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1.
Biomater Adv ; 160: 213830, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38552500

RESUMO

Cancer, namely breast and prostate cancers, is the leading cause of death in many developed countries. Controlled drug delivery systems are key for the development of new cancer treatment strategies, to improve the effectiveness of chemotherapy and tackle off-target effects. In here, we developed a biomaterials-based wireless electrostimulation system with the potential for controlled and on-demand release of anti-cancer drugs. The system is composed of curcumin-loaded poly(3,4-ethylenedioxythiophene) nanoparticles (CUR/PEDOT NPs), encapsulated inside coaxial poly(glycerol sebacate)/poly(caprolactone) (PGS/PCL) electrospun fibers. First, we show that the PGS/PCL nanofibers are biodegradable, which allows the delivery of NPs closer to the tumoral region, and have good mechanical properties, allowing the prolonged storage of the PEDOT NPs before their gradual release. Next, we demonstrate PEDOT/CUR nanoparticles can release CUR on-demand (65 % of release after applying a potential of -1.5 V for 180 s). Finally, a wireless electrostimulation platform using this NP/fiber system was set up to promote in vitro human prostate cancer cell death. We found a decrease of 67 % decrease in cancer cell viability. Overall, our results show the developed NP/fiber system has the potential to effectively deliver CUR in a highly controlled way to breast and prostate cancer in vitro models. We also show the potential of using wireless electrostimulation of drug-loaded NPs for cancer treatment, while using safe voltages for the human body. We believe our work is a stepping stone for the design and development of biomaterial-based future smarter and more effective delivery systems for anti-cancer therapy.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Glicerol/análogos & derivados , Nanopartículas , Poliésteres , Polímeros , Tecnologia sem Fio , Humanos , Compostos Bicíclicos Heterocíclicos com Pontes/química , Nanopartículas/química , Polímeros/química , Poliésteres/química , Curcumina/administração & dosagem , Curcumina/química , Glicerol/química , Masculino , Neoplasias da Próstata/terapia , Antineoplásicos/administração & dosagem , Decanoatos/química , Nanofibras/química , Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , Linhagem Celular Tumoral , Estimulação Elétrica/instrumentação , Estimulação Elétrica/métodos
2.
Bioelectrochemistry ; 153: 108484, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37302335

RESUMO

The continuous progression in the field of electrotherapies implies the development of multifunctional materials exhibiting excellent electrochemical performance and biocompatibility, promoting cell adhesion, and possessing antibacterial properties. Since the conditions favouring the adhesion of mammalian cells are similar to conditions favouring the adhesion of bacterial cells, it is necessary to engineer the surface to exhibit selective toxicity, i.e., to kill or inhibit the growth of bacteria without damaging mammalian tissues. The aim of this paper is to introduce a surface modification approach based on a subsequent deposition of silver and gold particles on the surface of a conducting polymer, poly(3,4-ethylenedioxythiophene) (PEDOT). The resulting PEDOT-Au/Ag surface is found to possess optimal wettability, roughness, and surface features making it an excellent platform for cell adhesion. By depositing Ag particles on PEDOT surface decorated with Au particles, it is possible to reduce toxic effects of Ag particles, while maintaining their antibacterial activity. Besides, electroactive and capacitive properties of PEDOT-Au/Ag account for its applicability in various electroceutical therapies.


Assuntos
Ouro , Prata , Animais , Prata/farmacologia , Prata/química , Ouro/química , Polímeros/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Antibacterianos/farmacologia , Mamíferos
3.
Int J Mol Sci ; 23(3)2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35163031

