Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23.593
Filtrar
1.
Int J Nanomedicine ; 14: 4741-4754, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456635

RESUMO

Background: Ipomoea batatas (L.) Lam.(Ib) has high content of various beneficial nutrients which helps in improving and maintaining human health. It is well known as a functional food and also a valuable source of unique natural products. It contains various phenolic and flavonoid bioactive compounds. Methods: In this study, using the outer peel of two varieties of Ib : Korean red skin sweet potato and Korean pumpkin sweet potato, silver nanoparticles (AgNPs) were synthesized (termed Ib1-AgNps and Ib2-AgNps), respectively. Characterization of Ib1-AgNPs and Ib2-AgNPs was carried out through scanning electron microscopy, Fourier-transform infrared (FT-IR) spectroscopy, energy-dispersive X-ray analysis, X-ray powder diffraction and UV-Vis spectroscopy. Further, the bio-potential of the synthesized AgNPs was investigated by antidiabetic (α-glucosidase assay), antioxidant (free radical scavenging assays), antibacterial (disc diffusion method) and cytotoxicity assays (cell viability against HepG2 cells). Results: FT-IR spectroscopy revealed the contribution of bioactive compounds existing in Ib1 and Ib2 extracts, in the biosynthesis and equilibrium of the AgNPs. Although the Ib2-AgNPs had a higher atomic percentage of Ag in comparison with Ib1-AgNPs, in the antidiabetic assay, the inhibition percentage of α-glucosidase was higher for AgNPs of Ib1 than Ib2, at all three concentrations examined. From the cytotoxicity results, HepG2 cancer cells were more sensitive to the Ib1-AgNPs in comparison to the Ib2-AgNPs-treated HepG2 cells. The antioxidant prospective was higher in Ib2-AgNPs than Ib1-AgNPs. Moreover, the Ib2-AgNPs showed inhibitory action against all five tested pathogenic bacteria, producing an inhibition zone of 8.74-11.52 mm while Ib1-AgNPs had an inhibitory effect on four of them, with an 8.67-11.23 (mm) inhibition zone. Conclusions: Overall, the results concluded that the Ib2-AgNPs exhibited relatively higher functional activity than Ib1-AgNPs, which might be credited to the greater abundance of bioactive compounds existing in Ib2 extract that acted as reducing as well as capping agents in the synthesis of Ib2-AgNPs. Overall, the current study highlights a novel cost-effective and eco-friendly AgNPs synthesis using food waste peels with biocompatibility and could be potentially utilized in biomedical and pharmaceutical industries.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Ipomoea batatas/química , Nanopartículas Metálicas/química , Prata/farmacologia , Bactérias/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Hipoglicemiantes/farmacologia , Concentração Inibidora 50 , Nanopartículas Metálicas/ultraestrutura , Testes de Sensibilidade Microbiana , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X , alfa-Glucosidases/metabolismo
2.
Chem Commun (Camb) ; 55(66): 9829-9832, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31363730

RESUMO

Polyethylene glycol grafted pyrrole-based conjugated polymers are synthesized through a one-pot multicomponent methodology, the self-assemblies of which enable nanoparticle size-selective encapsulation of drug molecules and their sustained release. Efficient loading of curcumin through drug-nanoparticle core interactions is probed using FRET, and the inherently fluorescent nature of polypyrrole could be used to detect these nanocarriers intracellularly.


Assuntos
Portadores de Fármacos , Nanopartículas/química , Polietilenoglicóis/química , Polímeros/química , Pirróis/química , Linhagem Celular Tumoral , Curcumina/administração & dosagem , Transferência Ressonante de Energia de Fluorescência , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Microscopia Eletrônica de Transmissão , Espectrofotometria Ultravioleta
4.
Exp Parasitol ; 205: 107747, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31442454

