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1.
Phys Chem Chem Phys ; 21(36): 20211-20218, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31486459

RESUMO

In spite of their well-known side effects, the nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed medications for their antipyretic and anti-inflammatory actions. Interaction of NSAIDs with the plasma membrane plays a vital role in their therapeutic actions and defines many of their side effects. In the present study, we investigate the effects of three NSAIDs, aspirin, ibuprofen, and indomethacin, on the structure and dynamics of a model plasma membrane using a combination of small angle neutron scattering (SANS) and neutron spin echo (NSE) techniques. The SANS and NSE measurements were carried out on a 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) membrane, with and without NSAIDs, at two different temperatures, 11 °C and 37 °C, where the DMPC membrane is in the gel and fluid phase, respectively. SANS data analysis shows that incorporation of NSAIDs leads to bilayer thinning of the membrane in both the phases. The dynamic properties of the membrane are represented by the intermediate scattering functions for NSE data, which are successfully described by the Zilman and Granek model. NSE data analysis shows that in both gel and fluid phases, addition of NSAIDs results in a decrease in the bending rigidity and compressibility modulus of the membrane, which is more prominent when the membrane is in the gel phase. The magnitude of the effect of NSAIDs on the bending rigidity and compressibility modulus of the membrane in the gel phase follows an order of ibuprofen > aspirin > indomethacin, whereas in the fluid phase, it is in the order of aspirin > ibuprofen > indomethacin. We find that the interaction between NSAIDs and phospholipid membranes is strongly dependent on the chemical structure of the drugs and physical state of the membrane. Mechanical properties of the membrane can be quantified by the membrane's bending rigidity. Hence, the present study reveals that incorporation of NSAIDs modulates the mechanical properties of the membrane, which may affect several physiological processes, particularly those linked to the membrane curvature.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Estruturas da Membrana Celular/química , Estruturas da Membrana Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Nêutrons , Espalhamento a Baixo Ângulo
2.
Exp Parasitol ; 206: 107730, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31494215

RESUMO

Phospholipids are the main component of membranes and are responsible for cell integrity. Alkylphospholipid analogues (APs) were first designed as antitumoral agents and were later tested against different cell types. Trypanosoma cruzi, the Chagas disease etiological agent, is sensitive to APs (edelfosine, miltefosine and ilmofosine) in vitro. We investigated the effect of synthetic ring substituted AP against epimastigotes, amastigotes and trypomastigotes. TCAN26, could inhibit the in vitro growth of epimastigotes and amastigotes with the 50% inhibitory concentrations (IC50) in the nanomolar range. Trypomastigotes lysis was also induced with 24-h treatment and a LC50 of 2.3 µM. Ultrastructural analysis by electron microscopy demonstrated that TCAN26 mainly affected the parasite's membranes leading to mitochondrial and Golgi cisternae swelling, membrane blebs, and autophagic figures in the different parasite developmental stages. While the Golgi of the parasites was significantly affected, the Golgi complex of the host cells remained normal suggesting a specific mechanism of action. In summary, our results suggest that TCAN 26 is a potent and selective inhibitor of T. cruzi growth probably due to disturbances of phospholipid biosynthesis.


Assuntos
Adamantano/farmacologia , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Adamantano/química , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Autofagia/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Relação Dose-Resposta a Droga , Citometria de Fluxo , Complexo de Golgi/efeitos dos fármacos , Concentração Inibidora 50 , Dose Letal Mediana , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Microscopia Imunoeletrônica , Mitocôndrias/efeitos dos fármacos , Fosforilcolina/química , Tripanossomicidas/química , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/ultraestrutura
3.
Pestic Biochem Physiol ; 159: 59-67, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400785

