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2.
Chem Biol Drug Des ; 94(4): 1824-1834, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31293023

RESUMO

Due to the potencies in the treatments of cancer, infectious diseases, and autoimmune diseases, the developments of human TLR8 (hTLR8) agonists and antagonists have attracted widespread attentions. The hTLR8 agonists and antagonists have similar structures but with completely opposite biological effects. Up to date, the subtle differences in the structures between the hTLR8 agonists and antagonists are still unknown. In this work, emerging chemical pattern (ECP) was successfully used to extract the key chemical patterns of the hTLR8 agonists and antagonists. By using CAEP classifier, an optimal ECP model with only 3 descriptors was established with the overall prediction accuracy larger than 90%. Further hierarchical cluster analysis and molecular docking showed that the H-bond and hydrophobic properties are the key features distinguishing the hTLR8 agonists from antagonists. Comparing with the antagonists, the agonists show stronger specific H-bond properties, while antagonists have stronger non-specific hydrophobic properties. The significant differences in the structural properties may be closely related to the activation/inhibition mechanism of hTLR8.

3.
J Chem Inf Model ; 59(1): 159-169, 2019 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-30422654

RESUMO

Recent research has increasingly suggested that the crucial factors affecting drug potencies are related not only to the thermodynamic properties but also to the kinetic properties. Therefore, in silico prediction of ligand-binding kinetic properties, especially the dissociation rate constant ( koff), has aroused more and more attention. However, there are still a lot of challenges that need to be addressed. In this paper, steered molecular dynamics (SMD) combined with residue-based energy decomposition was employed to predict the dissociation rate constants of 37 HIV-1 protease inhibitors (HIV-1 PIs). For the first time, a predictive model of the dissociation rate constant was established by using the interaction-energy fingerprints sampled along the ligand dissociation pathway. On the basis of the key fingerprints extracted it can be inferred that the dissociation rates of 37 HIV-1 PIs are basically determined in the first half of the dissociation processes and that the H-bond interactions with active-site Asp25 and van der Waals interactions with flap-region Ile47 and Ile50 have important influences on the dissociation processes. In general, the strategy established in this paper can provide an efficient way for the prediction of dissociation rate constants as well as the unbinding mechanism research.


Assuntos
Inibidores da Protease de HIV/química , Simulação de Dinâmica Molecular , Domínio Catalítico , Protease de HIV/metabolismo , Inibidores da Protease de HIV/farmacologia , Ligações de Hidrogênio , Cinética , Termodinâmica
4.
Lasers Med Sci ; 33(6): 1279-1286, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29915976

RESUMO

Hypericin, a powerful natural photosensitizer in photodynamic therapy (PDT), is suitable for treating skin diseases involving excess capillary proliferation. In the present study, we aimed to evaluate the skin penetrability of topically applied hypericin, expecting a reduced risk of prolonged skin photosensitivity, which often occurs after systemic administration. Firstly, the Franz diffusion cell assays were performed to evaluate the penetration effects of different enhancers, including menthol, propylene glycol, camphanone, azone, and carbamide. In view of above evaluation results, we selected menthol as the enhancer in the subsequent in vivo studies. The setting groups were as follows: the blank control group, the light-exposure control group, the gel-base control group, the hypericin gel group, and a hypericin gel-containing menthol group. Except for the blank control, all other animals were irradiated by a LED light. Then, fluorescence microscopy was performed to examine the distribution of hypericin in the skin of nude mouse. Macroscopic and microscopic analyses were also carried out to detect pathological changes in the skin after topical hypericin-PDT treatment. Immunohistochemistry was used to determine the expression change of PECAM-1. As shown in the results, menthol facilitated hypericin penetrate the skin of nude mice most. The results of in vivo assays revealed that hypericin penetrated nude mouse skin, spread to the dermis, and resulted in obvious photosensitivity reaction on the dermal capillaries. Moreover, skin injured by the photosensitive reaction induced by hypericin-PDT treatment was replaced by normal skin within 7 days. We concluded that topical applied hypericin could penetrate nude mouse skin well and has a great potential in PDT treatment of skin diseases.