RESUMO

Development of new chemotherapeutic agents is an essential issue in the treatment and control of a disease. This study aimed to evaluate the anti-leishmanial activity of amiodarone, an antiarrhythmic class III drug, against Leishmania major, the most prevalent etiological agent of cutaneous leishmaniasis in the old world. The proliferation of promastigotes and intracellular amastigotes in the absence or presence of amiodarone was estimated, in an in vitro study. For in vivo study, five weeks after infection of BALB/c mice with L. major, when the lesions appeared at the injection site, the mice were divided into four groups (n = 6 each); treatment was conducted for 28 consecutive days with vehicle, amiodarone at 40 mg/kg orally and glucantime at 60 mg/kg intraperitoneally. Therapy with amiodarone reduced the size of lesions compared to the untreated group after 12 days. Amiodarone decreased the parasite load and inflammatory responses, particularly the macrophages containing amastigotes, and enhanced granulation tissue formation in the dermis and subcutaneous area. The Tumor necrosis factor-α and Interleukin-6 levels were significantly lower in the cell culture supernatants of the inguinal lymph node in the amiodarone treated group compared to the vehicle and untreated groups. Amiodarone significantly increased the activity of glutathione peroxidase in comparison to the vehicle and untreated groups but did not affect the plasma levels of superoxide dismutase, malondialdehyde, adiponectin, and ferric reducing ability of plasma. Therefore, the anti- L. major activity and immunomodulatory effects of amiodarone reduced the parasitic load and enhanced wound healing in cutaneous leishmaniasis in BALB/c mice. Amiodarone reduced the lesion surface area, but it did not cure it completely.


Assuntos
Amiodarona/uso terapêutico , Antiprotozoários/uso terapêutico , Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Adiponectina/sangue , Amiodarona/farmacologia , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Antiprotozoários/farmacologia , Linhagem Celular , Feminino , Glutationa Peroxidase/metabolismo , Concentração Inibidora 50 , Interleucina-6/análise , Leishmania major/ultraestrutura , Leishmaniose Cutânea/parasitologia , Linfonodos/química , Linfonodos/imunologia , Macrófagos/parasitologia , Malondialdeído/sangue , Antimoniato de Meglumina/farmacologia , Antimoniato de Meglumina/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Distribuição Aleatória , Pele/parasitologia , Pele/patologia , Pele/ultraestrutura , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/análise
5.
Exp Parasitol ; 205: 107738, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31442456

RESUMO

Leishmaniases, caused by Leishmania spp., are among the most prevalent infectious diseases in the world and their treatment may present high toxicity and side/adverse effects. This study evaluated the antileishmanial activity of the Hexanic Eluate subfraction from Maytenus guianensis bark (HEMg) incorporated in microparticles of PLGA. One batch of microparticles produced contained HEMg (HEMgP) and another contained the PLGA polymer alone (PCTE). The microparticles were characterized in regards to diameter, Zeta potential, encapsulation rate and morphology and their cytotoxicity was evaluated against J774 macrophages. The infection assay employing peritoneal macrophages witth L. amazonensis and cytokine dosages were performed on the cell supernatants. The groups of infected BALB/C mice were treated, euthanized and the parasite load and cytokine production were evaluated. The diameters and zeta potential were: 4 µm and -11.6 mV (PCTE) and 7.8 µm and -26.7 mV (HEMgP). The encapsulation rate was ≅ 15% and the morphology of the particles was spherical and homogeneous. In the infection assay, HEMgP inhibited the amastigotes by 70% (24 h) and 59% (48 h) and induced IL-12 and TNF-α production. HEMg in solution reduced the number of parasites in the lymph nodes by 50% and HEMgP administration increased the levels of IL-12 and TNF-α cytokines in lymph nodes and in the lesion site. When encapsulated, HEMg maintained its antileishmanial activity, but in a more attenuated and sustained form over time, showing promise as complementary/alternative therapy against cutaneous leishmaniasis.