RESUMO

Phytophthora capsici is a plant oomycete pathogen, which causes many devastating diseases on a broad range of hosts. Zedoary turmeric oil (ZTO) is a kind of natural plant essential oil that has been widely used in pharmaceutical applications. However, the antifungal activity of ZTO against phytopathogens remains unknown. In this study, we found ZTO could inhibit P. capsici growth and development in vitro and in detached cucumber and Nicotiana benthamiana leaves. Besides, ZTO treatment resulted in severe damage to the cell membrane of P. capsici, leading to the leakage of intracellular contents. ZTO also induced a significant increase in relative conductivity, malondialdehyde concentration and glycerol content. Furthermore, we identified 50 volatile organic compounds from ZTO, and uncovered Curcumol, ß-elemene, curdione and curcumenol with strong inhibitory activities against mycelial growth of P. capsici. Overall, our results not only shed new light on the antifungal mechanism of ZTO, but also imply a promising alternative for the control of phytophthora blight caused by P. capsici.


Assuntos
Antifúngicos/farmacologia , Membrana Celular/efeitos dos fármacos , Óleos Voláteis/farmacologia , Phytophthora/efeitos dos fármacos , Extratos Vegetais/farmacologia , Óleos Vegetais/farmacologia , Curcuma , Phytophthora/metabolismo , Sesquiterpenos/farmacologia , Sesquiterpenos de Germacrano/farmacologia
4.
Int J Nanomedicine ; 14: 5061-5071, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371947

RESUMO

Background: Photodynamic therapy (PDT) is widely recognized as a promising way to cure cancer. However, the limited tumor homing property of currently available drug delivery systems (DDSs) is the bottleneck for the delivery of photodynamic agents. Purpose: In our study, we decorated silica nanoparticles (SLN) with cell membrane (CM) derived from SGC7901 cells to construct carrier (CM/SLN) which was able to to specifically target the homogenous SGC7901 cells. Materials and methods: Furthermore, the decent drug loading capability of CM/SLN was adopted to load photodynamic agent chlorins e6 (Ce6) to finally construct aDDS suitable for tumor-targeted PDT of gastric cancer. Results: The experimental results suggested that CM/SLN/Ce6 was nano-sized particles with good dispersion and stability in physiological conditions. Moreover, due to the modification of CM,CM/SLN/Ce6 could specifically target the homogenous SGC7901 cells both in vitro and in vivo. Most importantly, further in vivo results demonstrated that the CM/SLN/Ce6 showed a better anticancer outcome compared to SLN/Ce6. Conclusion: CM/SLN/Ce6 might be a promising platform for effective tumor targeted PDT of gastric cancer.


Assuntos
Membrana Celular/patologia , Nanopartículas/química , Fotoquimioterapia , Porfirinas/uso terapêutico , Dióxido de Silício/química , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Coloides , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Camundongos , Nanopartículas/ultraestrutura , Tamanho da Partícula , Porfirinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Eletricidade Estática , Distribuição Tecidual/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos
5.
Aquat Toxicol ; 214: 105265, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31416018

RESUMO

The increasing use of nanoparticles (NPs) unavoidably enhances their unintended introduction into the aquatic systems, raising concerns about their nanosafety. This work aims to assess the toxicity of five oxide NPs (Al2O3, Mn3O4, In2O3, SiO2 and SnO2) using the freshwater alga Pseudokirchneriella subcapitata as a primary producer of ecological relevance. These NPs, in OECD medium, were poorly soluble and unstable (displayed low zeta potential values and presented the tendency to agglomerate). Using the algal growth inhibition assay and taking into account the respective 72 h-EC50 values, it was possible to categorize the NPs as: toxic (Al2O3 and SnO2); harmful (Mn3O4 and SiO2) and non-toxic/non-classified (In2O3). The toxic effects were mainly due to the NPs, except for SnO2 which toxicity can mainly be attributed to the Sn ions leached from the NPs. A mechanistic study was undertaken using different physiological endpoints (cell membrane integrity, metabolic activity, photosynthetic efficiency and intracellular ROS accumulation). It was observed that Al2O3, Mn3O4 and SiO2 induced an algistatic effect (growth inhibition without loss of membrane integrity) most likely as a consequence of the cumulative effect of adverse outcomes: i) reduction of the photosynthetic efficiency of the photosystem II (ФPSII); ii) intracellular ROS accumulation and iii) loss of metabolic activity. SnO2 NPs also provoked an algistatic effect probably as a consequence of the reduction of ФPSII since no modification of intracellular ROS levels and metabolic activity were observed. Altogether, the results here presented allowed to categorize the toxicity of the five NPs and shed light on the mechanisms behind NPs toxicity in the green alga P. subcapitata.