RESUMO

Organic semiconductors are constantly gaining interest in regenerative medicine. Their tunable physico-chemical properties, including electrical conductivity, are very promising for the control of stem-cell differentiation. However, their use for combined material-based and electrical stimulation remains largely underexplored. Therefore, we carried out a study on whether a platform based on the conductive polymer poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) can be beneficial to the differentiation of mouse embryonic stem cells (mESCs). The platform was prepared using the layout of a standard 24-well cell-culture plate. Polyethylene naphthalate foil served as the substrate for the preparation of interdigitated gold electrodes by physical vapor deposition. The PEDOT:PSS pattern was fabricated by precise screen printing over the gold electrodes. The PEDOT:PSS platform was able to produce higher electrical current with the pulsed-direct-current (DC) electrostimulation mode (1 Hz, 200 mV/mm, 100 ms pulse duration) compared to plain gold electrodes. There was a dominant capacitive component. In proof-of-concept experiments, mESCs were able to respond to such electrostimulation by membrane depolarization and elevation of cytosolic calcium. Further, the PEDOT:PSS platform was able to upregulate cardiomyogenesis and potentially inhibit early neurogenesis per se with minor contribution of electrostimulation. Hence, the present work highlights the large potential of PEDOT:PSS in regenerative medicine.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Diferenciação Celular , Condutividade Elétrica , Células-Tronco Embrionárias Murinas/citologia , Polímeros/farmacologia , Poliestirenos/química , Animais , Técnicas de Cultura de Células , Eletrodos , Camundongos , Células-Tronco Embrionárias Murinas/efeitos dos fármacos , Polímeros/química
4.
Mol Inform ; 39(11): e2000163, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32964659

RESUMO

Medicinal plants have widely been used in the traditional treatment of ailments and have been proven effective. Their contribution still holds an important place in modern drug discovery due to their chemical, and biological diversities. However, the poor documentation of traditional medicine, in developing African countries for instance, can lead to the loss of knowledge related to such practices. In this study, we present the Eastern Africa Natural Products Database (EANPDB) containing the structural and bioactivity information of 1870 unique molecules isolated from about 300 source species from the Eastern African region. This represents the largest collection of natural products (NPs) from this geographical region, covering literature data of the period from 1962 to 2019. The computed physicochemical properties and toxicity profiles of each compound have been included. A comparative analysis of some physico-chemical properties like molecular weight, H-bond donor/acceptor, logPo/w , etc. as well scaffold diversity analysis has been carried out with other published NP databases. EANPDB was combined with the previously published Northern African Natural Products Database (NANPDB), to form a merger African Natural Products Database (ANPDB), containing ∼6500 unique molecules isolated from about 1000 source species (freely available at http://african-compounds.org). As a case study, latrunculins A and B isolated from the sponge Negombata magnifica (Podospongiidae) with previously reported antitumour activities, were identified via substructure searching as molecules to be explored as putative binders of histone deacetylases (HDACs).


Assuntos
Produtos Biológicos/farmacologia , Plantas Medicinais/química , África Oriental , Produtos Biológicos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Bases de Dados como Assunto , Inibidores de Histona Desacetilases/química , Ligação de Hidrogênio , Peso Molecular , Tiazolidinas/química , Testes de Toxicidade
5.
Environ Pollut ; 250: 196-205, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30995573

RESUMO

In recent years, water pollution caused by radionuclides has become a rising concern, among which uranium is a representative class of actinide element. Since hexavalent uranium, i.e. U(VI), is biologically hazardous with high migration, it's essential to develop efficient adsorbents to minimize the impact on the environment. Towards this end, we have synthesized a novel material (GO/PEDOT:PSS) by direct assembling graphene oxide (GO) and poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) through a facile ball milling method, which shows impressing performance for the immobilization of U(VI). On the basis of the batch experiments, GO/PEDOT:PSS exhibits ionic strength-independent sorption edges and temperature-promoted sorption isotherms, revealing an inner-sphere complexation with endothermic nature. The sorption kinetics can be illustrated by the pseudo-second-order model, yielding a rate constant of 1.09. × 10-2 g mg-1∙min-1, while the sorption isotherms are in coincidence with the Langmuir model, according to which the maximum sorption capacity is measured to be 384.51 mg g-1 at pH 4.5 under 298 K, indicating a monolayer sorption mechanism. In the light of the FT-IR and XPS investigations, the surface carboxyl/sulfonate group is responsible to the chelation of U(VI), indicating that the enhanced sorption capacity may be ascribed to the PSS moiety. These findings can greatly contribute to the design strategy for developing highly efficient adsorbents in the field of radioactive wastewater treatment.