Assuntos
Antiprotozoários/farmacologia , Leishmania mexicana/efeitos dos fármacos , Maytenus/química , Casca de Planta/química , Extratos Vegetais/farmacologia , Animais , Biodegradação Ambiental , Linhagem Celular , Micropartículas Derivadas de Células/química , Micropartículas Derivadas de Células/ultraestrutura , Concentração Inibidora 50 , Linfonodos/parasitologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Varredura
6.
Exp Parasitol ; 205: 107753, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31469986

RESUMO

Trypanosoma brucei causes human African trypanosomiasis and Nagana disease in cattle, imposing substantial medical and economic burden in sub-Saharan Africa. The current treatments have limitations, including the requirement for elaborated protocols, development of drug resistance, and they are prone to adverse side effects. In vitro screening of a library of 14 dinuclear-thiolato bridged arene ruthenium complexes, originally developed for treatment of cancer cells, resulted in the identification of 7 compounds with IC50 values ranging from 3 to 26 nM. Complex [(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-o-Pri)3]Cl (2) (IC50 = 4 nM) and complex [(η6-p-MeC6H4Pri)2Ru2(µ2-SCH2C6H4-p-But)2(µ2-SC6H4-p-OH)]BF4(9) (IC50 = 26 nM) were chosen for further assessments. Application of complex 2 and 9 at 20 nM and 200 nM, respectively, for 4.5 h induced alterations in the trypanosome mitochondrion as evidenced by immunofluorescence employing an antibody against mitochondrial Hsp70 and Mitotracker labeling. Transmission electron microscopy of parasites taken at 2 and 4h of treatment demonstrated massive alterations in the mitochondrial ultrastructure, while other organelles and structural elements of the parasites remained unaffected. Complex 2 treated trypanosomes exhibited a distorted mitochondrial membrane, and the mitochondrial matrix was transformed into an amorphous mass with different degrees of electron densities. Complex 9 did not notably impair the integrity of the membrane, but the interior of the mitochondrion appeared either completely translucent, or was filled with filamentous structures of unknown nature. Dose- and time-dependent effects of these two compounds on the mitochondrial membrane potential were detected by tetramethylrhodamine ethyl ester assay. Thus, the mitochondrion and associated metabolic processes are an important target of dinuclear thiolato-bridged arene ruthenium complexes in T. brucei.


Assuntos
Potencial da Membrana Mitocondrial/efeitos dos fármacos , Compostos de Rutênio/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/parasitologia , Animais , Relação Dose-Resposta a Droga , Imunofluorescência , Humanos , Concentração Inibidora 50 , Microscopia Eletrônica de Transmissão , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Compostos de Rutênio/química , Fatores de Tempo , Trypanosoma brucei brucei/metabolismo , Trypanosoma brucei brucei/ultraestrutura , Tripanossomíase Africana/sangue
7.
J Enzyme Inhib Med Chem ; 34(1): 1426-1438, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401883

RESUMO

Anaplastic lymphoma kinase (ALK) has been recognised as a promising molecular target of targeted therapy for NSCLC. We performed SAR study of pyrazolo[3,4-b]pyridines to override crizotinib resistance caused by ALK-L1196M mutation and identified a novel and potent L1196M inhibitor, 10g. 10g displayed exceptional enzymatic activities (<0.5 nM of IC50) against ALK-L1196M as well as against ALK-wt. In addition, 10g is an extremely potent inhibitor of ROS1 (<0.5 nM of IC50) and displays excellent selectivity over c-Met. Moreover, 10g strongly suppresses proliferation of ALK-L1196M-Ba/F3 and H2228 cells harbouring EML4-ALK via apoptosis and the ALK signalling blockade. The results of molecular docking studies reveal that, in contrast to crizotinib, 10g engages in a favourable interaction with M1196 in the kinase domain of ALK-L1196M and hydrogen bonding with K1150 and E1210. This SAR study has provided a useful insight into the design of novel and potent inhibitors against ALK gatekeeper mutant.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Quinase do Linfoma Anaplásico/metabolismo , Apoptose/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Transformada , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida , Cristalografia por Raios X , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Pirazóis/química , Piridinas/química , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
8.
J Enzyme Inhib Med Chem ; 34(1): 1451-1456, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31409143

RESUMO

Herein, we report the effect of nine FDA approved protease inhibitor drugs against a new HIV-1 subtype C mutant protease, E35D↑G↑S. The mutant has five mutations, E35D, two insertions, position 36 (G and S), and D60E. Kinetics, inhibition constants, vitality, Gibbs free binding energies are reported. The variant showed a decreased affinity for substrate and low catalytic efficiency compared to the wild type. There was a significant decrease in the binding of seven FDA approved protease inhibitors against the mutant (p < .0001). Amprenavir and ritonavir showed the least decrease, but still significant reduced activity in comparison to the wildtype (4 and 5 folds, respectively, p = .0021 and .003, respectively). Nelfinavir and atazanavir were the worst inhibitors against the variant as seen from the IC50, with values of 1401 ± 3.0 and 685 ± 3.0 nM, respectively. Thermodynamics data showed less favourable Gibbs free binding energies for the protease inhibitors to the mutant.