Assuntos
Perileno/análogos & derivados , Absorção Cutânea/efeitos dos fármacos , Administração Tópica , Animais , Masculino , Camundongos Nus , Microscopia de Fluorescência , Perileno/administração & dosagem , Perileno/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia
5.
Bioorg Med Chem ; 26(8): 1488-1494, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29452840

RESUMO

Borrelidin A (1) is produced by several species of Streptomyces and within its bioactive scaffold, the vinylic nitrile moiety is essential for activity. We report herein newly discovered members of the borrelidin family, borrelidin F (2), borrelidin G (3), borrelidin H (4) and borrelidin I (5); all were isolated from Streptomyces rochei SCSIO ZJ89 originating from a mangrove-derived sediment sample. These structurally diverse metabolites enabled a number of new structure-activity relationships (SARs) to be identified, especially with respect to the different configurations at the C11-OH and C12-C15 double bonds for which the absolute configurations were determined using spectroscopic methods. Importantly, borrelidin H (4) was found to have a therapeutic window superior to that of borrelidin A (1) in vitro and could inhibit migration of cancer cells.


Assuntos
Antineoplásicos/farmacologia , Streptomyces/química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Álcoois Graxos/química , Álcoois Graxos/isolamento & purificação , Álcoois Graxos/farmacologia , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Cicatrização/efeitos dos fármacos
6.
Artif Cells Nanomed Biotechnol ; 46(6): 1248-1257, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28826242

RESUMO

The anti-infection ability and skin regeneration are important aspects on the progress of wound healing, which needs an ideal wound dressing that not only resists bacteria but also promotes skin regeneration. In this study, zinc oxide/silver/polyvinylpyrrolidone/polycaprolactone (ZnO/Ag/PVP/PCL) nanofibres were prepared through electrospinning. Firstly, zinc oxide nanoparticles (ZnONPs) and silver nanoparticle (AgNPs) were synthesized respectively. Secondly, the two nanoparticles were mixed with polyvinylpyrrolidone (PVP) and polycaprolactone (PCL) to obtain the nanofibres. The results of scanning electron microscopy (SEM) showed that ZnONPs and AgNPs were 40.07 ± 9.70 nm and 37.46 ± 12.02 nm, respectively. After electrospinning, the nanofibres were 368.22 ± 123.96 nm in diameter. Infrared spectroscopy revealed that ZnONPs/AgNPs bimetallic nanomaterials were physically embedded in the nanofibres. The antibacterial effects against Staphylococcus aureus and Escherichia coli of ZnO/Ag/PVP/PCL nanofibres were significantly better than these of the single metal material-loaded nanofibres. More importantly, the combination of ZnO and Ag reduced the cytotoxicity of ZnO/Ag/PVP/PCL bimetallic nanofibres toward fibroblasts. These findings demonstrated that ZnO/Ag/PVP/PCL bimetallic nanofibres should be of greater interest than the single metal nanomaterial-loaded nanofibres in inhibiting growth of bacteria.


Assuntos
Antibacterianos/farmacologia , Nanofibras/química , Nanofibras/toxicidade , Prata/química , Óxido de Zinco/química , Antibacterianos/química , Composição de Medicamentos , Escherichia coli/efeitos dos fármacos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/toxicidade , Nanopartículas Metálicas/ultraestrutura , Nanofibras/ultraestrutura , Poliésteres/química , Povidona/química , Prata/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Óxido de Zinco/farmacologia
7.
Drug Deliv ; 24(1): 1230-1242, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28856937

RESUMO

A co-loaded drug delivery system based on ascorbyl palmitate that can transport various functional drugs to their targets within a tumor represents an attractive strategy for increasing the efficiency of anticancer treatment. In this study, we developed a dual drug delivery system to encapsulate ascorbyl palmitate (AP) and paclitaxel (PTX) for synergistic cancer therapy. AP, which is a vitamin C derivative, and PTX were incorporated into solid lipid nanoparticles (AP/PTX-SLNs), which were used to treat murine B16F10 melanoma that had metastasized to the lungs of mice. These nanoparticles were spherical with an average size of 223 nm as measured by transmission electron microscope and dynamic light scattering. In vitro cytotoxicity assays indicated that the AP/PTX-SLNs with an AP/PTX mass ratio of 2/1 provided the optimal synergistic anticancer efficacy. In vivo, AP/PTX-SLNs were revealed to be much more effective in suppressing tumor growth in B16F10-bearing mice and in eliminating cancer cells in the lungs than single drug (AP or PTX)-loaded SLNs via a synergistic effect through reducing the Bcl-2/Bax ratio. Furthermore, no marked side effects were observed during the treatment with the AP/PTX-SLNs, indicating that the co-delivery system with ascorbyl palmitate holds promising clinical potential in cancer therapy.