Assuntos
Clorofíceas/citologia , Exposição Ambiental , Água Doce , Nanopartículas/toxicidade , Óxidos/toxicidade , Morte Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Clorofíceas/efeitos dos fármacos , Clorofíceas/crescimento & desenvolvimento , Clorofíceas/metabolismo , Fotossíntese/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/toxicidade , Poluentes Químicos da Água/toxicidade
6.
Phys Chem Chem Phys ; 21(30): 16706-16717, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31321392

RESUMO

Herein, for the first time the complexation ability of a homological series of triphenylphosphonium surfactants (TPPB-n) toward DNA decamers has been explored. Formation of lipoplexes was confirmed by alternative techniques, including dynamic light scattering, indicating the occurrence of nanosized complexes (ca. 100-150 nm), and monitoring the charge neutralization of nucleotide phosphate groups and the fluorescence quenching of dye-intercalator ethidium bromide. The complexation efficacy of TPPB-surfactants toward an oligonucleotide (ONu) is compared with that of reference cationic surfactants. Strong effects of the alkyl chain length and the structure of the head group on the surfactant/ONu interaction are revealed, which probably occur via different mechanisms, with electrostatic and hydrophobic forces or intercalation imbedding involved. Phosphonium surfactants are shown to be capable of disordering lipid bilayers, which is supported by a decrease in the temperature of the main phase transition, Tm. This effect enhances with an increase in the alkyl chain length, indicating the integration of TPPB-n with lipid membranes. This markedly differs from the behavior of typical cationic surfactant cetyltrimethylammonium bromide, which induces an increase in the Tm value. It was demonstrated that the cytotoxicity of TPPB-n in terms of the MTT-test on a human cell line 293T nonmonotonically changes within the homological series, with the highest cytotoxicity exhibited by the dodecyl and tetradecyl homologs.


Assuntos
DNA/química , Bicamadas Lipídicas/química , Ácidos Nucleicos/química , Tensoativos/química , Membrana Celular/efeitos dos fármacos , Células HEK293 , Humanos , Tensoativos/toxicidade
7.
Fitoterapia ; 137: 104274, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31344394

RESUMO

We have previously demonstrated that out of the butyrolactones series synthesized based on the natural lichen metabolite lichesterinic acid, compound (B-13) was the most effective against oral bacteria. However, its antibacterial mechanism is still unknown. In this study, we have investigated its bacterial localization by synthesizing a fluorescently labeled B-13 with NBD while maintaining its antibacterial activity. We showed that this compound binds to Streptococcus gordonii cell surface, as demonstrated by HPLC analysis. By adhering to cell surface, B-13 induced cell wall disruption leading to the release of bacterial constituents and consequently, the death of S. gordonii, a Gram-positive bacterium. A Gram-negative counterpart, Porphyromanas gingivalis, showed also cracked and ruptured cells in the presence of B-13. Besides, we also demonstrated that the analog of B-13, B-12, has also induced disruption of P. gingivalis and S. gordonii. This study revealed that butyrolactones can be considered as potent antibacterial compounds against oral pathogens causing medical complications.