Assuntos
Inibidores da Protease de HIV/farmacologia , Protease de HIV/efeitos dos fármacos , HIV-1/enzimologia , Termodinâmica , Protease de HIV/genética , Protease de HIV/metabolismo , Inibidores da Protease de HIV/química , Concentração Inibidora 50 , Cinética , Simulação de Acoplamento Molecular , Mutação
9.
J Enzyme Inhib Med Chem ; 34(1): 1439-1450, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31409157

RESUMO

Leishmaniasis is a tropical disease found in more than 90 countries. The drugs available to treat this disease have nonspecific action and high toxicity. In order to develop novel therapeutic alternatives to fight this ailment, pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHF-TS) have been targeted, once Leishmania is auxotrophic for folates. Although PTR1 and DHFR-TS from other protozoan parasites have been studied, their homologs in Leishmania chagasi have been poorly characterized. Hence, this work describes the optimal conditions to express the recombinant LcPTR1 and LcDHFR-TS enzymes, as well as balanced assay conditions for screening. Last but not the least, we show that 2,4 diaminopyrimidine derivatives are low-micromolar competitive inhibitors of both enzymes (LcPTR1 Ki = 1.50-2.30 µM and LcDHFR Ki = 0.28-3.00 µM) with poor selectivity index. On the other hand, compound 5 (2,4-diaminoquinazoline derivative) is a selective LcPTR1 inhibitor (Ki = 0.47 µM, selectivity index = 20).


Assuntos
Inibidores Enzimáticos/farmacologia , Leishmania infantum/enzimologia , Complexos Multienzimáticos/antagonistas & inibidores , Oxirredutases/antagonistas & inibidores , Timidilato Sintase/antagonistas & inibidores , Catálise , Cromatografia de Afinidade , Clonagem Molecular , Avaliação Pré-Clínica de Medicamentos , Eletroforese em Gel de Poliacrilamida , Escherichia coli/genética , Concentração Inibidora 50 , Complexos Multienzimáticos/genética , Complexos Multienzimáticos/isolamento & purificação , Complexos Multienzimáticos/metabolismo , Oxirredutases/genética , Oxirredutases/isolamento & purificação , Oxirredutases/metabolismo , Tetra-Hidrofolato Desidrogenase/genética , Tetra-Hidrofolato Desidrogenase/isolamento & purificação , Tetra-Hidrofolato Desidrogenase/metabolismo , Timidilato Sintase/genética , Timidilato Sintase/isolamento & purificação , Timidilato Sintase/metabolismo
10.
Rev Inst Med Trop Sao Paulo ; 61: e33, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31269109

RESUMO

Leishmaniasis is a disease that affects millions of people and it is an important public health problem. The drugs currently used for the treatment of leishmaniasis present undesirable side effects and low efficacy. In this study, we evaluated the in vitro activity of Melampodium divaricatum (MD-EO) and Casearia sylvestris (CS-EO) essential oils (EO) against promastigote and amastigote forms of Leishmania amazonensis. Sesquiterpenes E-caryophyllene (56.0%), germacrene D (12.7%) and bicyclogermacrene (9.2%) were identified as the main components of MD-EO, whereas E-caryophyllene (22.2%), germacrene D (19.6%) and bicyclogermacrene (12.2%) were the main constituents of CS-EO. CS-EO and E-caryophyllene were active against promastigote forms of L. amazonensis (IC50 24.2, 29.8 and 49.9 µg/mL, respectively). However, MD-EO, CS-EO and E-caryophyllene were more active against amastigote forms, with IC50 values of 10.7, 14.0, and 10.7 µg/mL, respectively. E-caryophyllene presented lower cytotoxicity against macrophages J774-A1 (CC50 of 62.1 µg/mL) than the EO. The EOs and E-caryophyllene should be further studied for the development of new antileishmanial drugs.