Assuntos
Nanocompostos/química , Urânio/química , Eliminação de Resíduos Líquidos/métodos , Poluentes Radioativos da Água/química , Adsorção , Compostos Bicíclicos Heterocíclicos com Pontes/química , Grafite/química , Concentração de Íons de Hidrogênio , Cinética , Polímeros/química , Poliestirenos/química , Temperatura
6.
Adv Healthc Mater ; 7(17): e1800473, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29975820

RESUMO

Innovative neurostimulation therapies require improved electrode materials, such as poly(3,4-ethylenedioxythiophene) (PEDOT) polymers or IrOx mixed ionic-electronic conductors and better understanding of how their electrochemistry influences nerve growth. Amphibian neurons growing on transparent films of electronic (metal) conductors and electronic-ionic conductors (polymers and semiconducting oxides) are monitored. Materials are not connected directly to the power supply, but a dipole is created wirelessly within them by electrodes connected to the culture medium in which they are immersed. Without electrical stimulation neurons grow on gold, platinum, PEDOT-polystyrene sulfonate (PEDOT-PSS), IrOx , and mixed oxide (Ir-Ti)Ox , but growth is not related to surface texture or hydrophilicity. Stimulation induces a dipole in all conductive materials, but neurons grow differently on electronic conductors and mixed-valence mixed-ionic conductors. Stimulation slows, but steers neurite extension on gold but not on platinum. The rate and direction of neurite growth on PEDOT-PSS resemble that on glass, but on IrOx and (Ir-Ti)Ox neurites grow faster and in random directions. This suggests electrochemical changes induced in these materials control growth speed and direction selectively. Evidence that the electric dipole induced in conductive material controls nerve growth will impact electrotherapies exploiting wireless stimulation of implanted material arrays, even where transparency is required.


Assuntos
Condutividade Elétrica , Polímeros/química , Materiais Biocompatíveis/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Óxidos/química
7.
Biosens Bioelectron ; 110: 141-146, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29609160

RESUMO

Herein, aptamer-modified self-propelled nanomotors were used for transportation of human promyelocytic leukemia cells (HL-60) from a human serum sample. For this purpose, the fabricated manganese oxide nanosheets-polyethyleneimine decorated with nickel/gold nanoparticles (MnO2-PEI/Ni/Au) as nanomotors were added to a vial containing thiolated aptamer KH1C12 solution as a capture aptamer to attach to the gold nanoparticles on the surface of nanomotors covalently. The aptamer-modified self-propelled nanomotors (aptamerKH1C12/nanomotors) were then separated by placing the vial in a magnetic stand. The aptamer-modified self-propelled nanomotors were rinsed three times with water to remove the non-attached aptamers. Then, the resulting aptamerKH1C12/nanomotors were applied for the on-the-fly" transporting of HL-60 cancer cell from a human serum sample. To release of the captured HL-60 cancer cells, the complementary nucleotide sequences of KH1C12 aptamer solution (releasing aptamer) that has a with capture aptamer was added to phosphate buffer solution (1 M, pH 7.4) containing HL-60/aptamerKH1C12/nanomotors. Because of the high affinity of capture aptamer to complementary nucleotide sequences of aptamerKH1C12, the HL-60 cancer cells released on the surface of aptamerKH1C12/nanomotors into the solution. The second goal of the present work was determining the concentration of HL-60 cancer cell in the human serum samples. The electrochemical impedance spectroscopy technique (EIS) was used for the determination of HL-60 cancer cell. The concentration of separated cancer cell was determined by aptamer/gold nanoparticles-poly(3,4-ethylene dioxythiophene) modified GC electrode (GC/PEDOT-Aunano/aptamer KH1C12). The proposed aptasensor exhibited a good response to the concentration of HL-60 cancer cells in the range of 2.5 × 101 to 5 × 105 cells mL-1 with a low limit of detection of 250 cells mL-1.