Assuntos
Nanopartículas , Animais , Ácido Ascórbico/análogos & derivados , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Camundongos , Paclitaxel
8.
J Nat Prod ; 80(5): 1668-1673, 2017 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-28509552

RESUMO

Emodacidamides A-H (1-8), natural products featuring anthraquinone-amino acid conjugates, have been isolated from a marine-derived fungus, Penicillium sp. SCSIO sof101, together with known anthraquinones 9 and 10. The planar structures of 1-8 were elucidated using a combination of NMR spectroscopy and mass spectrometry. The absolute configurations of the amino acid residues were confirmed using Marfey's method and chiral-phase HPLC analyses. Additionally, isolates were evaluated for possible immunomodulatory and cytotoxic activities. Emodacidamides A (1), C (3), D (4), and E (5) inhibited interleukin-2 secretion from Jurkat cells with IC50 values of 4.1, 5.1, 12, and 5.4 µM, respectively.


Assuntos
Aminoácidos/isolamento & purificação , Aminoácidos/farmacologia , Antraquinonas/isolamento & purificação , Antraquinonas/farmacologia , Fungos/química , Interleucina-2/agonistas , Interleucina-2/química , Penicillium/química , Aminoácidos/química , Aminoácidos/imunologia , Antraquinonas/química , Cromatografia Líquida de Alta Pressão , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular
9.
J Biomed Nanotechnol ; 13(1): 17-34, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29372983

RESUMO

Wound healing is a complex pathophysiological process that occurs frequently in everyday pathology and remains a challenge during the treatment of trauma. Previously, we prepared silver nanoparticle/chitosan oligosaccharide/poly(vinyl alcohol) (PVA/COS-AgNP) nanofibers via an electrospinning technique. These nanofibers promoted the proliferation of human skin fibroblasts (HSFs) and the expression of transforming growth factor TGF-ß1 in the early stage of wound repair, although the specific mechanisms remain unclear. Therefore, considering that TGF-ß1 has emerged as a major modulator of wound healing, the objective of this study was to further understand whether the molecular mechanisms responsible for PVA/COS-AgNP nanofiber-mediated wound healing include the TGF-ß1/Smad signal transduction pathway. In this study, we used human skin fibroblasts (HSFs) to investigate the molecular and cellular mechanisms underlying PVA/COSAgNP nanofiber-mediated wound healing. Cell adhesion and proliferation experiments, immunofluorescence staining, hydroxyproline content measurements, flow cytometry, quantitative real-time PCR (qRT-PCR), and western blotting (WB) were used to analyze the wound healing mechanisms of human skin fibroblasts treated with various concentrations of PVA/COS-AgNP nanofibers and the combined application of silver nanofibers and SB431542 (an inhibitor of the TGF-ß1 receptor kinase). Our study showed that PVA/COS-AgNP nanofibers markedly promoted fibroblast proliferation, collagen synthesis, and cell adherence. We also found that treating fibroblasts with PVA/COS-AgNP nanofibers stimulated cell cycle progression from G1 into the S and G2 phases, reducing the proportion of cells in the G0/G1 phase and inducing S and G2/M arrest. Importantly, the cell factors associated with the TGF-ß1/Smad signal transduction pathway, such as TGF-ß1, TGFßRI, TGFßRII, pSmad2, pSmad3, collagen I, collagen III, and fibronectin were also up-regulated. Moreover, this enhancing effect was markedly inhibited by the TGFßRI receptor inhibitor, SB431542. Therefore, the PVA/COS-AgNP nanofibers used to accelerate wound healing do so by activating the TGF-ß1/Smad signal transduction pathway.


