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2.
Bol. latinoam. Caribe plantas med. aromát ; 18(4): 359-377, jul. 2019. tab
Artigo em Inglês | LILACS | ID: biblio-1008174

RESUMO

Plant species have been used for therapeutic purposes since ancient times and are still in use today since these products represent a source of raw material for the production of phytotherapeutic formulations. Screening and investigation of plants with pharmacological potential require the evaluation of characteristics related to their action, efficacy and safety in different steps. Among these steps, pre- clinical trials are used to evaluate the properties of the test product in in vitro experiments, such as cytotoxicity assays. Within this context, this study consists of a bibliometric analysis of some in vitro cytotoxicity and toxicity assays in erythrocytes used during bioprospecting of medicinal plants. The results demonstrated the wide application of erythrocytes to evaluate the biological effects of medicinal plant extracts. The methods were found to be valid and effective for the preliminary investigation of the in vitro cytotoxicity and toxicity of plant products.


El uso de especies vegetales para fines terapéuticos es una práctica histórica y todavía bastante actual, ya que estos productos pueden representar una fuente de materia prima para la producción de formulaciones fitoterápicas. En investigación de plantas con potencial farmacológico requiere la evaluación de su acción, eficacia y seguridad, a través de diferentes etapas. Entre estas, en los ensayos preclínicos se evalúan las propiedades del producto-prueba en experimentos in vitro, tales como ensayos de citotoxicidad, entre otros. En este aspecto, el presente estudio consiste en un análisis bibliométrico acerca de algunas pruebas de citotoxicidad y toxicidad in vitro en eritrocitos realizados en los ensayos de bioprospección de plantas medicinales. Los resultados evidencian la amplia utilización de eritrocitos para la evaluación de los efectos biológicos de extractos de plantas medicinales, apuntándolos como métodos válidos y eficaces para la investigación preliminar de la citotoxicidad y toxicidad in vitro de productos vegetales.


Assuntos
Bioensaio/métodos , Extratos Vegetais/toxicidade , Eritrócitos/efeitos dos fármacos , Antioxidantes/toxicidade , Fragilidade Osmótica , Estresse Oxidativo , Eritrócitos/citologia , Bioprospecção , Hemólise/efeitos dos fármacos
3.
J Photochem Photobiol B ; 197: 111541, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31272033

RESUMO

Here, we report the novel fabrication of ZnO nanoparticles using the Costus igneus leaf extract. Gas chromatography-mass spectrometry (GC-MS) and proton nuclear magnetic resonance (1H NMR) spectroscopy to determine the bioactive components present in the plant extract. The synthesis of Ci-ZnO NPs (C. igneus- coated zinc oxide nanoparticles) was accomplished using a cost-effective and simple technique. Ci-ZnO NPs were specified using UV-visible spectroscopy, FTIR, XRD, and TEM. Ci-ZnO NPs was authenticated by UV-Vis and exhibited a peak at 365 nm. The XRD spectra proved the crystalline character of the Ci-ZnO NPs synthesized as hexagonal wurtzite. The FTIR spectrum illustrated the presence of possible functional groups present in Ci-ZnO NPs. The TEM micrograph showed evidence of the presence of a hexagonal organization with a size of 26.55 nm typical of Ci-ZnO NPs. The α-amylase and α-glucosidase inhibition assays demonstrated antidiabetic activity of Ci-ZnO NPs (74 % and 82 %, respectively), and the DPPH [2,2-diphenyl-1-picrylhydrazyl hydrate] assay demonstrated the antioxidant activity of the nanoparticles (75%) at a concentration of 100 µg/ml. The Ci-ZnO NPs exhibited promising antibacterial and biofilm inhibition activity against the pathogenic bacteria Streptococcus mutans, Lysinibacillus fusiformis, Proteus vulgaris, and Vibrio parahaemolyticus. Additionally, the Ci-ZnO NPs showed biocompatibility with mammalian RBCs with minimum hemolytic activity (0.633 % ±â€¯0.005 %) at a concentration of 200 µg/ml.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/química , Biofilmes/efeitos dos fármacos , Nanopartículas Metálicas/química , Extratos Vegetais/química , Óxido de Zinco/química , Antibacterianos/síntese química , Antibacterianos/química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Costus/química , Costus/metabolismo , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/fisiologia , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/fisiologia , Química Verde , Hemólise/efeitos dos fármacos , Humanos , Insulina/química , Nanopartículas Metálicas/toxicidade , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Extratos Vegetais/metabolismo , Folhas de Planta/química , Folhas de Planta/metabolismo , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo
4.
N Engl J Med ; 381(6): 509-519, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31199090