Assuntos
Aptâmeros de Nucleotídeos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Contagem de Células/métodos , Separação Celular/métodos , Compostos de Manganês/química , Nanoestruturas/química , Neoplasias/sangue , Óxidos/química , Polímeros/química , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Eletrodos , Ouro/química , Células HL-60 , Humanos , Nanopartículas Metálicas/química , Níquel/química , Polietilenoimina/química
8.
Talanta ; 179: 490-500, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29310265

RESUMO

Buyang Huanwu decoction (BHD) was reported to exert angiogenesis-promoting effects, but its active ingredients remain unknown. In this study, we developed a method to screen potential angiogenesis-promoting compounds in BHD, which involved biospecific isolation using live rat brain microvascular endothelial cells (rBMECs) and characterization using solid-phase extraction (SPE) and high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Six compounds showed binding affinity to rBMECs and were further identified as 6-hydroxykaempferol-di-O-glucoside, paeoniflorin, calycosin-7-O-ß-D-glucoside, galloylpaeoniflorin, formononetin-7-O-ß-D-glucoside, and (3R)-7,2'-hydroxy-3',4'-dimethoxy-isoflavan. The results indicated that five of them except 6-hydroxykaempferol-di-O-glucoside showed a protective effect against oxygen glucose deprivation/reperfusion injury in rBMECs and upregulated the secretion of vascular endothelial growth factor and basic fibroblast growth factor, suggesting a mechanism underlying their angiogenic activity. Our findings suggest that biospecific live cell-based isolation combined with SPE and HPLC-MS/MS is an effective method for screening potential bioactive components in traditional Chinese medicines.


Assuntos
Indutores da Angiogênese/isolamento & purificação , Compostos Bicíclicos Heterocíclicos com Pontes/isolamento & purificação , Medicamentos de Ervas Chinesas/química , Células Endoteliais/efeitos dos fármacos , Glucosídeos/isolamento & purificação , Isoflavonas/isolamento & purificação , Monoterpenos/isolamento & purificação , Indutores da Angiogênese/química , Indutores da Angiogênese/farmacologia , Animais , Animais Recém-Nascidos , Encéfalo/irrigação sanguínea , Encéfalo/citologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Glucosídeos/química , Glucosídeos/farmacologia , Isoflavonas/química , Isoflavonas/farmacologia , Monoterpenos/química , Monoterpenos/farmacologia , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos
9.
Int J Nanomedicine ; 12: 615-632, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28144143

RESUMO

Laser-mediated photothermal ablation of cancer cells aided by photothermal agents is a promising strategy for localized, externally controlled cancer treatment. We report the synthesis, characterization, and in vitro evaluation of conductive polymeric nanoparticles (CPNPs) of poly(diethyl-4,4'-{[2,5-bis(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-1,4-phenylene] bis(oxy)}dibutanoate) (P1) and poly(3,4-ethylenedioxythiophene) (PEDOT) stabilized with 4-dodecylbenzenesulfonic acid and poly(4-styrenesulfonic acid-co-maleic acid) as photothermal ablation agents. The nanoparticles were prepared by oxidative-emulsion polymerization, yielding stable aqueous suspensions of spherical particles of <100 nm diameter as determined by dynamic light scattering and electron microscopy. Both types of nanoparticles show strong absorption of light in the near infrared region, with absorption peaks at 780 nm for P1 and 750 nm for PEDOT, as well as high photothermal conversion efficiencies (~50%), that is higher than commercially available gold-based photothermal ablation agents. The nanoparticles show significant photostability as determined by their ability to achieve consistent temperatures and to maintain their morphology upon repeated cycles of laser irradiation. In vitro studies in MDA-MB-231 breast cancer cells demonstrate the cytocompatibility of the CPNPs and their ability to mediate complete cancer cell ablation upon irradiation with an 808-nm laser, thereby establishing the potential of these systems as agents for laser-induced photothermal therapy.


Assuntos
Condutividade Elétrica , Hipertermia Induzida , Lasers , Nanopartículas/química , Neoplasias/terapia , Fototerapia , Polímeros/química , Polímeros/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Linhagem Celular Tumoral , Humanos , Maleatos/síntese química , Maleatos/química , Nanopartículas/ultraestrutura , Poliestirenos/síntese química , Poliestirenos/química , Temperatura
10.
Nat Prod Res ; 31(18): 2113-2118, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28067069

RESUMO

A new compound, (3aS,6aR)-4,5-dimethyl-3,3a,6,6a-tetrahydro-2H-cyclopenta [b]furan-2-one (2), along with two known metabolites, myrotheciumone A (1) and 4-oxo-4H-pyron-3-acetic acid (3) was isolated from the ethyl acetate extract of fermentation broth of Xylaria curta 92092022. The structures of these compounds were elucidated on the basis of spectroscopic methods (UV, IR, HRESITOFMS, 1D NMR, and 2D NMR). Compounds 1 and 2 showed moderate antibacterial and phytotoxic activities.