Assuntos
Antibacterianos/farmacologia , Lactonas/farmacologia , Líquens/química , Porphyromonas gingivalis/efeitos dos fármacos , Streptococcus gordonii/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular
8.
Int J Nanomedicine ; 14: 4277-4292, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239679

RESUMO

Background: Kidney stone formation is closely related to renal epithelial cell damage and the adhesion of calcium oxalate crystals to cells. Methods: In this research, the adhesion of human kidney proximal tubular epithelial cells (HK-2) to calcium oxalate monohydrate crystals with a size of approximately 100 nm was studied. In addition, the inhibition of crystal adhesion by four tea polysaccharides (TPS0, TPS1, TPS2, and TPS3) with the molecular weights of 10.88, 8.16, 4.82, and 2.31 kDa, respectively were compared. Results: When oxalic acid-damaged HK-2 cells were repaired, cell viability increased. By contrast, reactive oxygen species level, phosphatidylserine eversion, and osteopontin expression decreased, thus indicating that tea polysaccharides have a repairing effect on damaged HK-2 cells. Moreover, after repairing the damaged cells, the amount of adherent crystals was reduced. The repair effect of tea polysaccharides is closely related to molecular weight, and TPS2 with the moderate molecular weight displayed the best repair effect. Conclusion: These results suggest that tea polysaccharides, especially TPS2, may inhibit the formation and recurrence of calcium oxalate kidney stones.


Assuntos
Oxalato de Cálcio/farmacologia , Polissacarídeos/farmacologia , Chá/química , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cristalização , Fluorescência , Humanos , Nanopartículas/química , Osteopontina/metabolismo , Espécies Reativas de Oxigênio/metabolismo
9.
Carbohydr Polym ; 219: 414-422, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151542

RESUMO

The bioconversion of rice straw into ethanol can alleviate the energy crisis and solve problems related to waste treatment. In this study, the effect of soluble polysaccharides (SPs) produced during rice straw saccharification on the formation of extracellular matrices (EMs) by the yeast Saccharomyces cerevisiae was investigated. SPs were characterized by high-performance liquid chromatography (HPLC) and fourier transform infrared spectroscopy (FT-IR). SPs reduced the inhibition of alcohol dehydrogenase activity by phenolic acids (PAs) and regulated the intracellular redox state, resulting in higher ethanol production. The results of flow cytometry, confocal laser scanning microscopy, and atomic force microscopy indicated that PAs changed microbial morphology and caused damage in microbial cell membranes. The protective effect of SPs against cell membrane damage could be attributed to the synthesis of polysaccharide-dependent extracellular matrix, which maintained cellular integrity even under phenolic acid stress. These findings provide new strategies to improve pretreatment and saccharification processes.


Assuntos
Membrana Celular , Matriz Extracelular , Oryza/química , Extratos Vegetais , Polissacarídeos/farmacologia , Saccharomyces cerevisiae , Álcool Desidrogenase/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , China , Etanol/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fermentação , Hidrólise , Hidroxibenzoatos/toxicidade , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polissacarídeos/química , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/metabolismo
10.
Toxicol Lett ; 313: 137-149, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254607

RESUMO

Tordon® is the commercial name of a mixture of two organo-chlorinated herbicides, 2,4-D and picloram. Both compounds affect energy transduction in isolated mitochondria and the present study aimed at characterizing the actions of these two compounds on liver metabolism and their cellular distribution in the isolated perfused rat liver. 2,4-D, but not picloram, increased glycolysis in the range from 10 to 400 µM. The redox potential of the cytosolic NAD+-NADH couple was also increased by 2,4-D. Both compounds inhibited lactate gluconeogenesis. Inhibitions by 2,4-D and picloram were incomplete, reaching maximally 46% and 23%, respectively. Both compounds diminished the cellular ATP levels. No synergism between the actions of 2,4-D and picloram was detected. Biotransformations of 2,4-D and picloram were slow, but their distributions occurred at high rates and were concentrative. Molecular dynamics simulations revealed that 2,4-D presented low affinity for the hydrophobic lipid bilayers, the opposite occurring with picloram. Inhibition of energy metabolism is possibly a relevant component of the toxicity of 2,4-D and of the commercial product Tordon®. Furthermore, the interactions of 2,4-D with the membrane lipid bilayer can be highly destructive and might equally be related to its cellular toxicity at high concentrations.