RESUMO

BACKGROUND: Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor. METHODS: In a multicenter, phase 3, double-blind, randomized, placebo-controlled trial, we compared the efficacy and safety of two dose levels of voxelotor (1500 mg and 900 mg, administered orally once daily) with placebo in persons with sickle cell disease. The primary end point was the percentage of participants who had a hemoglobin response, which was defined as an increase of more than 1.0 g per deciliter from baseline at week 24 in the intention-to-treat analysis. RESULTS: A total of 274 participants were randomly assigned in a 1:1:1 ratio to receive a once-daily oral dose of 1500 mg of voxelotor, 900 mg of voxelotor, or placebo. Most participants had sickle cell anemia (homozygous hemoglobin S or hemoglobin Sß0-thalassemia), and approximately two thirds were receiving hydroxyurea at baseline. In the intention-to-treat analysis, a significantly higher percentage of participants had a hemoglobin response in the 1500-mg voxelotor group (51%; 95% confidence interval [CI], 41 to 61) than in the placebo group (7%; 95% CI, 1 to 12). Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. The percentage of participants with an adverse event that occurred or worsened during the treatment period was similar across the trial groups. Adverse events of at least grade 3 occurred in 26% of the participants in the 1500-mg voxelotor group, 23% in the 900-mg voxelotor group, and 26% in the placebo group. Most adverse events were not related to the trial drug or placebo, as determined by the investigators. CONCLUSIONS: In this phase 3 randomized, placebo-controlled trial involving participants with sickle cell disease, voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. These findings are consistent with inhibition of HbS polymerization and indicate a disease-modifying potential. (Funded by Global Blood Therapeutics; HOPE ClinicalTrials.gov number, NCT03036813.).


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/administração & dosagem , Benzaldeídos/administração & dosagem , Hemoglobina Falciforme/efeitos dos fármacos , Hemoglobinas/metabolismo , Pirazinas/administração & dosagem , Pirazóis/administração & dosagem , Adolescente , Adulto , Anemia Falciforme/sangue , Antidrepanocíticos/efeitos adversos , Antidrepanocíticos/uso terapêutico , Benzaldeídos/efeitos adversos , Biomarcadores/sangue , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemoglobina Falciforme/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Hidroxiureia/uso terapêutico , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Polimerização/efeitos dos fármacos , Pirazinas/efeitos adversos , Pirazóis/efeitos adversos , Adulto Jovem
5.
Food Chem Toxicol ; 131: 110553, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31163221

RESUMO

Ginseng and its active gradient, ginsenoside Rg3 (Rg3), are widely used for a variety of health benefits, but concerns over their misuses are increasing. Previously, it has been reported that Rg3 can cause hemolysis, but its health outcome remains unknown. Here, we demonstrated that Rg3 could promote the procoagulant activity of erythrocytes through the process of hemolysis, ultimately leading to increased thrombosis. In freshly isolated human erythrocytes, Rg3 caused pore formation and fragmentation of the erythrocyte membrane. Confocal microscopy observation and flow cytometric analysis revealed that remnant erythrocyte fragments after the exposure to Rg3 expressed phosphatidylserine (PS), which can promote blood coagulation through providing assembly sites for coagulation complexes. Rat in vivo experiments further confirmed that intravenous administration of Rg3 produced PS-bearing erythrocyte debris and increased thrombosis. Collectively, we demonstrated that Rg3 could induce the procoagulant activity of erythrocytes by generating PS-bearing erythrocyte debris through hemolysis, which might provoke thrombosis.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Ginsenosídeos/efeitos adversos , Hemólise/efeitos dos fármacos , Trombose/induzido quimicamente , Animais , Membrana Eritrocítica/química , Membrana Eritrocítica/efeitos dos fármacos , Eritrócitos/metabolismo , Eritrócitos/patologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Fosfatidilserinas/química , Ratos Sprague-Dawley
6.
J Agric Food Chem ; 67(27): 7650-7659, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31241944

RESUMO

Neutrase-hydrolysates hydrolyzed from mulberry leaf proteins were separated by ion exchange chromatography, gel filtration chromatography, and semipreparative reverse-phase HPLC. Purified fractions were analyzed for their radical scavenging activity, hemolysis inhibition ability, and cellular antioxidant activity (CAA). Three new antioxidant peptides, P1 (SVL, 317 Da), P2 (EAVQ, 445 Da), and P3 (RDY, 452 Da), were obtained from the most active HPLC fraction (R1) and identified using UPLC-QTOF-MS. These three peptides were then synthesized, and their antioxidant activities were analyzed. P1 and P2 had no ability to inhibit hemolysis of erythrocytes but did show antioxidant activity on HepG2 cells. P3 showed the highest hemolysis inhibition ability (92%) and CAA value (2204 µM QE/100 g peptide). The Tyr residues at the C-terminal region play an important role in the antioxidant activity in P3. Thus, the natural peptide R1 and synthesized P3 could be used as antioxidants and might be promising components of functional foods.