Assuntos
Quitosana/farmacologia , Nanopartículas Metálicas/química , Nanofibras/química , Prata/farmacologia , Cicatrização/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Quitosana/química , Técnicas Eletroquímicas , Fibroblastos/efeitos dos fármacos , Humanos , Álcool de Polivinil/farmacologia , Transdução de Sinais/efeitos dos fármacos , Prata/química , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
10.
PLoS One ; 11(11): e0166141, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27824933

RESUMO

BACKGROUND: Post-operative endophthalmitis is a rare and dreaded complication in ophthalmic operations because it often induces irreparable vision loss. Although many ophthalmological studies aimed at reducing the rate of endophthalmitis have been performed around the world, controversy continues to surround some issues, including the choice of antimicrobials and their route of administration, duration and timing. The aim of this study is to investigate some of these unresolved issues. METHODS: A systematic review and meta-analysis of randomized controlled trials and observational studies was performed. The PubMed, EMBASE, Cochrane Library and Clinical Trials databases were searched to identify studies published until Feb. 2016. The relative risk (RR) for each clinical outcome data is presented with 95% confidence intervals (CIs). Pooled estimates of effects were calculated using random-effect models. RESULTS: Thirty-four studies from twenty-four reports involving 1264797 eyes were included in this analysis. Endophthalmitis occurred, on average, in one out of 6177 eyes when intracameral vancomycin/moxifloxacin were used and in one out of 1517 eyes when intracameral vancomycin/moxifloxacin were not used. The relative risk (95% CI) of endophthalmitis was reduced to 0.20 (0.10, 0.42) when intracameral antibiotics were used (p<0.0001). The subconjunctival injection of antibiotics was not superior to other administration routes included in this study (RR = 1.67, 95% CI (0.55, 5.05), p = 0.36). A statistically significant difference was found in the rate of endophthalmitis between the use and lack of use of topical antibiotics (RR = 0.65, 95% CI (0.43, 0.99), p = 0.04). However, no statistically significant difference was found in microbial isolation rates between these groups (RR = 0.77, 95% CI (0.34, 1.75), p = 0.53). When long-term and short-term use of topical antibiotics before surgery were compared, a statistically significant difference was found in microbial isolation rates (RR = 0.57, 95% CI (0.44, 0.74), p<0.0001). CONCLUSIONS: This meta-analysis concluded intracameral antibiotics are effective at preventing endophthalmitis in ocular surgery. A randomized controlled trial confirms the efficacy of cefuroxime but recent large cohort studies support the efficacy of vancomycin/moxifloxacin intracamerally. Intracameral antibitoics are superior to subconjunctival injections but that irrigation antibitoic data are not of enough quality to make a comparison. Different results were found in two clinical outcomes between the use or lack of use of topical antibiotic therapy, we did not find sufficient evidence to conclude that its use prevents endophthalmitis.


Assuntos
Antibacterianos/uso terapêutico , Endoftalmite/prevenção & controle , Infecções Oculares Bacterianas/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Doença Aguda , Idoso , Câmara Anterior/microbiologia , Câmara Anterior/cirurgia , Extração de Catarata/efeitos adversos , Feminino , Humanos , Masculino , Estudos Observacionais como Assunto , Assistência Perioperatória/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
J Control Release ; 235: 1-13, 2016 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-27235150

RESUMO

Conventional enhanced permeation and retention (EPR) mediates the effects of many drugs, including the accumulation of nanocarriers at tumor sites, but its efficiency remains low. In this study, this limitation was overcome by developing a dual-targeting delivery system based on hyaluronan (HA, a major ligand of CD44) and tetraiodothyroacetic acid (tetrac, a specific ligand of αvß3), which was exploited to carry docetaxel (DTX) for the synergistic active targeting to tumors. First, a tetrac-HA (TeHA) conjugate was synthesized and grafted onto the surfaces of solid lipid nanoparticles (SLNs) (TeHA-SLNs/DTX), with a high encapsulation efficiency of >91.6%. The resulting SLNs exhibited an approximately toroid morphology revealed using TEM. The cellular uptake and cytotoxicity of various formulations on CD44/αvß3-enriched B16F10 cells were then assessed, and both results confirmed the selective uptake and high cytotoxicity of the TeHA-SLNs/DTX in a TeHA-dependent manner. In vivo imaging and vessel distribution tests revealed the efficiency of synergistic active targeting was higher than that of EPR-mediated passive targeting by the TeHA-SLNs to αvß3-expressing tumor blood vessels and CD44-expressing tumor cells via selective targeting. Finally, in both xenograft tumor mice and in situ lung metastasis tumor mice, tumor growth was significantly inhibited by TeHA-SLNs/DTX. Therefore, TeHA-SLNs are an efficient system for the dual-targeted delivery of drugs to treat cancer in vivo.