Assuntos
Antiprotozoários/farmacologia , Asteraceae/química , Casearia/química , Leishmania mexicana/efeitos dos fármacos , Óleos Voláteis/farmacologia , Antiprotozoários/isolamento & purificação , Humanos , Concentração Inibidora 50 , Leishmania mexicana/isolamento & purificação , Testes de Sensibilidade Parasitária
11.
Pharm Res ; 36(9): 131, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263962

RESUMO

PURPOSE: Intranasal administration has been extensively applied to deliver drugs to the brain. In spite of its unfavorable biopharmaceutic properties, melatonin (MLT) has demonstrated anticancer effects against glioblastoma. This study describes the nose-to-brain delivery of MLT-loaded polycaprolactone nanoparticles (MLT-NP) for the treatment of glioblastoma. METHODS: MLT-NP were prepared by nanoprecipitation. Following intranasal administration in rats, brain targeting of the formulation was demonstrated by fluorescence tomography. Brain and plasma pharmacokinetic profiles were analyzed. Cytotoxicity against U87MG glioblastoma cells and MRC-5 non-tumor cells was evaluated. RESULTS: MLT-NP increased the drug apparent water solubility ~35 fold. The formulation demonstrated strong activity against U87MG cells, resulting in IC50 ~2500 fold lower than that of the free drug. No cytotoxic effect was observed against non-tumor cells. Fluorescence tomography images evidenced the direct translocation of nanoparticles from nasal cavity to the brain. Intranasal administration of MLT-NP resulted in higher AUCbrain and drug targeting index compared to the free drug by either intranasal or oral route. CONCLUSIONS: Nanoencapsulation of MLT was crucial for the selective antitumoral activity against U87MG. In vivo evaluation confirmed nose-to-brain delivery of MLT mediated by nanoparticles, highlighting the formulation as a suitable approach to improve glioblastoma therapy.


Assuntos
Antineoplásicos/farmacocinética , Encéfalo/metabolismo , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Melatonina/farmacocinética , Nanopartículas/química , Poliésteres/química , Administração Intranasal , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Masculino , Melatonina/administração & dosagem , Ratos Wistar , Solubilidade , Distribuição Tecidual
12.
Exp Parasitol ; 204: 107724, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31279930

RESUMO

Only two drugs are currently available for the treatment of Chagas disease and their effectiveness are unsatisfactory. Photorhabdus luminescens and Xenorhabdus nematophila, two enteric bacteria highly pathogenic to a broad range of insects, have been studied as potential source for bioactive metabolites against protozoa causing neglected tropical diseases. Therefore, we tested the in vitro anti-Trypanosoma cruzi activity of secreted metabolites from these bacteria. The conditioned medium of X. nematophila and P. luminescens showed significant parasiticidal activity in a concentration-dependent manner (IC50XN = 0.34 mg/mL, IC50PL = 1.0 mg/mL). The parasiticidal compound was identified as a small molecule stable to heating and pH changes ranging from 2 to 12. Moreover, anti-Trypanosoma molecules secreted by both bacteria stimulate the trypanocidal activity of macrophages by a mechanism independent of nitric oxide. Summarizing, our studies reveal that P. luminescens and X. nematophila are potential sources of putative novel drugs against Chagas disease.


Assuntos
Proteínas de Bactérias/farmacologia , Photorhabdus/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Xenorhabdus/química , Análise de Variância , Animais , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/uso terapêutico , Bioensaio , Doença de Chagas/tratamento farmacológico , Meios de Cultivo Condicionados , Endopeptidase K/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Temperatura Ambiente , Tripanossomicidas/efeitos adversos , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/crescimento & desenvolvimento
13.
BMC Bioinformatics ; 20(1): 408, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31357929