Assuntos
Ácido 2,4-Diclorofenoxiacético/toxicidade , Membrana Celular/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Herbicidas/toxicidade , Bicamadas Lipídicas/metabolismo , Fígado/efeitos dos fármacos , Picloram/toxicidade , Ácido 2,4-Diclorofenoxiacético/metabolismo , Animais , Membrana Celular/metabolismo , Membrana Celular/patologia , Gluconeogênese/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Herbicidas/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Cinética , Fígado/metabolismo , Fígado/patologia , Masculino , Simulação de Dinâmica Molecular , NAD/metabolismo , Oxirredução , Perfusão , Picloram/metabolismo , Ratos Wistar
11.
Subcell Biochem ; 92: 1-5, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214982

RESUMO

Astonishing progress has been made in recent years to understand the structural complexity and functions of the biosynthetic pathways of the bacterial and archaeal envelopes. This progress has prompted me to assemble the present book that provides a detailed overview and the state-of-art of the respective research field. Ideally, the book will provide students and advanced scientists an up to date picture of the different parts of the bacterial and archaeal cell envelope and enable them to understand their functional roles.


Assuntos
Antibacterianos/farmacologia , Archaea/citologia , Archaea/efeitos dos fármacos , Bactérias/citologia , Bactérias/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Parede Celular/efeitos dos fármacos
12.
Nat Commun ; 10(1): 2607, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197133

RESUMO

Inhibiting the RAS oncogenic protein has largely been through targeting the switch regions that interact with signalling effector proteins. Here, we report designed ankyrin repeat proteins (DARPins) macromolecules that specifically inhibit the KRAS isoform by binding to an allosteric site encompassing the region around KRAS-specific residue histidine 95 at the helix α3/loop 7/helix α4 interface. We show that these DARPins specifically inhibit KRAS/effector interactions and the dependent downstream signalling pathways in cancer cells. Binding by the DARPins at that region influences KRAS/effector interactions in different ways, including KRAS nucleotide exchange and inhibiting KRAS dimerization at the plasma membrane. These results highlight the importance of targeting the α3/loop 7/α4 interface, a previously untargeted site in RAS, for specifically inhibiting KRAS function.


Assuntos
Sítio Alostérico/efeitos dos fármacos , Antineoplásicos/farmacologia , Desenho de Drogas , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Repetição de Anquirina , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Histidina/metabolismo , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Neoplasias/genética , Neoplasias/patologia , Biblioteca de Peptídeos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Multimerização Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
Phys Chem Chem Phys ; 21(23): 12530-12539, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31147666

RESUMO

The emergence of antibiotic-resistance is a major concern to global human health and identification of novel antibiotics is critical to mitigate the threat. Mutacin 1140 (MU1140) is a promising antimicrobial lanthipeptide and is effective against Gram-positive bacteria. Like nisin, MU1140 targets and sequesters lipid II and interferes with its function, which results in the inhibition of bacterial cell wall synthesis, and leads to bacteria cell lysis. MU1140 contains a structurally similar thioether cage for binding the lipid II pyrophosphate as for nisin. In addition to lipid II binding, nisin is known to form membrane pores. Membrane pore formation and membrane disruption is a common mode of action for many antimicrobial peptides, including gallidermin, a lantibiotic peptide with similar structural features as MU1140. However, whether and how MU1140 and its variants can form permeable membrane pores remains to be demonstrated. In this work, we explored the potential mechanisms of membrane pore formation by performing molecular simulations of the MU1140-lipid II complex in the bacterial membrane. Our results suggest that MU1140-lipid II complexes are able to form water permeating membrane pores. We find that a single chain of MU1140 complexed with lipid II in the transmembrane region can permeate water molecules across the membrane via a single-file water transport mechanism. The ordering of the water molecules in the single-file chain region as well as the diffusion behavior is similar to those observed in other biological water channels. Multiple complexes of MU1140-lipid II in the membrane showed enhanced permeability for the water molecules, as well as a noticeable membrane distortion and lipid relocation, suggesting that a higher concentration of MU1140 assembly in the membrane can cause significant disruption of the bacterial membrane. These investigations provide an atomistic level insight into a novel mode of action for MU1140 that can be exploited to develop optimized peptide variants with improved antimicrobial properties.