Assuntos
Antioxidantes/farmacologia , Hemólise/efeitos dos fármacos , Morus/química , Peptídeos/farmacologia , Folhas de Planta/química , Proteínas de Plantas/metabolismo , Cromatografia Líquida de Alta Pressão , Células Hep G2 , Humanos , Hidrólise , Fígado/efeitos dos fármacos , Metaloendopeptidases/metabolismo , Peso Molecular , Peptídeos/química , Peptídeos/isolamento & purificação
7.
Eur J Med Chem ; 178: 214-231, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185412

RESUMO

Discovery of antimicrobial agents with a novel model of action is in urgent need for the clinical management of multidrug-resistant bacterial infections. Recently, we reported the identification of a first-in-class bacterial ribosomal RNA synthesis inhibitor, which interrupted the interaction between the bacterial transcription factor NusB and NusE. In this study, a series of diaryl derivatives were rationally designed and synthesized based on the previously established pharmacophore model. Inhibitory activity against the NusB-NusE binding, circular dichroism of compound treated NusB, antimicrobial activity, cytotoxicity, hemolytic property and cell permeability using Caco-2 cells were measured. Structure-activity relationship and quantitative structure-activity relationship were also concluded and discussed. Some of the derivatives demonstrated improved antimicrobial activity than the hit compound against a panel of clinically important pathogens, lowering the minimum inhibition concentration to 1-2 µg/mL against Staphylococcus aureus, including clinical strains of methicillin-resistant Staphylococcus aureus at a level comparable to some of the marketed antibiotics. Given the improved antimicrobial activity, specific inhibition of target protein-protein interaction and promising pharmacokinetic properties without significant cytotoxicity, this series of diaryl compounds have high potentials and deserve for further studies towards a new class of antimicrobial agents in the future.


Assuntos
Compostos de Anilina/farmacologia , Antibacterianos/farmacologia , Benzilaminas/farmacologia , Ligação Proteica/efeitos dos fármacos , Bases de Schiff/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/química , Compostos de Anilina/toxicidade , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/toxicidade , Proteínas de Bactérias/metabolismo , Benzilaminas/síntese química , Benzilaminas/química , Benzilaminas/toxicidade , Células CACO-2 , Desenho de Drogas , Eritrócitos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Células HeLa , Hemólise/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/toxicidade , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo
8.
Nat Commun ; 10(1): 2702, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221991

RESUMO

Most cationic vectors are difficult to avoid the fate of small interfering RNA (siRNA) degradation following the endosome-lysosome pathway during siRNA transfection. In this study, the endoplasmic reticulum (ER) membrane isolated from cancer cells was used to fabricate an integrative hybrid nanoplexes (EhCv/siRNA NPs) for improving siRNA transfection. Compared to the undecorated Cv/siEGFR NPs, the ER membrane-decorated EhCv/siRNA NPs exhibits a significantly higher gene silencing effect of siRNA in vitro and a better antitumor activity in nude mice bearing MCF-7 human breast tumor in vivo. Further mechanistic studies demonstrate that functional proteins on the ER membrane plays important roles on improving cellular uptake and altering intracellular trafficking pathway of siRNA. It is worth to believe that the ER membrane decoration on nanoplexes can effectively transport siRNA through the endosome-Golgi-ER pathway to evade lysosomal degradation and enhance the silencing effects of siRNA.