Assuntos
Antineoplásicos/administração & dosagem , Receptores de Hialuronatos/metabolismo , Integrina alfaVbeta3/metabolismo , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Taxoides/administração & dosagem , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Docetaxel , Liberação Controlada de Fármacos , Feminino , Humanos , Ácido Hialurônico/química , Células MCF-7 , Camundongos Endogâmicos C57BL , Nanopartículas/química , Neoplasias/metabolismo , Neoplasias/patologia , Taxoides/química , Taxoides/farmacocinética , Taxoides/uso terapêutico , Tiroxina/análogos & derivados , Tiroxina/química , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Int J Nanomedicine ; 11: 373-86, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26855575

RESUMO

Wound healing occupies a remarkable place in everyday pathology and remains a challenging clinical problem. In our previous study, we prepared a silver nanoparticle/chitosan oligosaccharide/poly(vinyl alcohol) (PVA/COS-AgNPs) nanofiber via electrospinning and revealed that it could promote wound healing; however, the healing mechanism remained unknown. Therefore, we aimed to clarify the mechanism underlying the accelerated healing effect of the PVA/COS-AgNPs nanofiber. The TGFß1/Smad signaling pathway is actively involved in wound healing. Considering the key role of this signaling pathway in wound healing, our preliminary study showed that the TGFß1 level was significantly increased during the early stage of wound healing. Thus, in this study, hematoxylin-eosin, Masson's trichrome, immunofluorescent staining, hydroxyproline content, quantitative real-time polymerase chain reaction, and Western blot analyses were used to analyze the wound healing in a rat model treated with gauze, the PVA/COS-AgNPs nanofiber, and the nanofiber plus SB431542 (an inhibitor of TGFß1 receptor kinase). The results showed that the PVA/COS-AgNPs nanofiber promoted wound healing and upregulated the expression levels of cytokines associated with the TGFß1/Smad signaling pathway such as TGFß1, TGFßRI, TGFßRII, collagen I, collagen III, pSmad2, and pSmad3. Inhibiting this pathway with SB431542 resulted in prevention of the PVA/COS-AgNPs nanofiber-associated salutary effects on the early stage of wound healing and relative cytokines expression. In conclusion, the wound healing effect of the PVA/COS-AgNPs nanofiber involves activation of the TGFß1/Smad signaling pathway.


Assuntos
Quitosana/química , Nanopartículas Metálicas/administração & dosagem , Nanofibras/administração & dosagem , Prata/química , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Cicatrização/efeitos dos fármacos , Animais , Bandagens , Western Blotting , Imunofluorescência , Técnicas Imunoenzimáticas , Masculino , Nanopartículas Metálicas/química , Nanofibras/química , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/metabolismo , Proteínas Smad/genética , Fator de Crescimento Transformador beta1/genética
13.
Drug Deliv ; 23(3): 828-39, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-24870202

RESUMO

This study reports on the performance of sodium alginate (SA)/poly(vinyl alcohol) (PVA)/moxifloxacin hydrochloride (MH) nanofibrous membranes (NFM) capable of providing antibacterial agent delivery for wound-dressing applications. The aim of this work was to prepare antibacterial NFM with good permeability properties by employing PVA and SA as carriers. A group of 12% PVA/2% SA solutions blended in various ratios (8:2, 7:3, 6:4, 5:5 and 4:6, v/v) and containing 0.5, 1, 2 or 4 wt% MH were studied for electrospinning into nanoscale fibermats. The optimum ratio found to form smooth fibers with uniform fibrous features was 6:4. The drug release behavior of the electrospun, the antibacterial effects on Pseudomonas aeruginosa and Staphylococcus aureus and the animal wound dressing capabilities were also investigated. As much as 80% of the MH was released from the electrospun after 10 h of incubation at 37 °C. In addition, the NFM with 0.5 MH exhibited less activity, whereas those with higher concentrations of MH exhibited greater antibacterial effect. Furthermore, the MH-loaded electrospun accelerated the rate of wound dressing compared to other groups. The results of the in vitro and in vivo experiments suggest that MH/PVA/SA nanofibers might be an interesting bioactive wound dressing for clinical applications.