Assuntos
Antibacterianos/farmacologia , Lactonas/química , Xylariales/química , Acetatos/química , Antibacterianos/química , Antifúngicos/química , Antifúngicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/isolamento & purificação , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Ciclopentanos/química , Avaliação Pré-Clínica de Medicamentos , Endófitos/química , Fermentação , Furanos/química , Lactonas/isolamento & purificação , Lactonas/farmacologia , Lactuca/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Pironas/química , Espectrofotometria Ultravioleta , Testes de Toxicidade
11.
Bioorg Med Chem Lett ; 26(21): 5164-5167, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27720549

RESUMO

Monocyclic analog of neuroexcitatory neodysiherbaine has been designed and stereoselectively synthesized in 0.40% yield over total 24 steps starting from d-ribose, by employing domino aldol-Cannizzaro reaction and stereoselective aldol reaction for construction of two quaternary carbon stereogenic centers at C4 and C6 positions, respectively. The hyperactivity of neodysiherbaine in mice was found to deteriorate in the novel analog, upon intracerebroventricular injection.


Assuntos
Alanina/análogos & derivados , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Alanina/síntese química , Alanina/química , Alanina/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Espectroscopia de Ressonância Magnética , Camundongos , Relação Estrutura-Atividade
12.
J Pharm Biomed Anal ; 129: 581-592, 2016 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-27521818

RESUMO

Monoterpenoids with "cage-like" pinane skeleton are the unique and main bioactive constituents in peony root, the root of Paeonia lactiflora. A liquid chromatography coupled with ion trap and time-of-flight mass spectrometry (LC-IT-TOF-MS) method was developed for characterization and quantification of monoterpenoids in different types of peony root and the roots of related Paeonia species. MS/MS fragmentation patterns of monoterpenoids with paeoniflorin-, albiflorin- and sulfonated paeoniflorin-type of skeletons were elucidated, which provided basic clues enabling subsequent identification of 35 monoterpenoids in LC-MS profiles of Paeonia species. The profiling analysis and further quantification of 15 main monoterpenoids in 56 samples belonged to red peony root (RPR), white peony root (WPR), peony root in Japanese market (PR) and the roots of related Paeonia species revealed that paeoniflorin, benzoylpaeoniflorin, galloylpaeoniflorin, oxypaoniflorin and albiflorin were predominant constituents in all the samples; mudanpioside C was the characteristic component of P. lactiflora, and 4-O-methyl-paeoniflorin was only detected in P. veitchii and P. anomala. Total contents of the 15 monoterpenoids were obviously higher in the roots of P. lactiflora and P. veitchii than in those of P. anomala and P. japonica. Principal component analysis based on the quantitative results showed that the samples derived from P. lactiflora were clearly classified into RPR, WPR/PR, and sulfur-fumigated WPR groups, besides the respective group of P. veitchii and P. anomala. This study clarified the chemical characteristics of the respective type of peony root and the related Paeonia species, as well as the marker constituents for their discrimination.


Assuntos
Monoterpenos/química , Paeonia/química , Raízes de Plantas/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/química , Cromatografia Líquida/métodos , Medicamentos de Ervas Chinesas/química , Glucosídeos/química , Espectrometria de Massas em Tandem/métodos
13.
J Asian Nat Prod Res ; 18(6): 509-19, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27140322

RESUMO

Nine new compounds, together with 16 known analogs, were isolated from the whole plants of Rehmannia chingii. The structures of compounds 1-9 were elucidated on the basis of their spectroscopic data and chemical evidence. In addition, the new compounds were tested for their hepatoprotective activities against APAP-induced HepG2 cell damage and their ability to inhibit LPS-induced nitric oxide production in the murine microglia BV2 cell line. Compounds 2 and 5 exhibited pronounced hepatoprotective activities against APAP-induced HepG2 cell damage at a concentration of 10 µM, and compounds 4 and 9 showed moderate inhibitory activity against microglial inflammation factor with IC50 values of 3.51 and 7.11 µM, respectively.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/isolamento & purificação , Medicamentos de Ervas Chinesas/isolamento & purificação , Glicosídeos/isolamento & purificação , Rehmannia/química , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Glicosídeos/química , Glicosídeos/farmacologia , Células Hep G2 , Humanos , Lipopolissacarídeos/farmacologia , Fígado/efeitos dos fármacos , Camundongos , Microglia/efeitos dos fármacos , Estrutura Molecular , Óxido Nítrico/biossíntese
14.
J Drugs Dermatol ; 15(4): 390-6, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27050693