Assuntos
Portadores de Fármacos/química , Interferência de RNA , RNA Interferente Pequeno/administração & dosagem , Transfecção/métodos , Animais , Linhagem Celular Tumoral , Membrana Celular , Portadores de Fármacos/efeitos adversos , Retículo Endoplasmático/metabolismo , Endossomos/metabolismo , Receptores ErbB/genética , Feminino , Terapia Genética/métodos , Complexo de Golgi/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Nanopartículas/química , Neoplasias/genética , Neoplasias/terapia , RNA Interferente Pequeno/efeitos adversos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Photochem Photobiol B ; 196: 111496, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31129507

RESUMO

Surgical resection is one of the most common radical treatments for cancers. However, tumors may be compressed or the local intravascular pressure may be increased during surgical manipulation, causing the shedding and entry of tumor cells into the blood circulation and hence distant recurrence and metastasis of tumors. We have preliminarily established a method of riboflavin photosensitization treatment (RPT) for inactivation of circulating tumor cells. This technology promises to solve the problems of shedding and entry of solid tumor cells into blood circulation before surgical manipulation, and almost unavoidable hematogenous dissemination of tumor cells during surgical resection. In the present study, apoptosis detection and tumorigenicity experiment in immunodeficient mice were conducted to evaluate the effect of RPT for inactivation of circulating tumor cells respectively. Next, functional evaluation was carried out for the immune cells through detecting apoptosis rate and cytokine secretion of lymphocyte. Finally, thromboelastography (TEG) and free hemoglobin were detected to assess peripheral blood coagulation and red blood cell damage. The results showed that RPT (50 µmol/L riboflavin, 10.8 J/cm2 UV) could effectively make tumor cell lose the ability of proliferation in the peripheral blood. In the meantime, the damage caused to peripheral blood coagulation, immune cell function and red blood cells was generally acceptable. The results of the study showed that RPT had huge potential in addressing the problems of shedding and entry of solid tumor cells into blood circulation before surgical manipulation, and almost unavoidable hematogenous dissemination of tumor cells during surgical resection. This therapy is expected to be an auxiliary and supportive method to reduce the risk of hematogenous metastasis and recurrence of cancers, and to increase the surgical success rate of malignant solid tumors.


Assuntos
Células Neoplásicas Circulantes/efeitos dos fármacos , Fármacos Fotossensibilizantes/farmacologia , Riboflavina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Coagulação Sanguínea/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Células HCT116 , Hemólise/efeitos dos fármacos , Humanos , Luz , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias/tratamento farmacológico , Células Neoplásicas Circulantes/metabolismo , Fármacos Fotossensibilizantes/uso terapêutico , Riboflavina/uso terapêutico
10.
AAPS PharmSciTech ; 20(5): 186, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31065931

RESUMO

Surfactants occupy an important place owing to their wide application, but primarily compromised due to its toxicity issues. This raises the need for exploration of newer surfactants with increased biocompatibility. Novel fatty acid- and amino acid-based surfactants were prepared using standard carbodiimide chemistry. Pyrene assay was implemented to confirm the amphiphilic nature of the surfactants and to calculate their CMC (critical micellar concentration). In vitro hemolytic and cell culture study in MCF-7 and HEK cell line were done to check the in vitro biocompatibility of the developed surfactants in comparison to marketed surfactants Triton X-100 and Tween ® 80. In vivo biocompatibility test in female Swiss albino mice was carried out in comparison to marketed surfactants with respect to serum markers, organ histology, and RBC morphology. Surfactant synthesis provided more than 60% yield in all the conjugates. Pyrene assay concluded the amphiphilic nature of the surfactants with lowest CMC of 0.083% w/v in the case of stearic acid and valine conjugate. In vitro hemolytic and cell culture study depicted highest biocompatibility in vitro as compared to marketed surfactants. Similar results were obtained in in vivo biocompatibility with respect to AST (aspartate transaminase), ALT (alanine transaminase), BUN (blood urea nitrogen), and creatinine serum levels and histology of spleen, liver, and kidney in comparison to marketed surfactants Triton X-100 and Tween ® 80. The developed surfactant also depicted least RBC morphology changes in vivo. Stearic acid valine conjugate thus depicted potential for further application in formulation development replacing the commercially available surfactants.


Assuntos
Aminoácidos/administração & dosagem , Aminoácidos/toxicidade , Materiais Biocompatíveis/administração & dosagem , Materiais Biocompatíveis/toxicidade , Ácidos Graxos/administração & dosagem , Ácidos Graxos/toxicidade , Tensoativos/administração & dosagem , Tensoativos/toxicidade , Aminoácidos/química , Animais , Materiais Biocompatíveis/química , Desenho de Drogas , Ácidos Graxos/química , Feminino , Hemólise/efeitos dos fármacos , Humanos , Células MCF-7 , Camundongos , Micelas , Ratos , Ratos Sprague-Dawley , Tensoativos/química
11.
Chemosphere ; 228: 577-585, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31075638

RESUMO

Although Persistent Organic Pollutants (POPs) are some of the most dangerous environmental toxicants, data on their impact on hemostasis are virtually limited. 1,2,3,5,6,7-hexachloronaphthalene (PCN67) seems to be one of the most toxic congeners of polychlorinated naphthalenes (PCNs), which have recently been listed as POPs. The toxic effects of PCNs are similar to other chlorinated aromatics, e.g. polychlorinated dibenzo-p-dioxins (PCDDs), so an impact on hemostasis could not be excluded. Therefore, this study examines, for the first time, if short-term (two and four weeks) exposure of a mixture of hexachloronaphthalene congeners with a PCN67 as a predominant component to female Wistar rats may have an impact on selected hemostasis parameters, such as overall potential and kinetic parameters of clot formation and fibrinolysis; hematology and basic coagulology parameters. It also examines the influence of PCN67 on the stability of erythrocyte membranes. Obtained results indicate that PCN67 may be an important disturbing factor regarding both coagulation and fibrinolysis processes, as well as platelet count. Exposure to PCN67 significantly affected clot formation and lysis processes and diminished fibrinogen concentration after both administration periods. After two weeks of administration, an increased activated partial thromboplastin time (APTT) was noted; after four weeks - decreased platelet count with concomitant increased in mean platelet volume. Moreover, PCN67 may exert adverse effects on the red blood cells membrane stability, which were manifested by a statistically significant increase of red blood cells lysis.


Assuntos
Hemostasia/efeitos dos fármacos , Naftalenos/toxicidade , Projetos Piloto , Animais , Poluentes Ambientais/análise , Poluentes Ambientais/toxicidade , Membrana Eritrocítica/efeitos dos fármacos , Feminino , Hemólise/efeitos dos fármacos , Tempo de Tromboplastina Parcial , Contagem de Plaquetas , Dibenzodioxinas Policloradas , Ratos , Ratos Wistar
12.
Chem Biodivers ; 16(7): e1900216, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31131525

RESUMO

A particular interest is nowadays given to natural antioxidants occurring in foods which can reduce the risk of several diseases through their protective effect. The genus Limonium is widely distributed in different salt regions of Tunisia and known in traditional medicine for the presence of highly effective viral and bacterial replication inhibitors. Limonium leaves have possible beneficial effects on human health for their antioxidant activities and free radical scavenging abilities. To exploit the potential of plants from extreme environments as new sources of natural antioxidants, we studied the extracts from leaves of eight Limonium species growing in extreme environments in Tunisia. Antioxidant molecules (polyphenols, flavonoids, flavonols, ascorbate, tocopherols), in vitro (DPPH, ORAC) and ex vivo antioxidant potential on human erythrocytes, antioxidant enzymes activities (superoxide dismutase, peroxidases, glutathione reductase) were evaluated to identify the species with the best antioxidant capacity. The results showed variability among the species considered in function of the environmental conditions of their natural biotopes, as for the antioxidants measured. In particular, L. vulgare from Oued Rane biotope, characterized by dryness and high temperatures, was the species with the highest enzymatic activity and antioxidant capacity, making it interesting as possible edible halophyte plant or as food complement.


Assuntos
Antioxidantes/farmacologia , Compostos Fitoquímicos/farmacologia , Plumbaginaceae/química , Antioxidantes/química , Antioxidantes/isolamento & purificação , Compostos de Bifenilo/antagonistas & inibidores , Hemólise/efeitos dos fármacos , Capacidade de Absorbância de Radicais de Oxigênio , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Picratos/antagonistas & inibidores , Folhas de Planta/química , Análise de Componente Principal , Especificidade da Espécie , Tunísia
13.
Eur J Med Chem ; 175: 187-200, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31078866

RESUMO

The inability to discover novel class of antibacterial agents, especially against Gram-negative bacteria (GNB), compel us to consider a broader non-conventional approach to treat infections caused by multidrug-resistant (MDR) bacteria. One such approach is the use of adjuvants capable of revitalizing the activity of current existing antibiotics from resistant pathogens. Recently, our group reported a series of tobramycin (TOB)-based hybrid adjuvants that were able to potentiate multiple classes of legacy antibiotics against various MDR GNB. Herein, we report the modification of TOB-based hybrid adjuvants by replacing TOB domain by the pseudo-disaccharide nebramine (NEB) through selective cleavage of the α-d-glucopyranosyl linkage of TOB. Potent synergism was found for combinations of NEB-based hybrid adjuvants with multiple classes of legacy antibiotics including fluoroquinolones (moxifloxacin and ciprofloxacin), tetracyclines (minocycline), or rifamycin (rifampicin) against both wild-type and MDR P. aeruginosa clinical isolates. We also demonstrated that a combination of the optimized NEB-CIP hybrid 1b and rifampicin protects Galleria mellonella larvae from the lethal effects of extensively drug-resistant (XDR) P. aeruginosa. Mechanistic evaluation of NEB-based hybrid adjuvants revealed that the hybrids affect the outer- and inner membranes of wild-type P. aeruginosa PAO1. This study describes an approach to optimize aminoglycoside-based hybrids to yield lead adjuvant candidates that are able to resuscitate the activity of partner antibiotics against MDR GNB.


Assuntos
Antibacterianos/farmacologia , Dissacarídeos/química , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Piranos/química , Animais , Antibacterianos/administração & dosagem , Antibacterianos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Sinergismo Farmacológico , Quimioterapia Combinada , Células HEK293 , Hemólise/efeitos dos fármacos , Humanos , Larva/efeitos dos fármacos , Lepidópteros/crescimento & desenvolvimento , Lepidópteros/microbiologia , Testes de Sensibilidade Microbiana , Espectroscopia de Prótons por Ressonância Magnética , Pseudomonas aeruginosa/efeitos dos fármacos , Rifampina/administração & dosagem , Espectrometria de Massas por Ionização por Electrospray , Suínos
14.
Artif Cells Nanomed Biotechnol ; 47(1): 1702-1709, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31062603

RESUMO

The objective of this study was to hydrophobically modify fenugreek gum (FG) and to further evaluate the potential application of the obtained derivative in liver-targeted drug delivery system. Stearic acid (C18) was conjugated with FG (FG-C18) by a simple esterification reaction. The obtained FG-C18 was then characterized on its chemical structure by Fourier transform infrared spectroscopy and 1H-nuclear magnetic resonance. The self-assembled nanomicelles (NMs) of FG-C18 in water were prepared by an ultrasonication method. The average diameter and zeta potential of FG-C18 NMs were 196.70 ± 6.12 nm and -31.79 ± 1.58 mV, respectively. FG-C18 NMs appeared as spherical particles under transmission electron microscopy and possessed a critical micellar concentration of 0.042 mg/ml by pyrene fluorescence probe method. A low toxicity of FG-C18 was revealed on both HepG2 and MCF-7 cells at 0.1-100 mg/ml. Haemolysis of FG-C18 was less than 5%. Cellular uptake of coumarin-6 into HepG2 cells was enhanced by treating with C6-loaded FG-C18 NMs compared to free coumarin-6. These results suggest that FG-C18 have a potential application for a liver targeted drug delivery.


Assuntos
Portadores de Fármacos/química , Portadores de Fármacos/síntese química , Interações Hidrofóbicas e Hidrofílicas , Fígado/metabolismo , Gomas Vegetais/química , Gomas Vegetais/síntese química , Trigonella/química , Transporte Biológico , Técnicas de Química Sintética , Cumarínicos/química , Cumarínicos/metabolismo , Portadores de Fármacos/toxicidade , Hemólise/efeitos dos fármacos , Células Hep G2 , Humanos , Células MCF-7 , Gomas Vegetais/toxicidade
15.
Toxicol Lett ; 312: 204-213, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047999

RESUMO

Phosgene (Carbonyl Chloride, COCl2) remains an important chemical intermediate in many industrial processes such as combustion of chlorinated hydrocarbons and synthesis of solvents (degreasers, cleaners). It is a sweet smelling gas, and therefore does not prompt escape by the victim upon exposure. Supplemental oxygen and ventilation are the only available management strategies. This study was aimed to delineate the pathogenesis and identify novel biomarkers of acute lung injury post exposure to COCl2 gas. Adult male and female C57BL/6 mice (20-25 g), exposed to COCl2 gas (10 or 20 ppm) for 10 min in environmental chambers, had a dose dependent reduction in PaO2 and an increase in PaCO2, 1 day post exposure. However, mortality increased only in mice exposed to 20 ppm of COCl2 for 10 min. Correspondingly, these mice (20 ppm) also had severe acute lung injury as indicated by an increase in lung wet to dry weight ratio, extravasation of plasma proteins and neutrophils into the bronchoalveolar lavage fluid, and an increase in total lung resistance. The increase in acute lung injury parameters in COCl2 (20 ppm, 10 min) exposed mice correlated with simultaneous increase in oxidation of red blood cells (RBC) membrane, RBC fragility, and plasma levels of cell-free heme. In addition, these mice had decreased plasmalogen levels (plasmenylethanolamine) and elevated levels of their breakdown product, polyunsaturated lysophosphatidylethanolamine, in the circulation suggesting damage to cellular plasma membranes. This study highlights the importance of free heme in the pathogenesis of COCl2 lung injury and identifies plasma membrane breakdown product as potential biomarkers of COCl2 toxicity.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Substâncias para a Guerra Química/toxicidade , Hemólise/efeitos dos fármacos , Fosgênio/toxicidade , Administração por Inalação , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosgênio/administração & dosagem
16.
Chemosphere ; 229: 103-111, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31078025

RESUMO

Triclosan (TCS) is a broad-spectrum antimicrobial used in personal care products, household items, and medical devices. Owing to its apoptotic potential against tumor cells, TCS has been proposed for the treatment of malignancy. A major complication of chemotherapy is anemia, which may result from direct erythrocyte hemolysis or premature cell death known as eryptosis. Similar to nucleated cells, eryptotic cells lose membrane asymmetry and Ca2+ regulation, and undergo oxidative stress, shrinkage, and activation of a host of kinases. In this report, we sought to examine the hemolytic and eryptotic potential of TCS and dissect the underlying mechanistic scenarios involved there in. Hemolysis was spectrophotometrically evaluated by the degree of hemoglobin release into the medium. Flow cytometry was utilized to detect phosphatidylserine (PS) exposure by annexin-V binding, intracellular Ca2+ by Fluo-3/AM fluorescence, and oxidative stress by 2-,7-dichlorodihydrofluorescin diacetate (DCFH2-DA). Incubation of cells with 10-100 µM TCS for 1-4 h induced time- and dose-dependent hemolysis. Moreover, TCS significantly increased the percentage of eryptotic cells as evident by PS exposure (significantly enhanced annexin-V binding). Interestingly, TCS-induced eryptosis was preceded by elevated intracellular Ca2+ levels but was not associated with oxidative stress. Cotreatment of erythrocytes with 50 µM TCS and 50 µM SB203580 (p38 MAPK inhibitor), or 300 µM necrostatin-1 (receptor-interacting protein 1 (RIP1) inhibitor) significantly ameliorated TCS-induced PS externalization. We conclude that TCS is cytotoxic to erythrocytes by inducing hemolysis and stimulating premature death at least in part through Ca2+ mobilization, and p38 MAPK and RIP1 activation.


Assuntos
Cálcio/metabolismo , Poluentes Ambientais/toxicidade , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Triclosan/toxicidade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Eriptose/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Humanos , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilserinas , Espécies Reativas de Oxigênio/metabolismo
17.
AAPS PharmSciTech ; 20(5): 201, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31139968

RESUMO

Nanostructured lipid carrier (NLC) of propofol was formulated using hot emulsification-probe sonication method for improvising its parenteral delivery by reducing pain on injection and risk of microbial contamination. The formulated NLC was optimized using central composite design and evaluated for particle size, zeta potential, morphology, free propofol concentration, hemocompatibility, stability, pain on injection, in vivo anesthetic activity, pharmacokinetics, and antimicrobial effectiveness in comparison to the marketed formulation. Optimized NLCs exhibited globule size, less than 200 nm, and zeta potential - 24.1 mV, indicating its stability. TEM images confirmed the spherical shape and nanosize (200 nm) of optimized NLCs. Free propofol concentration was also found to be 40% lesser than marketed formulation. Optimized NLC was found to be non-hemolytic. Rat paw-lick study showed that propofol NLC was significantly less painful compared to the marketed formulation. Anesthetic potential and pharmacokinetics of optimized NLCs were found to be similar to that of the marketed formulation. NLC was found stable in long-term storage under room temperature. Antimicrobial effectiveness study showed that propofol NLC suppressed microbial growth to a greater extent as compared to the marketed formulation. Hence, the developed propofol NLCs appeared to be clinically useful as a potential carrier for propofol delivery.


Assuntos
Emulsões/administração & dosagem , Nanoestruturas/administração & dosagem , Propofol/administração & dosagem , Óleo de Soja/administração & dosagem , Animais , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Emulsões/química , Feminino , Hemólise/efeitos dos fármacos , Hemólise/fisiologia , Humanos , Nanoestruturas/química , Tamanho da Partícula , Propofol/química , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Óleo de Soja/química
18.
Malar J ; 18(1): 123, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30961636

RESUMO

BACKGROUND: Delayed haemolysis is a frequent adverse event after treatment with artesunate (AS). Removing once-infected "pitted" erythrocytes by the spleen is the most accepted mechanism of haemolysis in these cases. However, an increasing number of cases with positive direct antiglobulin test (DAT) haemolysis after AS have been reported. METHODS: All malaria cases seen at Hospital Clinic of Barcelona between 2015 and 2017 were retrospectively reviewed. Clinical, parasitological and laboratory data from patients treated with intravenous artesunate-specifically looking for delayed haemolysis and DAT-was collected. RESULTS: Among the 36 severe malaria patients treated with artesunate at the hospital, 10 (27.8%) developed post-artesunate delayed haemolysis. Out of these, DAT was performed in six, being positive in four of them (at least 40%). DAT was positive only for complement-without IgG-suggesting drug-dependent immune-haemolytic anaemia of the immune-complex type. Three of the four patients were treated with corticosteroids and two also received blood transfusion, with a complete recovery. CONCLUSIONS: Drug-induced auto-immune phenomena in post-artesunate delayed haemolysis may be underreported and must be considered. The role of corticosteroids should be reassessed.


Assuntos
Anemia Hemolítica/tratamento farmacológico , Antimaláricos/administração & dosagem , Artesunato/administração & dosagem , Hemólise/efeitos dos fármacos , Malária/tratamento farmacológico , Administração Intravenosa/efeitos adversos , Adolescente , Adulto , Anemia Hemolítica/induzido quimicamente , Teste de Coombs/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Espanha
19.
Mater Sci Eng C Mater Biol Appl ; 100: 94-103, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30948130

RESUMO

Various glucose-sensitive drug delivery platforms have been developed recently to treat diabetes. However, there is much less work has been reported on treatment of diabetes and vascular diabetes complications simultaneously. In this work, a novel polysaccharide-based micelle-hydrogel synergistic therapy system was fabricated to address this limitation. Zwitterionic dialdehyde starch-based micelles (SB-DAS-VPBA) were synthesized via single electron transfer-living radical polymerization (SET-LRP). Hydrophilic segment sulfobetaine (SB) and hydrophobic segment 4­vinylphenylboronic acid (VPBA) were grafted to the dialdehyde starch (DAS) backbones. Then, chitosan/dialdehyde starch derivatives (CS/SB-DAS-VPBA) micelle-hydrogel was synthesized by Schiff-base bonds. Insulin and nattokinase were loaded to obtain the micelle-hydrogel synergistic therapy system. In vitro drug delivery and blood clots dissolution behaviors were determined. Results suggest that the micelle-hydrogel synergistic therapy system not only possesses glucose-responsive insulin delivery property, but also provides good thrombolytic capacity. Thus, this micelle-hydrogel synergistic therapy system can be used as a platform for diabetes and vascular diabetes complications treatment.


Assuntos
Hidrogéis/química , Micelas , Amido/análogos & derivados , Betaína/análogos & derivados , Betaína/química , Ácidos Borônicos/química , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Hidrogéis/farmacologia , Amido/química , Compostos de Vinila/química
20.
Molecules ; 24(7)2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30986961

RESUMO

Ligustrum lucidum Aiton and its berries have been used in Chinese traditional medicine for around two thousand years. In the present study, L. lucidium berries harvested in two regions of Portugal were studied. Haemolytic activity and inhibition of oxidative haemolysis as well as the enzyme inhibitory activities (α-amylase enzyme and acetylcholinesterase) were assessed. Results suggest that the different biological activities varied according to the region where samples were collected. Results demonstrated that the sample obtained from region R1 was the most efficient extract for all parameters evaluated, presenting the lowest values of IC50, 10.67 ± 0.46 µg/mL for the inhibition of erythrocyte oxidative haemolysis, 58.28 ± 3.77 µg/mL for the α-amylase enzyme and 67.67 ± 2.10 µg/mL for the acetylcholinesterase inhibition. L. Lucidum berries may be an interesting source of compounds for use in the development of the therapeutic armamentarium for diseases where enzymatic disruption is believed to play a role.


Assuntos
Frutas/química , Ligustrum/química , Extratos Vegetais/farmacologia , Acetilcolinesterase/metabolismo , Ativação Enzimática/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Extratos Vegetais/química , alfa-Amilases/metabolismo
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