Assuntos
Bacteriocinas/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Simulação de Dinâmica Molecular , Peptídeos/farmacologia , Bacteriocinas/química , Membrana Celular/efeitos dos fármacos , Bactérias Gram-Positivas/citologia , Lipídeos/química , Lipídeos/farmacologia , Testes de Sensibilidade Microbiana , Peptídeos/química , Água/química
14.
Environ Sci Pollut Res Int ; 26(20): 20654-20668, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31104239

RESUMO

Copper (Cu) is widely used in various industries, and human exposure to this metal results in severe multi-organ toxicity, which is thought to be due to the generation of free radicals by Fenton-like reaction. The generation of reactive oxygen as well as nitrogen species and free radicals results in induction of oxidative stress in the cell. We have studied the effect of different concentrations of Cu(II) on human erythrocytes and lymphocytes. Incubation of erythrocytes with copper chloride, a Cu(II) compound, enhanced the production of reactive oxygen and nitrogen species, decreased glutathione and total sulphydryl content and increased protein oxidation and lipid peroxidation. All changes were in a Cu(II) concentration-dependent manner. This strongly suggests that Cu(II) causes oxidative damage in erythrocytes. The activities of major antioxidant enzymes were altered, and antioxidant power was lowered. Cu(II) treatment also resulted in membrane damage in erythrocytes as seen by electron microscopy and lowered activities of plasma membrane-bound enzymes. Incubation of human lymphocytes with Cu(II) resulted in DNA damage when studied by the sensitive comet assay. These results show that Cu(II) exerts cytotoxic and genotoxic effects on human blood cells probably by enhancing the generation of reactive oxygen and nitrogen species.


Assuntos
Antioxidantes/metabolismo , Cobre/toxicidade , Dano ao DNA/efeitos dos fármacos , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Membrana Celular/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Eritrócitos/patologia , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Linfócitos/patologia , Estresse Oxidativo/efeitos dos fármacos
15.
Ecotoxicol Environ Saf ; 180: 208-214, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31096126

RESUMO

Dimethyl phthalate (DMP), a phthalate ester (PAE), is a ubiquitous and organic pollutant. In this study, the toxicity of DMP to Escherichia coli K12 and its underlying mechanism were investigated. The results showed that DMP inhibited the growth of E. coli K12 and induced cell inactivation and/or death. DMP caused serious damage to the cell membrane of E. coli K12, and the damage increased with higher DMP concentrations. DMP exposure disrupted cell membranes, as evidenced by dose-dependent variations of cell structures, surface properties, and membrane compositions. Increases in the malondialdehyde (MDA) content indicated an increase in oxidative stress induced by DMP in E. coli K12. The activity of succinic dehydrogenase (SDH) was changed by DMP, which could affect energy metabolism in the membrane of E. coli K12. The expression levels of OmpA and OmpX were increased, and the expression levels of OmpF and OmpW were decreased, in E. coli K12 exposed to DMP. The toxicities of DMP to E. coli K12 could be ascribed to membrane disruption and oxidative stress-induced cell inactivation and/or death. The outcomes will shed new light on the assessment of the ecological effects of DMP.