RESUMO

Crisaborole topical ointment, 2% (formerly known as AN2728) is a benzoxaborole, nonsteroidal, topical, anti-inflammatory phosphodiesterase 4 (PDE4) inhibitor investigational compound that recently completed phase 3 studies for the treatment of mild to moderate atopic dermatitis (AD). The unique configuration of boron within the crisaborole molecule enables selective targeting and inhibition of PDE4, an enzyme that converts the intracellular second messenger 3'5'-cyclic adenosine monophosphate (cAMP) into the active metabolite adenosine monophosphate (AMP). By inhibiting PDE4 and thus increasing levels of cAMP, crisaborole controls inflammation. The use of boron chemistry enabled synthesis of a low-molecular-weight compound (251 daltons), thereby facilitating effective penetration of crisaborole through human skin. In vitro experiments showed that crisaborole inhibits cytokine production from peripheral blood mononuclear cells in a pattern similar to other PDE4 inhibitors and distinct from corticosteroids. Crisaborole also displayed topical anti-inflammatory activity in a skin inflammation model. Once crisaborole reaches systemic circulation after topical application, it is metabolized to inactive metabolites. This limits systemic exposure to crisaborole and systemic PDE4 inhibition. In phase 1 and 2 clinical studies, crisaborole ointment, 2% was generally well tolerated and improved AD disease severity scores, pruritus, and all other AD signs and symptoms. Two large, randomized, controlled, phase 3, pivotal clinical trials assessing the efficacy and safety of crisaborole topical ointment, 2% in children, adolescents, and adults with mild to moderate AD were recently completed with positive results.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Compostos de Boro/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Dermatite Atópica/tratamento farmacológico , Inibidores da Fosfodiesterase 4/administração & dosagem , Administração Tópica , Animais , Anti-Inflamatórios não Esteroides/química , Compostos de Boro/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Dermatite Atópica/diagnóstico , Dermatite Atópica/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Pomadas , Inibidores da Fosfodiesterase 4/química , Resultado do Tratamento
15.
Biochem Pharmacol ; 109: 14-26, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27002182

RESUMO

Cantharidin is a natural toxin and an active constituent in a traditional Chinese medicine used to treat tumors. Cantharidin acts as a semi-selective inhibitor of PPP-family ser/thr protein phosphatases. Despite sharing a common catalytic mechanism and marked structural similarity with PP1C, PP2AC and PP5C, human PP4C was found to be insensitive to the inhibitory activity of cantharidin. To explore the molecular basis for this selectivity, we synthesized and tested novel C5/C6-derivatives designed from quantum-based modeling of the interactions revealed in the co-crystal structures of PP5C in complex with cantharidin. Structure-activity relationship studies and analysis of high-resolution (1.25Å) PP5C-inhibitor co-crystal structures reveal close contacts between the inhibitor bridgehead oxygen and both a catalytic metal ion and a non-catalytic phenylalanine residue, the latter of which is substituted by tryptophan in PP4C. Quantum chemistry calculations predicted that steric clashes with the bulkier tryptophan side chain in PP4C would force all cantharidin-based inhibitors into an unfavorable binding mode, disrupting the strong coordination of active site metal ions observed in the PP5C co-crystal structures, thereby rendering PP4C insensitive to the inhibitors. This prediction was confirmed by inhibition studies employing native human PP4C. Mutation of PP5C (F446W) and PP1C (F257W), to mimic the PP4C active site, resulted in markedly suppressed sensitivity to cantharidin. These observations provide insight into the structural basis for the natural selectivity of cantharidin and provide an avenue for PP4C deselection. The novel crystal structures also provide insight into interactions that provide increased selectivity of the C5/C6 modifications for PP5C versus other PPP-family phosphatases.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Cantaridina/química , Inibidores Enzimáticos/química , Proteínas Nucleares/química , Fosfoproteínas Fosfatases/química , Proteína Fosfatase 1/química , Sequência de Aminoácidos , Sítios de Ligação , Domínio Catalítico , Clonagem Molecular , Cristalografia por Raios X , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Humanos , Cinética , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas Fosfatases/antagonistas & inibidores , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Ligação Proteica , Domínios Proteicos , Proteína Fosfatase 1/antagonistas & inibidores , Proteína Fosfatase 1/genética , Proteína Fosfatase 1/metabolismo , Estrutura Secundária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Relação Estrutura-Atividade
16.
Bioorg Med Chem Lett ; 26(3): 774-777, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26764188

