extended in their constitutional scope. Under mild conditions, orthogonal recognition motifs have been shown to lead to templation with positive cooperativity that is fast and all but quantitative, as well as being green and efficient.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Imidazóis/química , Compostos de Amônio Quaternário/química , Rotaxanos/síntese química , Hidrocarbonetos Aromáticos com Pontes/síntese química , Calixarenos , Ligação de Hidrogênio , Imidazóis/síntese química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Compostos de Amônio Quaternário/síntese química , Rotaxanos/químicaRESUMO
Interspin distances between 0.8 nm and 2.0 nm can be measured through the dipolar broadening of the continuous wave (cw) EPR spectrum of nitroxide spin labels at X-band (9.4 GHz, 0.35 T). We introduce Gd(3+) as a promising alternative spin label for distance measurements by cw EPR above 7 Tesla, where the |-1/2ã to |1/2ã transition narrows below 1 mT and becomes extremely sensitive to dipolar broadening. To estimate the distance limits of cw EPR with Gd(3+), we have measured spectra of frozen solutions of GdCl3 at 8.6 T (240 GHz) and 10 K at concentrations ranging from 50 mM to 0.1 mM, covering a range of average interspin distances. These experiments show substantial dipolar broadening at distances where line broadening cannot be observed with nitroxides at X-band. This data, and its agreement with calculated dipolar-broadened lineshapes, show Gd(3+) to be sensitive to distances as long as â¼3.8 nm. Further, the linewidth of a bis-Gd(3+) complex with a flexible â¼1.6 nm bridge is strongly broadened as compared to the mono-Gd(3+) complex, demonstrating the potential for application to pairwise distances. Gd-DOTA-based chelates that can be functionalized to protein surfaces display linewidths narrower than aqueous GdCl3, implying they should be even more sensitive to dipolar broadening. Therefore, we suggest that the combination of tailored Gd(3+) labels and high magnetic fields can extend the longest interspin distances measurable by cw EPR from 2.0 nm to 3.8 nm. cw EPR data at 260 K demonstrate that the line broadening remains clear out to similar average interspin distances, offering Gd(3+) probes as promising distance rulers at temperatures higher than possible with conventional pulsed EPR distance measurements.
Assuntos
Quelantes/química , Gadolínio/química , Compostos Organometálicos/química , Espectroscopia de Ressonância de Spin Eletrônica , Campos MagnéticosRESUMO
Platinum-based drugs have been used to successfully treat diverse cancers for several decades. Cisplatin, the original compound of this class, cross-links DNA, resulting in cell cycle arrest and cell death via apoptosis. Cisplatin is effective against several tumor types, yet it exhibits toxic side effects and tumors often develop resistance. To mitigate these liabilities while maintaining potency, we generated a library of non-classical platinum-acridine hybrid agents and assessed their mechanisms of action using a validated genome-wide screening approach in Saccharomyces cerevisiae and in the distantly related yeast Schizosaccharomyces pombe. Chemogenomic profiles from both S. cerevisiae and S. pombe demonstrate that several of the platinum-acridines damage DNA differently than cisplatin based on their requirement for distinct modules of DNA repair.
Assuntos
Acridinas/química , Acridinas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Dano ao DNA/efeitos dos fármacos , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Cisplatino/farmacologia , DNA Fúngico/genética , Genômica , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Schizosaccharomyces/efeitos dos fármacos , Schizosaccharomyces/genéticaRESUMO
The reactivity of two DNA-targeted platinum-acridine conjugates with cysteine sulfur was studied. The conjugate containing an amidine-NH donor group cis to the chloride leaving group showed considerably reduced reactivity with N-acetylcysteine compared to the prototypical derivative containing a thiourea-S linkage. The opposite scenario has been observed previously in reactions with nucleobase nitrogen. Possible consequences of the unique target-selective tuning of the substitution chemistry for the pharmacodynamic properties and biological activity of these agents are discussed.