RESUMO

BACKGROUND: Understanding the phenotypic drug response on cancer cell lines plays a vital role in anti-cancer drug discovery and re-purposing. The Genomics of Drug Sensitivity in Cancer (GDSC) database provides open data for researchers in phenotypic screening to build and test their models. Previously, most research in these areas starts from the molecular fingerprints or physiochemical features of drugs, instead of their structures. RESULTS: In this paper, a model called twin Convolutional Neural Network for drugs in SMILES format (tCNNS) is introduced for phenotypic screening. tCNNS uses a convolutional network to extract features for drugs from their simplified molecular input line entry specification (SMILES) format and uses another convolutional network to extract features for cancer cell lines from the genetic feature vectors respectively. After that, a fully connected network is used to predict the interaction between the drugs and the cancer cell lines. When the training set and the testing set are divided based on the interaction pairs between drugs and cell lines, tCNNS achieves 0.826, 0.831 for the mean and top quartile of the coefficient of determinant (R2) respectively and 0.909, 0.912 for the mean and top quartile of the Pearson correlation (Rp) respectively, which are significantly better than those of the previous works (Ammad-Ud-Din et al., J Chem Inf Model 54:2347-9, 2014), (Haider et al., PLoS ONE 10:0144490, 2015), (Menden et al., PLoS ONE 8:61318, 2013). However, when the training set and the testing set are divided exclusively based on drugs or cell lines, the performance of tCNNS decreases significantly and Rp and R2 drop to barely above 0. CONCLUSIONS: Our approach is able to predict the drug effects on cancer cell lines with high accuracy, and its performance remains stable with less but high-quality data, and with fewer features for the cancer cell lines. tCNNS can also solve the problem of outliers in other feature space. Besides achieving high scores in these statistical metrics, tCNNS also provides some insights into the phenotypic screening. However, the performance of tCNNS drops in the blind test.


Assuntos
Antineoplásicos/uso terapêutico , Aprendizado Profundo , Neoplasias/tratamento farmacológico , Redes Neurais (Computação) , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Bases de Dados Factuais , Genômica , Humanos , Concentração Inibidora 50 , Especificidade de Órgãos/efeitos dos fármacos , Fenótipo , Análise de Regressão
14.
Vet Microbiol ; 235: 21-24, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31282375

RESUMO

Occurrence of avian influenza (AI) with Neuraminidase (NA) mutations which confer reduced neuraminidase inhibitor (NAI) susceptibility has remained a cause of concern. The susceptibility to NAIs of 67 highly pathogenic avian influenza H5N1 viruses isolated during 2006-2012 in India was tested in phenotypic fluorescence-based NA inhibition assay, sequence analysis and in ovo. One isolate showed a novel NA I117T amino acid substitution (N2 numbering) and eight isolates showed previously known NAI-resistance marker mutations (I117V, E119D, N294S, total 9/67). The overall incidence of resistant variants was 13.4%. The novel I117T substitution reduced oseltamivir susceptibility by 18.6-fold and zanamivir susceptibility by 11.8-fold, compared to the wild type AI H5N1virus, thus showed cross-resistance to both oseltamivir and zanamivir in NA inhibition assays. However, the other two isolates with I117V substitution were sensitive to both the NAIs. In addition, the comparison of growth of the I117T and I117V variants in presence of NAI's in the in ovo assays exhibited difference in growth levels. The present study reports the natural occurrence of a novel I117T mutation in AI H5N1 virus conferring cross-resistance to oseltamivir and zanamivir highlighting the urgent need of antiviral surveillance of AI viruses.


Assuntos
Antivirais/farmacologia , Virus da Influenza A Subtipo H5N1/efeitos dos fármacos , Neuraminidase/genética , Oseltamivir/farmacologia , Proteínas Virais/genética , Zanamivir/farmacologia , Substituição de Aminoácidos , Animais , Galinhas , Farmacorresistência Viral , Índia , Virus da Influenza A Subtipo H5N1/genética , Concentração Inibidora 50 , Mutação de Sentido Incorreto , Zigoto
15.
Phytochemistry ; 166: 112060, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302343

RESUMO

Continued interest in bioactive alkaloids led to the isolation of four undescribed alkaloids along with 74 known ones from the aerial parts of Tabernaemontana bufalina Lour. The structures of the yet undescribed alkaloids were elucidated based on NMR, IR, UV, MS and CD spectroscopic data and X-ray crystal diffraction and, according to the plant source, named as taberhaines A-D (1-4). The known compounds comprised of 66 monoterpenoid indole, three carboline and five isoquinoline alkaloids. Among them, the known apparicine inhibited significantly the activity of xanthine oxidase, which plays an important role for gout, with an IC50 value of 0.65 µM, compared to the standard drug allopurinol (IC50 = 0.60 µM).