RESUMO

Direct coupling of a hydrophobic drug and a hydrophilic natural product via an ester bond produced an amphiphilic adduct that formed liposomes. Liposomes of resveratrol-norcantharidin adduct are capable of forming a tadpole-like nanoparticle and exhibited high toxicity in zebrafish embryos to give the better transportation and the effective concentration into cells. Using fluorescent chromophore showed the liposome in the stomach and intestinal villi rather than in the skin and muscle. This result may provide an insight into the mechanism of action of traditional Chinese medicines, which often contain a significant amount of flavonoids and polyphenol analogs.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Nanopartículas/química , Estilbenos/química , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/toxicidade , Portadores de Fármacos/química , Embrião não Mamífero/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Lipossomos/química , Medicina Tradicional Chinesa , Tamanho da Partícula , Resveratrol , Estilbenos/toxicidade , Peixe-Zebra/crescimento & desenvolvimento
17.
J Sep Sci ; 38(24): 4187-95, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26456358

RESUMO

Shuanghuanlian oral liquid, a traditional Chinese medicine preparation, is a mixture of three herbs (Flos Lonicerae, Radix Scutellariae and Fructus Forsythiae). In this study, the quantitative analysis of three main active compounds, chlorogenic acid, forsythin and baicalin in samples from different manufacturers was performed rapidly by high-performance liquid chromatography coupled with photodiode array detection followed by Contour Projection coupled to stepwise regression treatment of the obtained three-dimensional spectra in which the partial overlap between adjacent target components existed. The method was validated for linearity (R>0.9940), precision (RSD<1.25%), recovery (92.20-102.50%), limit of detection (0.01-0.02 µg/mL) and limit of quantification (0.03-0.07 µg/mL). The results indicated that the combination of the three-dimensional spectra of traditional Chinese medicine and Contour Projection-stepwise regression offered an accurate, simple, low-cost and eco-friendly way for the rapid quantitative analysis of Shuanghuanlian oral liquid samples.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/análise , Técnicas de Química Analítica/métodos , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/química , Flavonoides/análise , Furanos/análise , Administração Oral , Compostos Bicíclicos Heterocíclicos com Pontes/química , Técnicas de Química Analítica/instrumentação , Ácido Clorogênico/química , Cromatografia Líquida de Alta Pressão/economia , Flavonoides/química , Furanos/química , Modelos Lineares , Reprodutibilidade dos Testes , Fatores de Tempo
18.
Nat Prod Commun ; 10(2): 341-4, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25920279

RESUMO

Two new ramulosin derivatives, 7α-hydroxy-8-dihydroramulosin (1) and 7-ketoramulosin (2), along with three known metabolites, (+)-ramulosin (3), 6-hydroxyramulosin (4), and 8-dihydroramulosin (5), were isolated from the crude extract of Truncatella angustata, an entomogenous fungus isolated from the Septobasidium-infected insect Aspidiotus sp. The structures of 1 and 2 were elucidated by nuclear magnetic resonance experiments, and 1 was further confirmed by X-ray crystallography. The absolute configuration of 1 was assigned by single-crystal X-ray diffraction analysis using Cu Kα radiation, whereas that of 2 was determined by electronic circular dichroism (ECD) calculations. Compounds 1-5 were tested for cytotoxicity against four human carcinoma cell lines, HeLa, A549, MCF-7, and T24. Compound 4 showed weak cytotoxic effects against A549 and T24.