Assuntos
Poluentes Ambientais/toxicidade , Escherichia coli K12/efeitos dos fármacos , Ácidos Ftálicos/toxicidade , Proteínas da Membrana Bacteriana Externa/metabolismo , Membrana Celular/efeitos dos fármacos , Escherichia coli K12/metabolismo , Malondialdeído/análise , Estresse Oxidativo
16.
Aquat Toxicol ; 212: 214-221, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31132739

RESUMO

Beta-N-methylamino-L-alanine (BMAA) is a non-proteinogenic amino acid produced by several cyanobacteria species. It is considered to be a potent neurotoxin. Although its neurotoxic effects are well studied, other negative effects of BMAA have not yet been completely elucidated. In the present study, we studied the cytotoxic effects of a wide range of concentrations of BMAA (0.25-2.0 mM) on a stable fish immune cell line (CLC) obtained from carp monocytes. The cells exposed to higher concentrations of BMAA exhibited an altered morphology, changed ATP levels, and reduced proliferation. On the basis of toxic effects of BMAA on lysosomes, mitochondrial dehydrogenases activity, and cell membrane integrity, we determined its cytotoxic concentrations. We also investigated effects of the toxin at non-cytotoxic concentrations on the basic functions of CLC cells. BMAA did not affect the production and release of IL-1ß or phagocytic activity of the cells. However, higher non-toxic BMAA concentrations altered the levels of extracellular and intracellular total proteins compared to those in control cells.


Assuntos
Diamino Aminoácidos/toxicidade , Peixes , Animais , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cianobactérias/química , Ativação Enzimática/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Oxirredutases/metabolismo , Poluentes Químicos da Água/toxicidade
17.
Chem Biol Interact ; 308: 20-44, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31067438

RESUMO

Ischemic heart disease (IHD) is a major cause of cardiovascular morbidity and mortality worldwide, which is characterized by an imbalance between cardiac oxygen supply and demand predominantly due to obstruction of coronary arteries. Activation of the innate immune system and the consequent inflammatory response plays a role in the pathogenesis of IHD. Where an excessive inflammatory response may contribute to adverse cardiac remodeling and fibrosis, making inflammation an important therapeutic target for improving outcomes of IHD. While there are many discrepancies in the literature, evidence from both bench and clinical research demonstrate important effects of n-3 polyunsaturated fatty acids (n-3 PUFA), eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA), toward IHD. N-3 PUFAs, and their metabolites, have been demonstrated to modulate various components of the immune system, including regulation of chemokines and cytokines, leukocyte chemotaxis and inflammasome formation. In this article, we provide an overview of the role the innate immune system has in IHD and focus on the immunomodulatory effects of n-3 PUFAs and their biologically active metabolites.


Assuntos
Cardiotônicos/uso terapêutico , Ácidos Graxos Ômega-3/uso terapêutico , Imunidade Inata , Isquemia Miocárdica/tratamento farmacológico , Alarminas/metabolismo , Cardiotônicos/farmacologia , Membrana Celular/química , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Humanos , Imunidade Inata/efeitos dos fármacos , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Isquemia Miocárdica/imunologia , Isquemia Miocárdica/patologia , Proteína-Lisina 6-Oxidase/metabolismo
18.
Eur J Med Chem ; 176: 162-174, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31103897

RESUMO

Chagas disease is a neglected protozoan disease that affects more than eight million people in developing countries. Due to the limited number and toxicity profiles of therapies in current use, new drugs are urgently needed. In previous studies, we reported the isolation of two related antitrypanosomal neolignans from Nectandra leucantha (Lauraceae). In this work, a semi-synthetic library of twenty-three neolignan derivatives was prepared to explore synthetically accessible structure activity relationships (SAR) against Trypanosoma cruzi. Five compounds demonstrated activity against trypomastigotes (IC50 values from 8 to 64 µM) and eight showed activity against intracellular amastigotes (IC50 values from 7 to 16 µM). Eighteen derivatives demonstrated no mammalian cytotoxicity up to 200 µM. The phenolic acetate derivative of natural dehydrodieugenol B was effective against both parasite forms and eliminated 100% of amastigotes inside macrophages. This compound caused rapid and intense depolarization of the mitochondrial membrane potential, with decreased levels of intracellular reactive oxygen species being observed. Fluorescence assays demonstrated that this derivative affected neither the permeability nor the electric potential of the parasitic plasma membrane, an effect also corroborated by scanning electron microscopy studies. Structure-activity relationship studies (SARs) demonstrated that the presence of at least one allyl side chain on the biaryl ether core was important for antitrypanosomal activity, and that the free phenol is not essential. This set of neolignan derivatives represents a promising starting point for future Chagas disease drug discovery studies.