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Tabernaemontana/química , Xantina Oxidase/antagonistas & inibidores , Alcaloides/isolamento & purificação , Domínio Catalítico , Inibidores Enzimáticos/isolamento & purificação , Concentração Inibidora 50 , Modelos Moleculares , Xantina Oxidase/química
16.
Chem Pharm Bull (Tokyo) ; 67(6): 556-565, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155561

RESUMO

Aldose reductase (AR) is associated with the onset of diabetic complications. Botryllazine A and its analogues were synthesized and evaluated for human AR inhibitory activity. Analogues possessing aromatic bicyclic systems at the C5 position of the central pyrazine ring exhibited superior AR inhibiting activity relative to the parent botryllazine A. In addition, the benzoyl groups at positions C2 and C3 of the pyrazine ring were dispensable for this improved inhibitory activity. Conversely, a benzoyl group-containing phenolic hydroxyl groups-at either position C2 or C3 of the pyrazine ring was essential for attainment of high inhibitory activity approaching that of sorbinil (a highly effective AR inhibitor).


Assuntos
Aldeído Redutase/metabolismo , Inibidores Enzimáticos/síntese química , Pirazinas/química , Aldeído Redutase/antagonistas & inibidores , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Ligações de Hidrogênio , Concentração Inibidora 50 , Conformação Molecular , Simulação de Acoplamento Molecular , Pirazinas/síntese química , Pirazinas/metabolismo
17.
Chem Pharm Bull (Tokyo) ; 67(6): 566-575, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155562

RESUMO

We report here the development of phenylamino-1,3,5-triazine derivatives as novel nonsteroidal progesterone receptor (PR) antagonists. PR plays key roles in various physiological systems, including the female reproductive system, and PR antagonists are promising candidates for clinical treatment of multiple diseases. By using the phenylamino-1,3,5-triazine scaffold as a template structure, we designed and synthesized a series of 4-cyanophenylamino-1,3,5-triazine derivatives. The synthesized compounds exhibited PR antagonistic activity, and among them, compound 12n was the most potent (IC50 = 0.30 µM); it also showed significant binding affinity to the PR ligand-binding domain. Docking simulation supported the design rationale of the compounds. Our results suggest that the phenylamino-1,3,5-triazine scaffold is a versatile template for development of nonsteroidal PR antagonists and that the developed compounds are promising lead compounds for further structural development of nonsteroidal PR antagonists.


Assuntos
Antineoplásicos/síntese química , Desenho de Drogas , Receptores de Progesterona/antagonistas & inibidores , Triazinas/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Receptores de Progesterona/metabolismo , Relação Estrutura-Atividade , Triazinas/metabolismo , Triazinas/farmacologia
18.
Chem Pharm Bull (Tokyo) ; 67(6): 599-603, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155566

RESUMO

The PF-543 is known as a potent and selective inhibitor of sphingosine kinase (SK) 1 amongst all the SK inhibitors known to date. In a recently reported study by Pfizer on the synthesis of PF-543 derivatives and the SK inhibitory effects, the introduction of propyl moiety into sulfonyl group of PF-543 in the case of 26b revealed an excellent result of 1.7 nM of IC50 of SK1, suggesting the potential substitution of chain structure for benzenesulfonyl structure. In the present work, we aimed for identification of antitumor activity and inhibitory effects of PF-543 derivative containing aliphatic long chain (similar to known SK inhibitors) on SK1. The synthesized compound 2 exhibited an inhibitory effect on SK1 in a manner similar to that of PF-543; the PF-543 derivative manifested similar antitumor activity on HT29, HCT116 (colorectal cancer cell line), and AGS (gastric cancer cell line) cells. Also, from the docking study conducted with PF-543 and compound 2, it was apparent that the aliphatic chain in compound 2 could probably replace benzenesulfonyl structure of PF-543.