Assuntos
Antineoplásicos/síntese química , DNA/metabolismo , Acridinas/química , Acridinas/farmacologia , Amidinas/química , Antineoplásicos/farmacologia , Fenômenos Químicos , Cisteína/química , Compostos de Platina/química , Compostos de Platina/farmacologia , Relação Estrutura-Atividade , Tioureia/químicaRESUMO
The cytotoxic complex, [PtCl(Am)2(ACRAMTU)](NO3)2 (1) ((Am)2 = ethane-1,2-diamine, en; ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea), is a dual platinating/intercalating DNA binder that, unlike clinical platinum agents, does not induce DNA cross-links. Here, we demonstrate that substitution of the thiourea with an amidine group leads to greatly enhanced cytotoxicity in H460 non-small-cell lung cancer (NSCLC) in vitro and in vivo. Two complexes were synthesized: 4a (Am2 = en) and 4b (Am = NH3), in which N-[2-(acridin-9-ylamino)ethyl]-N-methylpropionamidine replaces ACRAMTU. Complex 4a proves to be a more efficient DNA binder than complex 1 and induces adducts in sequences not targeted by the prototype. Complexes 4a and 4b induce H460 cell kill with IC(50) values of 28 and 26 nM, respectively, and 4b slows tumor growth in a H460 mouse xenograft study by 40% when administered at a dose of 0.5 mg/kg. Compound 4b is the first non-cross-linking platinum agent endowed with promising activity in NSCLC.
Assuntos
Acridinas/química , Antineoplásicos/farmacologia , Compostos Organoplatínicos/farmacologia , Platina/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de TempoRESUMO
Novel thiourea- and guanidine-modified acridine-4-carboxamides (4, 7) and a corresponding platinum-intercalator conjugate (4') have been synthesized and evaluated as cytotoxic agents in human promyelocytic leukemia, HL-60, and a non-small cell lung cancer, NCI-H460. Modification of thiourea sulfur in derivative 4 with a DNA platinating moiety, giving 4', resulted in a pronounced cytotoxic enhancement, and the conjugate proved to be the most active of the newly synthesized compounds in NCI-H460 cells. Conjugate 4' represents a new chemotype with potential applications in the treatment of chemoresistant tumors.
Assuntos
Acridinas/farmacologia , Antineoplásicos/farmacologia , Guanidina/análogos & derivados , Platina/química , Tioureia/química , Ureia/análogos & derivados , Acridinas/química , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Guanidina/química , Células HL-60 , Humanos , Concentração Inibidora 50 , Modelos Químicos , Relação Estrutura-Atividade , Ureia/químicaRESUMO
The 9-aminoacridine chromophore is an important building block of DNA-targeted chemotherapeutic agents. The success of 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea as a carrier group in cytotoxic platinum-intercalator conjugates prompted us to explore the synthesis of an analogous guanidine-functionalized acridine. In a successful effort to generate such a derivative, various methods of guanidylation were employed, which demonstrate that the acridine C9-N9 linkage is highly susceptible to electrophilic and nucleophilic attack. The newly established reactivities provide efficient pathways to novel cyclic and spirocyclic acridine derivatives.
Assuntos
Aminacrina/química , Guanina/química , Aminacrina/farmacologia , Animais , Bovinos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA/química , Guanina/análogos & derivados , Humanos , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
The polarographic behavior of the reaction product of formaldehyde and phenyldrazine hydrochloride on the drop mercury electrode was investigated in a medium of 0.01 mol/L H3PO4 and sensitive second order polarographic reduction wave was obtained at -0.76 V (vs. SCE). The optimum conditions and disturbance of other co-existing substances were also studied, and were compared with those of national standard method. In the study, the detectable range, detection limit, recovery rate, relative standard deviation(RSD) of the improved method were 0.005-0.25 mg/L, 0.005 mg/L, 92.3%-104.6%, 1.1%-3.0% respectively, revealing the accordance with the national standard method.
Assuntos
Contaminação de Alimentos/análise , Embalagem de Alimentos/normas , Formaldeído/análise , PolarografiaRESUMO
A coordinated functional genomics program was implemented to identify secreted polypeptides with therapeutic applications in the treatment of diabetes. Secreted factors were predicted from a diverse expressed-sequence tags (EST) database, representing >1,000 cDNA libraries, using a combination of bioinformatic algorithms. Subsequently, approximately 8,000 human proteins were screened in high-throughput cell-based assays designed to monitor key physiological transitions known to be centrally involved in the physiology of type 2 diabetes. Bone morphogenetic protein-9 (BMP-9) gave a positive response in two independent assays: reducing phosphoenolpyruvate carboxykinase (PEPCK) expression in hepatocytes and activating Akt kinase in differentiated myotubes. Purified recombinant BMP-9 potently inhibited hepatic glucose production and activated expression of key enzymes of lipid metabolism. In freely fed diabetic mice, a single subcutaneous injection of BMP-9 reduced glycemia to near-normal levels, with maximal reduction observed 30 hours after treatment. BMP-9 represents the first hepatic factor shown to regulate blood glucose concentration. Using a combination of bioinformatic and high-throughput functional analyses, we have identified a factor that may be exploited for the treatment of diabetes.