Assuntos
Anisóis/farmacologia , Lignanas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Anisóis/síntese química , Anisóis/química , Anisóis/toxicidade , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Humanos , Lignanas/síntese química , Lignanas/química , Lignanas/toxicidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Testes de Sensibilidade Parasitária , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Tripanossomicidas/toxicidade , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/metabolismo
19.
Int J Nanomedicine ; 14: 2705-2718, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118607

RESUMO

Purpose: In the present study, we investigated the effects of 17ß-estradiol (E2) on membrane roughness and gold nanoparticle (AuNP) uptake in MCF-7 breast cancer cells. Methods: Estrogen receptor (ER)-positive breast cancer cells (MCF-7) were exposed to bare 20 nm AuNPs in the presence and absence of 1×10-9 M E2 for different time intervals for up to 24 hrs. The effects of AuNP incorporation and E2 incubation on the MCF-7 cell surface roughness were measured using atomic force microscopy (AFM). Endocytic vesicle formation was studied using confocal laser scanning microscopy (CLSM). Finally, the results were confirmed by hyperspectral optical microscopy. Results: High-resolution AFM images of the surfaces of MCF-7 membranes (up to 250 nm2) were obtained. The incubation of cells for 12 hrs with AuNP and E2 increased the cell membrane roughness by 95% and 30% compared with the groups treated with vehicle (ethanol) or AuNPs only, respectively. This effect was blocked by an ER antagonist (7α,17ß-[9-[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol [ICI] 182,780). Higher amounts of AuNPs were localized inside MCF-7 cells around the nucleus, even after 6 hrs of E2 incubation, compared with vehicle-treated cells. Endolysosome formation was induced by E2, which may be associated with an increase in AuNP-uptake. Conclusions: E2 enhances AuNP incorporation in MCF-7 cells by modulating of plasma membrane roughness and inducing lysosomal endocytosis. These findings provide new insights into combined nanotherapies and hormone therapies for breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Estradiol/farmacologia , Ouro/metabolismo , Nanopartículas Metálicas/química , Neoplasias da Mama/patologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Feminino , Humanos , Células MCF-7 , Microscopia de Força Atômica , Modelos Biológicos , Receptores Estrogênicos/antagonistas & inibidores , Receptores Estrogênicos/metabolismo
20.
Int J Mol Sci ; 20(9)2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31052427

RESUMO

Biological membranes are key elements for the maintenance of cell architecture and physiology. Beyond a pure barrier separating the inner space of the cell from the outer, the plasma membrane is a scaffold and player in cell-to-cell communication and the initiation of intracellular signals among other functions. Critical to this function is the plasma membrane compartmentalization in lipid microdomains that control the localization and productive interactions of proteins involved in cell signal propagation. In addition, cells are divided into compartments limited by other membranes whose integrity and homeostasis are finely controlled, and which determine the identity and function of the different organelles. Here, we review current knowledge on membrane lipid composition in the plasma membrane and endomembrane compartments, emphasizing its role in sustaining organelle structure and function. The correct composition and structure of cell membranes define key pathophysiological aspects of cells. Therefore, we explore the therapeutic potential of manipulating membrane lipid composition with approaches like membrane lipid therapy, aiming to normalize cell functions through the modification of membrane lipid bilayers.


Assuntos
Membrana Celular/efeitos dos fármacos , Ácidos Graxos Insaturados/farmacologia , Lipídeos de Membrana/química , Doenças Metabólicas/tratamento farmacológico , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Animais , Compartimento Celular , Membrana Celular/química , Membrana Celular/metabolismo , Ácidos Graxos Insaturados/uso terapêutico , Humanos , Lipídeos de Membrana/metabolismo
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