Assuntos
Alginatos/química , Antibacterianos/administração & dosagem , Antibacterianos/química , Fluoroquinolonas/administração & dosagem , Fluoroquinolonas/química , Álcool de Polivinil/química , Cicatrização/efeitos dos fármacos , Animais , Bandagens , Feminino , Ácido Glucurônico/química , Ácidos Hexurônicos/química , Masculino , Moxifloxacina , Nanofibras/administração & dosagem , Nanofibras/química , Pseudomonas aeruginosa/efeitos dos fármacos , Coelhos , Ratos , Ratos Sprague-Dawley , Staphylococcus aureus/efeitos dos fármacos
14.
Nat Prod Res ; 30(2): 138-43, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26197797

RESUMO

A new diketopiperazine (DKP) derivative, (6R,3Z)-3-benzylidene-6-isobutyl-1-methyl piperazine-2,5-dione (1), as well as five known DKPs 2-6 was isolated from a deep sea-derived Streptomyces sp. SCSIO 04496. The structure of 1 was elucidated using a combination of 1D and 2D NMR, HR-ESI-MS and chiral-phase HPLC techniques. Compounds 1-6 did not show cytotoxic activity at a concentration of 100 µM in bioactivity assay.


Assuntos
Compostos de Benzilideno/química , Compostos de Benzilideno/farmacologia , Dicetopiperazinas/química , Piperazinas/química , Piperazinas/farmacologia , Streptomyces/química , Compostos de Benzilideno/isolamento & purificação , Linhagem Celular Tumoral/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Dicetopiperazinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oceanos e Mares , Piperazinas/isolamento & purificação , Espectrometria de Massas por Ionização por Electrospray , Streptomyces/isolamento & purificação , Microbiologia da Água
15.
Sci Rep ; 5: 18398, 2015 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-26673286

RESUMO

The conventional photosensitizers used in photodynamic therapy (PDT), such as haematoporphyrin (HP), have not yet reached satisfactory therapeutic effects on port-wine stains (PWSs), due largely to the long-term dark toxicity. Previously we have showed that hypericin exhibited potent photocytotoxic effects on Roman chicken cockscomb model of PWSs. However, the molecular mechanism of hypericin-mediated photocytotoxicity remains unclear. In this study, we employed human umbilical vein endothelial cells (HUVECs) to investigate the hypericin-photolytic mechanism. Our study showed that hypericin-PDT induced reactive oxygen species (ROS), resulting in cell killings and an activation of the inflammatory response. Importantly, we have also discovered that photoactivated hypericin induced apoptosis by activating the mitochondrial caspase pathway and inhibiting the activation of the vascular endothelial growth factor-A (VEGF-A)-mediated PI3K/Akt pathway. Notably, we found that hypericin exhibited a more potent photocytotoxic effect than HP, and largely addressed the inconvenience issue associated with the use of HP. Thereby, hypericin may be a better alternative to HP in treating PWSs.


Assuntos
Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos da radiação , Luz , Perileno/análogos & derivados , Western Blotting , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular , Citocinas/genética , Citocinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/efeitos da radiação , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos da radiação , Perileno/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Fotoquimioterapia/métodos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Radiossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Fator A de Crescimento do Endotélio Vascular/metabolismo
16.
PLoS One ; 10(10): e0137252, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26444424

RESUMO

BACKGROUND: Clostridium difficile infection (CDI) has become a global epidemiological problem for both hospitalized patients and outpatients. The most commonly used drugs to treat CDI are metronidazole and vancomycin. The aim of this study was to compare the efficacy and safety of metronidazole monotherapy with vancomycin monotherapy and combination therapy in CDI patients. METHODS: A comprehensive search without publication status or other restrictions was conducted. Studies comparing metronidazole monotherapy with vancomycin monotherapy or combination therapy in patients with CDI were considered eligible. Meta-analysis was performed using the Mantel-Haenszel fixed-effects model, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated and reported. RESULTS: Of the 1910 records identified, seventeen studies from thirteen articles (n = 2501 patients) were included. No statistically significant difference in the rate of clinical cure was found between metronidazole and vancomycin for mild CDI (OR = 0.67, 95% CI (0.45, 1.00), p = 0.05) or between either monotherapy and combination therapy for CDI (OR = 1.07, 95% CI (0.58, 1.96), p = 0.83); however, the rate of clinical cure was lower for metronidazole than for vancomycin for severe CDI (OR = 0.46, 95% CI (0.26, 0.80), p = 0.006). No statistically significant difference in the rate of CDI recurrence was found between metronidazole and vancomycin for mild CDI (OR = 0.99, 95% CI (0.40, 2.45), p = 0.98) or severe CDI (OR = 0.98, 95% CI (0.63, 1.53), p = 0.94) or between either monotherapy and combination therapy for CDI (OR = 0.91, 95% CI (0.66, 1.26), p = 0.56). In addition, there was no significant difference in the rate of adverse events (AEs) between metronidazole and vancomycin (OR = 1.18, 95% CI (0.80, 1.74), p = 0.41). In contrast, the rate of AEs was significantly lower for either monotherapy than for combination therapy (OR = 0.30, 95% CI (0.17, 0.51), p < 0.0001). CONCLUSIONS: Metronidazole and vancomycin are equally effective for the treatment of mild CDI, but vancomycin is superior for the treatment of severe CDI. Combination therapy is not superior to monotherapy because it appears to be associated with an increase in the rate of AEs.


Assuntos
Antibacterianos/uso terapêutico , Clostridium difficile/efeitos dos fármacos , Enterocolite Pseudomembranosa/tratamento farmacológico , Metronidazol/uso terapêutico , Vancomicina/uso terapêutico , Adulto , Idoso , Antibacterianos/efeitos adversos , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metronidazol/efeitos adversos , Pessoa de Meia-Idade , Resultado do Tratamento , Vancomicina/efeitos adversos
17.
Diagn Pathol ; 9: 214, 2014 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-25421173

RESUMO

BACKGROUND: Pre-clinical evidence shows that fixed dose rate (FDR) infusion of gemcitabine could optimize plasma concentration of gemcitabine, while the clinical efficacy and toxicity of FDR infusion of gemcitabine in advanced pancreatic carcinoma has not been systematically investigated. Thus, this meta-analysis was designed to ascertain this issue. METHODS: Databases of EMBASE, PubMed, and Cochrane Library were searched for eligible randomized controlled trials (RCTs). RCTs comparing FDR and standard 30-min infusion of gemcitabine in advanced pancreatic carcinoma were included. The primary endpoints were treatment efficacy (overall response rate, 1-year survival rate, median survival, and time to treatment failure) and toxicities were secondary endpoints (neutropenia, thrombocytopenia, anemia, and vomiting). Relative risks or mean differences and corresponding 95% confidence intervals (CIs) were calculated. RESULT: After careful and rigorous selection, 3 eligible RCTs including 764 patients of advanced pancreatic adenocarcinoma were included in this meta-analysis. For treatment efficacy, FDR gemcitabine provided significantly longer median survival over standard gemcitabine (Mean Difference = 1.24 months, 95% CI: 0.39-2.09), while there was no statistical difference in other endpoints of treatment efficacy. For toxicities, patients with FDR gemcitabine experienced significantly more grade 3/4 hematological toxicities than those received standard gemcitabine (neutropenia, thrombocytopenia, and anemia), while there was no difference for vomiting. CONCLUSION: Compared with standard 30-min infusion, FDR gemcitabine provide longer median survival, but increased the risk of hematological toxicities for patients with advanced pancreatic adenocarcinoma. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_214.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antimetabólitos Antineoplásicos/administração & dosagem , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Antimetabólitos Antineoplásicos/efeitos adversos , Distribuição de Qui-Quadrado , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Progressão da Doença , Humanos , Infusões Parenterais , Razão de Chances , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento
18.
Photochem Photobiol ; 90(6): 1368-75, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25065502

RESUMO

Hypericin (HY) is a promising photosensitizer (PS) for use in photodynamic therapy (PDT). Port-wine stains (PWSs) are congenital superficial dermal capillary malformations. In this study, we evaluated the photocytotoxic effects of HY for PDT in human vascular endothelial cells and a chicken cockscomb model. HY significantly inhibited the growth of human umbilical vein endothelial cells (HUVECs), as determined by colorimetric assays and morphological observation, and flow cytometry assays indicated induction of apoptosis and collapse of the mitochondrial membrane potential. In addition, HY more effectively inhibited growth of and induced apoptosis in HUVECs compared with hematoporphyrin (HP). Further experiments performed in a Roman chicken cockscomb model also showed a clear photocytotoxic effect on the cockscomb dermal capillary upon intravenous injection of HY. This effect may be due to the role of HY in the induction of apoptosis. Transmission electron microscopical analysis showed mitochondrial morphological changes such as incomplete ridges and swelling, and immunohistochemical assays showed an increase in the release of cytochrome c. In conclusion, HY exhibited a greater photocytotoxic activity than did HP toward the growth of endothelial cells and may thus represent a potent PS for PWS PDT.


Assuntos
Apoptose/efeitos dos fármacos , Capilares/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Hematoporfirinas/farmacologia , Modelos Biológicos , Perileno/análogos & derivados , Linhagem Celular , Citocromos c/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/enzimologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Perileno/farmacologia , Fotoquimioterapia
19.
Cell Biochem Biophys ; 69(1): 93-101, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24163109

RESUMO

To develop an efficient method for extracting and purifying the active ingredient, arctiin, from Fructus arctii and to investigate the protective effect of arctiin against glucose-induced rat aortic endothelial cell (RAEC) injury was investigated. Using a L9 (34) orthogonal array and two-step column chromatography (with AB-8 macroporous resin) arctiin extraction was optimized using a reflux method with 70% ethanol. The RAECs were then treated with different concentrations of arctiin (1, 10, or 100 µg/ml). The effects of arctiin on cell viability in a high glucose medium, malondialdehyde (MDA) levels, and lactate dehydrogenase were measured using commercially available assays. After extraction, the purity of arctiin reached 95.7%. In rats, arctiin was shown to stimulate the proliferation of RAECs in a high glucose medium in a dose-dependent manner. Exposure of RAECs to high glucose resulted in a significant increase in MDA and release of lactate dehydrogenase. This was accompanied by significant increase in nitric oxide release and expression of antiendothelial nitric oxide synthase. This technique resulted in relatively pure arctiin extraction. Furthermore, the results from this study suggest that arctiin could potentially function as a protector against vascular endothelial cell injury and further investigation is warranted.


Assuntos
Antioxidantes/isolamento & purificação , Arctium/química , Células Endoteliais/efeitos dos fármacos , Furanos/isolamento & purificação , Glucose/farmacologia , Glucosídeos/isolamento & purificação , Animais , Antioxidantes/farmacologia , Aorta/citologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Células Cultivadas , Medicamentos de Ervas Chinesas , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Furanos/farmacologia , Expressão Gênica , Glucosídeos/farmacologia , Malondialdeído/antagonistas & inibidores , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/genética , Extratos Vegetais/química , Ratos , Ratos Wistar
20.
Int J Nanomedicine ; 8: 4131-45, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24204142

RESUMO

In this study, a mixture of poly(vinyl alcohol) (PVA) and chitosan oligosaccharides (COS) was electrospun with silver nanoparticles (AgNPs) to produce fibrous mats for use in wound healing. The AgNPs were reduced by COS prior to electrospinning or Ag(+) was reduced via ultraviolet irradiation in nanofibers. The morphologies of the PVA/COS/AgNO3 and PVA/COS-AgNP nanofibers were analyzed by scanning electron microscopy. Formation of the AgNPs was investigated by field emission transmission electron microscopy, ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, and X-ray diffraction. We also evaluated the biocompatibility of the nanofibers, particularly their cytotoxicity to human skin fibroblasts and potential to cause primary skin irritation. The in vitro antibacterial activity and in vivo wound healing capacity of the nanofibers were also investigated. The nanofibers had a smooth surface with an average diameter of 130-192 nm. The diameters of the AgNPs were in the range of 15-22 nm. The nanofibers significantly inhibited growth of Escherichia coli and Staphylococcus aureus bacteria. PVA/COS-AgNP nanofibers accelerated the rate of wound healing over that of the control (gauze). The results of our in vitro and in vivo animal experiments suggest that PVA/COS-AgNP nanofibers should be of greater interest than PVA/COS/AgNO3 nanofibers for clinical use as a bioactive wound dressing.


Assuntos
Bandagens , Quitosana/farmacologia , Nanopartículas Metálicas/química , Álcool de Polivinil/farmacologia , Prata/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Células Cultivadas , Quitosana/química , Técnicas Eletroquímicas , Escherichia coli/efeitos dos fármacos , Fibroblastos , Humanos , Teste de Materiais , Tamanho da Partícula , Álcool de Polivinil/química , Coelhos , Ratos Sprague-Dawley , Prata/química , Staphylococcus aureus/efeitos dos fármacos
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