Assuntos
Ascomicetos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Ascomicetos/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Modelos Moleculares , Estrutura Molecular
19.
J Neural Eng ; 12(1): 016014, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25588201

RESUMO

OBJECTIVE: The aim of this study was to compare two different microelectrode materials--the conductive polymer composite poly-3,4-ethylenedioxythiophene (PEDOT)-carbon nanotube(CNT) and titanium nitride (TiN)--at activating spikes in retinal ganglion cells in whole mount rat retina through stimulation of the local retinal network. Stimulation efficacy of the microelectrodes was analyzed by comparing voltage, current and transferred charge at stimulation threshold. APPROACH: Retinal ganglion cell spikes were recorded by a central electrode (30 µm diameter) in the planar grid of an electrode array. Extracellular stimulation (monophasic, cathodic, 0.1-1.0 ms) of the retinal network was performed using constant voltage pulses applied to the eight surrounding electrodes. The stimulation electrodes were equally spaced on the four sides of a square (400 × 400 µm). Threshold voltage was determined as the pulse amplitude required to evoke network-mediated ganglion cell spiking in a defined post stimulus time window in 50% of identical stimulus repetitions. For the two electrode materials threshold voltage, transferred charge at threshold, maximum current and the residual current at the end of the pulse were compared. MAIN RESULTS: Stimulation of retinal interneurons using PEDOT-CNT electrodes is achieved with lower stimulation voltage and requires lower charge transfer as compared to TiN. The key parameter for effective stimulation is a constant current over at least 0.5 ms, which is obtained by PEDOT-CNT electrodes at lower stimulation voltage due to its faradaic charge transfer mechanism. SIGNIFICANCE: In neuroprosthetic implants, PEDOT-CNT may allow for smaller electrodes, effective stimulation in a safe voltage regime and lower energy-consumption. Our study also indicates, that the charge transferred at threshold or the charge injection capacity per se does not determine stimulation efficacy.


Assuntos
Potenciais de Ação/fisiologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Terapia por Estimulação Elétrica/instrumentação , Microeletrodos , Nanotubos de Carbono/química , Polímeros/química , Células Ganglionares da Retina/fisiologia , Animais , Materiais Revestidos Biocompatíveis/síntese química , Impedância Elétrica , Eletrodos Implantados , Análise de Falha de Equipamento , Feminino , Teste de Materiais , Desenho de Prótese , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Eletricidade Estática , Titânio/química , Próteses Visuais
20.
Biomaterials ; 41: 132-40, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25522972

RESUMO

PEDOT nanoparticles with a suitable nanosize of 17.2 nm, broad adsorption from 700 to 1250 nm, and photothermal conversion efficiency (η) of 71.1%, were synthesized using an environmentally friendly hydrothermal method. Due to the electrostatic attraction between indocyanine green (ICG) and PEDOT, the stability of ICG in aqueous solution was effectively improved. The PEDOT nanoparticles modified with glutaraldehyde (GTA) targeted bacteria directly, and MTT experiments demonstrated the low toxicity of PEDOT:ICG@PEG-GTA in different bacteria and cells. Pathogenic bacteria were effectively killed by photodynamic therapy (PDT) and photothermal therapy (PTT) with PEDOT:ICG@PEG-GTA in the presence of near-infrared (NIR) irradiation (808 nm for PDT, and 1064 nm for PTT). The combination of the two different bacteriostatic methods was significantly more effective than PTT or PDT alone. The obtained PEDOT:ICG@PEG-GTA may be used as a novel synergistic agent in combination photodynamic and photothermal therapy to inactivate pathogenic bacteria in both the NIR I and II window.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Hipertermia Induzida , Nanocompostos/química , Fotoquimioterapia , Polímeros/química , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Esterilização , Compostos Bicíclicos Heterocíclicos com Pontes/toxicidade , Linhagem Celular Tumoral , Escherichia coli/efeitos dos fármacos , Escherichia coli/ultraestrutura , Fluorescência , Glutaral/toxicidade , Humanos , Verde de Indocianina/toxicidade , Viabilidade Microbiana/efeitos dos fármacos , Nanocompostos/ultraestrutura , Tamanho da Partícula , Polietilenoglicóis/toxicidade , Polímeros/toxicidade , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/ultraestrutura
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