Assuntos
Antineoplásicos/síntese química , Pirrolidinas/química , Sulfonas/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/farmacologia
19.
Anal Bioanal Chem ; 411(17): 3881-3890, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31152222

RESUMO

Aflatoxin B1 (AFB1) is one of the major mycotoxins, which naturally occurs in food and agricultural products. In this study, a cyclic peptide (CVPSKPGLC) mimicking AFB1 was used to develop a biotinylated peptide-based immunoassay (bp-ELISA) for AFB1 determination. This cyclic peptide was isolated from a commercially available phage-displayed random 7-mer cyclic peptide library, and then synthesized chemically. Instead of phage particles, the peptide was biotinylated and used to detect AFB1 by bp-ELISA, with an IC50 of 0.92 ng/mL, which was approximately 60-fold better than that of phage ELISA. Good recoveries (83-102%) were obtained in spiked rice and corn samples, which were further validated by high-performance liquid chromatography-fluorescence detector. As better sensitivities (0.92-1.21 ng/mL) were obtained by bp-ELISA even using selected anti-AFB1 antibodies prepared previously in laboratory, this cyclic peptide is suitable as a substitute for synthetic competitive AFB1 antigens in food contamination monitoring. Graphical abstract.


Assuntos
Aflatoxina B1/imunologia , Antígenos/química , Antígenos/imunologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/imunologia , Sequência de Aminoácidos , Anticorpos Monoclonais/imunologia , Biotina/química , Técnicas de Visualização da Superfície Celular , Cromatografia Líquida de Alta Pressão/métodos , Reações Cruzadas , Ensaio de Imunoadsorção Enzimática , Contaminação de Alimentos/análise , Concentração Inibidora 50 , Limite de Detecção , Espectrometria de Fluorescência/métodos , Estreptavidina/química
20.
Int J Nanomedicine ; 14: 3533-3541, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190810

RESUMO

Background: Himalayan honey, a natural product of wild honey bees found in the Himalayan mountains of Nepal, has been used in medicine for many years. The successful development of nanotechnology and beneficial effects of honey would bring a new opportunity to synthesize hybrid nanomaterials for biomedical applications. Thus, the purpose of this study was to load Himalayan honey onto iron oxide nanoparticles (IO-NPs) and study their antioxidant and antimicrobial activities. Methods: Himalayan honey loaded iron oxide nanoparticles (HHLIO-NPs) were synthesized and X-ray diffraction (XRD) and scanning electron microscope (SEM) analyses were performed for characterization. UV-VIS spectra confirmed the loading of honey onto nanoparticles. The antioxidant activity of these nanoparticles was studied against 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical system. We also tested antimicrobial activity of HHLIO-NPs using well diffusion method towards both Gram-positive and Gram-negative bacterial strains of Staphylococus aureus & Escherichia coli. Results: From XRD analysis, the average particle size was found to be 33-40 nm. The SEM images show needle shape porous structures of HHLIO-NPs compared to free IO-NPs indicating the surfactant-like behaviour of honey. In DPPH radical system, the scavenging activities of Himalayan honey (HH), free IO-NPs and HHLIO-NPs ranged 7.93-35.99%, 11.02-52.02% and 16.10-80.52% respectively, with corresponding IC50 values of 1.36 mg/mL, 1.09 mg/mL and 0.52 mg/mL. The antimicrobial property of all test samples showed a noteworthy inhibition on both bacterial strains. However, the HH and HHLIO-NPs exhibited strong antibacterial activity against E. coli. Conclusion: This work reveals that the biological activity of HH is enhanced significantly after loading into IO-NPs. Thus, the HHLIO-NPs would be a promising alternative for antioxidant and antimicrobial agents.


Assuntos
Anti-Infecciosos/farmacologia , Antioxidantes/farmacologia , Compostos Férricos/química , Mel , Nanopartículas Metálicas/química , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Concentração Inibidora 50 , Nanopartículas Metálicas/ultraestrutura , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Espectrofotometria Ultravioleta , Staphylococcus aureus/efeitos dos fármacos , Difração de Raios X
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA