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1.
J Agric Food Chem ; 67(38): 10637-10645, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31513389

RESUMO

Previous studies have shown that selenite, a representative of inorganic form selenium, exerts its anticancer effect by inducing apoptosis in androgen-dependent LNCaP prostate cancer cells, but few studies have determined the nature of cell death induced by selenite in metastatic androgen-refractory PC-3 cells. Our study showed that necrosis-like cell death rather than apoptosis, pyroptosis, or autophagic cell death was caused by selenite in PC-3 cells. Mechanistically, this type of cell death was caused by ATP depletion (26.28 ± 3.39 nmol/mg of control versus 9.12 ± 2.44 nmol/mg of 10 µM selenite treatment) that resulted from phosphofructokinase activity reduction (100.17 ± 0.17% of control versus 21.74 ± 6.65% of 10 µM selenite treatment). Our study also showed that ROS production is necessary for the decrease in cellular ATP levels and in phosphofructokinase activity. To our knowledge, this is the first study showing that selenite can induce necrosis-like cell death in PC-3 cells. Our findings support selenite as an effective compound for the therapy of apoptosis-resistant prostate cancer.


Assuntos
Morte Celular/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Neoplasias da Próstata/fisiopatologia , Ácido Selenioso/farmacologia , Trifosfato de Adenosina/metabolismo , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Masculino , Fosfofrutoquinases/metabolismo , Neoplasias da Próstata/metabolismo
2.
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
3.
Chem Commun (Camb) ; 55(69): 10192-10213, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31411602

RESUMO

Light is unsurpassed in its ability to modulate biological interactions. Since their discovery, chemists have been fascinated by photosensitive molecules capable of switching between isomeric forms, known as photoswitches. Photoswitchable peptides have been recognized for many years; however, their functional implementation in biological systems has only recently been achieved. Peptides are now acknowledged as excellent protein-protein interaction modulators and have been important in the emergence of photopharmacology. In this review, we briefly explain the different classes of photoswitches and summarize structural studies when they are incorporated into peptides. Importantly, we provide a detailed overview of the rapidly increasing number of examples, where biological modulation is driven by the structural changes. Furthermore, we discuss some of the remaining challenges faced in this field. These exciting proof-of-principle studies highlight the tremendous potential of photocontrollable peptides as optochemical tools for chemical biology and biomedicine.


Assuntos
Descoberta de Drogas , Peptídeos/química , Peptídeos/farmacologia , Sequência de Aminoácidos , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Morte Celular/efeitos dos fármacos , Descoberta de Drogas/métodos , Humanos , Isomerismo , Luz , Modelos Moleculares , Ácidos Nucleicos/metabolismo , Peptídeos/metabolismo , Processos Fotoquímicos , Mapas de Interação de Proteínas/efeitos dos fármacos
4.
Inorg Chem ; 58(17): 11294-11299, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31411862

RESUMO

The first two examples of polyoxopalladates(II) (POPs) containing tetravalent metal ion guests, [MO8Pd12(PO4)8]12- (M = SnIV, PbIV), have been prepared and structurally characterized in the solid state, solution, and gas phase. The interactions of the metal ion guests and the palladium-oxo shell were studied by theoretical calculations. The POPs were shown to possess anticancer activity by causing oxidative stress inducing caspase activation and consecutive apoptosis of leukemic cells.


Assuntos
Antineoplásicos/farmacologia , Metais Pesados/química , Compostos Organometálicos/farmacologia , Polímeros/química , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Íons/química , Modelos Moleculares , Compostos Organometálicos/síntese química , Compostos Organometálicos/química
5.
Int J Nanomedicine ; 14: 5017-5032, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371944

RESUMO

Background: Epigallocatechin gallate (EGCG), the major anti-inflammatory compound in green tea, has been shown to suppress osteoclast (OC) differentiation. However, the low aqueous solubility of EGCG always leads to poor bioavailability, adverse effects, and several drawbacks for clinical applications. Purpose: In this study, we synthesized EGCG-capped gold nanoparticles (EGCG-GNPs) to solve the drawbacks for clinical uses of EGCG in bone destruction disorders by direct reduction of HAuCl4 in EGCG aqueous solution. Methods and Results: The obtained EGCG-GNPs were negatively charged and spherical. Theoretical calculation results suggested that EGCG was released from GNPs in an acidic environment. Cellular uptake study showed an obviously large amount of intracellular EGCG-GNPs without cytotoxicity. EGCG-GNPs exhibited better effects in reducing intracellular reactive oxygen species levels than free EGCG. A more dramatic anti-osteoclastogenic effect induced by EGCG-GNPs than free EGCG was observed in lipopolysaccharide (LPS)-stimulated bone marrow macrophages, including decreased formation of TRAP-positive multinuclear cells and actin rings. Meanwhile, EGCG-GNPs not only suppressed the mRNA expression of genetic markers of OC differentiation but also inhibited MAPK signaling pathways. Furthermore, we confirmed that EGCG-GNPs greatly reversed bone resorption in the LPS-induced calvarial bone erosion model in vivo, which was more effective than applying free EGCG, specifically in inhibiting the number of OCs, improving bone density, and preventing bone loss. Conclusion: EGCG-GNPs showed better anti-osteoclastogenic effect than free EGCG in vitro and in vivo, indicating their potential in anti-bone resorption treatment strategy.


Assuntos
Catequina/análogos & derivados , Ouro/farmacologia , Nanopartículas Metálicas/química , Osteogênese/efeitos dos fármacos , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Reabsorção Óssea/patologia , Catequina/farmacologia , Morte Celular/efeitos dos fármacos , Teoria da Densidade Funcional , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Ligantes , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Nanopartículas Metálicas/ultraestrutura , Camundongos Endogâmicos BALB C , Modelos Biológicos , Ligante RANK/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Crânio/patologia , Transcrição Genética/efeitos dos fármacos
6.
Int J Nanomedicine ; 14: 5147-5157, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371953

RESUMO

Background: Kaempferol (K) is a recognized anticancer drug that can conjugate with small-size gold nanoclusters (AuNCs). Materials and methods: K-AuNCs were synthesized and their use as an anticancer drug was explored using A549 lung cancer cells. Colony formation and cell migration assays were carried out. The morphology of the K-AuNCs treated A549 cells was explored using bio-atomic force microscopy. Results: The K-AuNCs were 1-3 nm in diameter and emitted strong fluorescent at 650 nm following excitation at 550 nm. The stretching and bending nature of the K-AuNCs were analyzed by the Fourier transform infrared spectroscopy. The presence of kaempferol in the AuNCs were confirmed by the PL spectroscopy. Conclusion: The synthesized K-AuNCs mainly targeted and damaged the nuclei of the cancer cells. This composite nanocluster was less toxicity to the normal human cell and higher toxicity to the A549 lunch cancer cell and these material is potential for anticancer drug delivery and bio imaging applications.


Assuntos
Antineoplásicos/uso terapêutico , Ouro/química , Quempferóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas Metálicas/química , Células A549 , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/patologia , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Humanos , Quempferóis/farmacologia , Nanopartículas Metálicas/toxicidade , Nanopartículas Metálicas/ultraestrutura , Fenômenos Ópticos , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
7.
J Enzyme Inhib Med Chem ; 34(1): 1347-1367, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31322015

RESUMO

In the designed compounds, either a biarylamide or biarylurea moiety or an N-substituted piperazine motif was linked to position 1 of the phthalazine core. The anti-proliferative activity of the synthesised compounds revealed that eight compounds (6b, 6e, 7b, 13a, 13c, 16a, 16d and 17a) exhibited excellent broad spectrum cytotoxic activity in NCI 5-log dose assays against the full 60 cell panel with GI50 values ranging from 0.15 to 8.41 µM. Moreover, the enzymatic assessment of the synthesised compounds against VEGFR-2 tyrosine kinase showed the significant inhibitory activities of the biarylureas (12b, 12c and 13c) with IC50s of 4.4, 2.7 and 2.5 µM, respectively, and with 79.83, 72.58 and 71.6% inhibition of HUVEC at 10 µM, respectively. Additionally, compounds (7b, 13c and 16a) were found to induce cell cycle arrest at S phase boundary. Compound 7b triggered a concurrent increase in cleaved caspase-3 expression level, indicating the apoptotic-induced cell death.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Ftalazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Ftalazinas/síntese química , Ftalazinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
8.
Photochem Photobiol Sci ; 18(8): 2003-2011, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31268087

RESUMO

Here we report the activatable photosensitizer BromoAcroB, a brominated BODIPY dye incorporating a reactive acrolein warhead. The acrolein moiety serves as an intramolecular switch, deactivating the BODIPY dye in its singlet and triplet excited states via internal conversion. Thiolate addition to this moiety disables the intramolecular quenching mechanism restoring the photosensitizing properties of the parent dye, characterized by a quantum yield of singlet oxygen photosensitization of 0.69 ± 0.02. In cell cultures, and upon thiol adduct formation, BromoAcroB induced light-dependent cell death in MRC-5 and HeLa cell lines. Using fluorescence microscopy and upon measuring the low yet non-negligible emission of the activated compound, we show that the phototoxicity of the dormant photosensitizer correlated with the quantity of BromoAcroB adducts generated. BromoAcroB thus serves as a dormant photosensitizer sensitive to intracellular electrophile response. Our results highlight the effective control of a triplet state process by modulation of an unsaturated moiety on the BODIPY scaffold and underscore the mechanistic opportunities arising for controlled singlet oxygen production in cells specifically sensitive to electrophile stress.


Assuntos
Acroleína/farmacologia , Compostos de Boro/farmacologia , Corantes/farmacologia , Cisteína/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Oxigênio Singlete/farmacologia , Acroleína/química , Compostos de Boro/química , Morte Celular/efeitos dos fármacos , Corantes/síntese química , Corantes/química , Cisteína/química , Células HeLa , Humanos , Luz , Microscopia de Fluorescência , Estrutura Molecular , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Teoria Quântica , Oxigênio Singlete/química
9.
Anticancer Res ; 39(7): 3519-3529, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262876

RESUMO

BACKGROUND/AIM: Although adrenergic agonists have been used in dental treatments and oral surgery for general anesthesia, their cytotoxicity against human oral malignant and non-malignant cell has not been well- understood. The present study was undertaken to investigate the cytotoxicity of five adrenergic agonists against human oral squamous cell carcinoma (OSCC), glioblastoma, promyelocytic leukemia, and normal oral mesenchymal cells (gingival fibroblast, pulp cell, periodontal ligament fibroblast) and normal epidermal keratinocytes. MATERIALS AND METHODS: Tumor-specificity (TS) was calculated by the ratio between the mean 50% cytotoxic concentration against normal cells to that of tumor cells. Internucleosomal DNA fragmentation was detected using agarose gel electrophoresis. Caspase-3 activity was measured by substrate cleavage. RESULTS: Both cytotoxicity and tumor-specificity of adrenergic agonists against OSCC cell lines was in the order of isoprenaline>dexmedetomidine> adrenaline>clonidine and phenylephrine. Isoprenaline and dexmedetomidine did not induce apoptosis markers, such as internucleosomal DNA fragmentation and caspase-3 activation, but induced a smear pattern of DNA fragmentation in OSCC cell lines. Their cytotoxicity was not reduced by pretreatment with autophagy inhibitors, or by adrenoceptors antagonists. Addition of superoxide dismutase and catalase significantly reduced the cytotoxicity of isoprenaline, but not that of dexmedetomidine. CONCLUSION: Isoprenaline and dexmedetomidine induce non-apoptotic cell death by different mechanisms.


Assuntos
Agonistas Adrenérgicos/farmacologia , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Neoplasias Bucais/tratamento farmacológico , Catalase/farmacologia , Células Cultivadas , Criança , Clonidina/farmacologia , Fragmentação do DNA , Dexmedetomidina/farmacologia , Epinefrina/farmacologia , Humanos , Isoproterenol/farmacologia , Fenilefrina/farmacologia , Superóxido Dismutase/farmacologia
10.
Chem Biol Interact ; 310: 108733, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276663

RESUMO

Plumbagin (PLB) is an active secondary metabolite extracted from the roots of Plumbago rosea. In this study, we report that plumbagin effectively induces paraptosis by triggering extensive cytoplasmic vacuolation followed by cell death in triple negative breast cancer cells (MDA-MB-231), cervical cancer cells (HeLa) and non-small lung cancer cells (A549) but not in normal lung fibroblast cells (WI-38). The vacuoles originated from the dilation of the endoplasmic reticulum (ER) and were found to be empty. The cell death induced by plumbagin was neither apoptotic nor autophagic. Plumbagin induced ER stress mainly by inhibiting the chymotrypsin-like activity of 26S proteasome as also evident from the accumulation of polyubiquitinated proteins. The vacuolation and cell death were found to be independent of reactive oxygen species generation but was effectively inhibited by thiol antioxidant suggesting that plumbagin could modify the sulfur homeostasis in the cellular milieu. Plumbagin also resulted in a decrease in mitochondrial membrane potential eventually decreasing the ATP production. This is the first study to show that Plumbagin induces paraptosis through proteasome inhibition and disruption of sulfhydryl homeostasis and thus further opens up the lead molecule to potential therapeutic strategies for apoptosis-resistant cancers.


Assuntos
Morte Celular/efeitos dos fármacos , Naftoquinonas/farmacologia , Neoplasias/patologia , Linhagem Celular , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Homeostase , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Naftoquinonas/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteassoma/farmacologia , Compostos de Sulfidrila/metabolismo , Vacúolos/metabolismo
11.
Int J Nanomedicine ; 14: 4961-4974, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308666

RESUMO

Background: Lipid polymer hybrid nanoparticles (LPHNPs) for the controlled delivery of hydrophilic doxorubicin hydrochloride (DOX.HCl) and lipophilic DOX base have been fabricated by the single step modified nanoprecipitation method. Materials and methods: Poly (D, L-lactide-co-glicolide) (PLGA), lecithin, and 1,2-distearoyl-Sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000 (DSPE-PEG 2000) were selected as structural components. Results: The mean particle size was 173-208 nm, with an encapsulation efficiency of 17.8±1.9 to 43.8±4.4% and 40.3±0.6 to 59. 8±1.4% for DOX.HCl and DOX base, respectively. The drug release profile was in the range 33-57% in 24 hours and followed the Higuchi model (R2=0.9867-0.9450) and Fickian diffusion (n<0.5). However, the release of DOX base was slower than DOX.HCl. The in vitro cytotoxicity studies and confocal imaging showed safety, good biocompatibility, and a higher degree of particle internalization. The higher internalization of DOX base was attributed to higher permeability of lipophilic component and better hydrophobic interaction of particles with cell membranes. Compared to the free DOX, the DOX.HCl and DOX base loaded LPHNPs showed higher antiproliferation effects in MDA-MB231 and PC3 cells. Conclusion: Therefore, LPHNPs have provided a potential drug delivery strategy for safe, controlled delivery of both hydrophilic and lipophilic form of DOX in cancer cells.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/uso terapêutico , Interações Hidrofóbicas e Hidrofílicas , Lipídeos/química , Nanopartículas/química , Polímeros/química , Varredura Diferencial de Calorimetria , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Coloides/química , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Feminino , Humanos , Cinética , Nanopartículas/ultraestrutura , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática
12.
Analyst ; 144(17): 5232-5244, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31360935

RESUMO

Leishmaniasis comprises a group of infectious diseases with worldwide distribution, of which both the visceral and cutaneous forms are caused by Leishmania parasites. In the absence of vaccines, efficacious chemotherapy remains the basis for leishmaniasis control. The available drugs are expensive and associated with several secondary adverse effects. Due to these limitations, the development of new antileishmanial compounds is imperative, and plants offer various perspectives in this regard. The present study evaluated the in vitro leishmanicidal activity of flavonoids isolated from Solanum paludosum Moric. and investigated the mechanisms of cell death induced by them. These compounds were evaluated in vitro for their antileishmanial activity against Leishmania amazonensis promastigotes and they showed prominent leishmanicidal activity. The EtOAc fraction, gossypetin 3,7,8,4'-tetra-O-methyl ether (1), and kaempferol 3,7-di-O-methyl ether (3) were selected to be used in an in vitro assay against L. amazonensis amastigotes and cell death assays. The flavonoids (1) and (3) presented significant activity against L. amazonensis amastigotes, exhibiting the IC50 values of 23.3 ± 4.5 µM, 34.0 ± 9.6 µM, and 10.5 ± 2.5 µM for the EtOAc fraction, (1), and (3), respectively, without toxic effects to the host cells. Moreover, (1) and (3) induced blocked cell cycle progression at the G1/S transition, ultimately leading to G1/G0 arrest. Flavonoid (3) also induced autophagy. Using Raman spectroscopy in conjunction with principal component analysis, the biochemical changes in the cellular components induced by flavonoids (1) and (3) were presented. The obtained results indicated that the mechanisms of action of (1) and (3) occurred through different routes. The results support that the flavonoids derived from S. paludosum can become lead molecules for the design of antileishmanial prototypes.


Assuntos
Antiprotozoários/farmacologia , Morte Celular/efeitos dos fármacos , Flavonoides/farmacologia , Citometria de Fluxo/métodos , Leishmania/efeitos dos fármacos , Animais , Antiprotozoários/química , Autofagia/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Flavonoides/química , Quempferóis/química , Quempferóis/farmacologia , Leishmania/citologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Análise Espectral Raman , Estreptófitas/química
13.
Int J Nanomedicine ; 14: 4801-4816, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308659

RESUMO

Background: Silver nanoparticles (AgNPs) inhibit the proliferation of various fungi; however, their mechanisms of action remain poorly understood. To better understand the inhibitory mechanisms, we focused on the early events elicited by 5 nm AgNPs in pathogenic Candida albicans and non-pathogenic Saccharomyces cerevisiae. Methods: The effect of 5 nm and 100 nm AgNPs on fungus cell proliferation was analyzed by growth kinetics monitoring and spot assay. We examined cell cycle progression, reactive oxygen species (ROS) production, and cell death using flow cytometry. Glucose uptake was assessed using tritium-labeled 2-deoxyglucose. Results: The growth of both C. albicans and S. cerevisiae was suppressed by treatment with 5 nm AgNPs but not with 100 nm AgNPs. In addition, 5 nm AgNPs induced cell cycle arrest and a reduction in glucose uptake in both fungi after 30 minutes of culture in a dose-dependent manner (P<0.05). However, in C. albicans only, an increase in ROS production was detected after exposure to 5 nm AgNPs. Concordantly, an ROS scavenger blocked the effect of 5 nm AgNPs on the cell cycle and glucose uptake in C. albicans only. Furthermore, the growth-inhibition effect of 5 nm AgNPs was not greater in S. cerevisiae mutant strains deficient in oxidative stress response genes than it was in wild type. Finally, 5 nm AgNPs together with a glycolysis inhibitor, 3-bromopyruvate, synergistically enhanced cell death in C. albicans (P<0.05) but not in S. cerevisiae. Conclusion: AgNPs exhibit antifungal activity in a manner that may or may not be ROS dependent, according to the fungal species. The combination of AgNPs with 3-bromopyruvate may be more useful against infection with C. albicans.


Assuntos
Candida albicans/citologia , Ciclo Celular/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Piruvatos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Saccharomyces cerevisiae/citologia , Prata/farmacologia , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Parede Celular/efeitos dos fármacos , Parede Celular/genética , Depuradores de Radicais Livres/farmacologia , Fase G1/efeitos dos fármacos , Genes Fúngicos , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento
14.
Int J Nanomedicine ; 14: 4367-4381, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354266

RESUMO

Purpose: Polyethylenimine (PEI) has been widely used as a versatile template to develop multifunctional nanosystems for disease diagnosis and treatment. In this study, we manufactured iodine-131 (131I)-labeled PEI-entrapped gold nanoparticles (Au PENPs) as a novel nanoprobe for single-photon emission computed tomography/computed tomography (SPECT/CT) imaging and radionuclide therapy. Materials and methods: PEI was PEGylated and sequentially conjugated with Buthus martensii Karsch chlorotoxin (BmK CT, a tumor-specific ligand which can selectively bind to MMP2), 3-(4'-hydroxyphenyl)propionic acid-OSu (HPAO), and fluorescein isothiocyanate to form the multifunctional PEI template for entrapment of Au NPs. Then, the PEI surface was radiolabeled with 131I via HPAO to produce the novel nanoprobe (BmK CT-Au PENPs-131I). Results: The synthesized multifunctional Au PENPs before and after 131I radiolabeling were well-characterized as follows: structure, X-ray attenuation coefficient, colloid stability, cytocompatibility, and radiochemical stability in vitro. Furthermore, BmK CT-Au PENPs-131I were suitable for targeted SPECT/CT imaging and radionuclide therapy of tumor cells in vitro and in a xenograft tumor model in vivo. Conclusion: The developed multifunctional Au PENPs are a promising theranostic platform for targeted imaging and treatment of different MMP2-overexpressing tumors.


Assuntos
Ouro/química , Radioisótopos do Iodo/química , Nanopartículas Metálicas/química , Polietilenoimina/química , Compostos Radiofarmacêuticos/uso terapêutico , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Coloides/química , Glioma/patologia , Glioma/radioterapia , Humanos , Nanopartículas Metálicas/ultraestrutura , Camundongos Endogâmicos BALB C , Camundongos Nus , Especificidade de Órgãos , Tamanho da Partícula , Propionatos/química , Venenos de Escorpião/toxicidade
15.
Life Sci ; 232: 116665, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31323273

RESUMO

AIMS: Overexpression of the mechanistic target of rapamycin (mTOR), a member of the PIKK (phosphoinositide kinase-related kinase) family, protects cardiomyocytes from cell death induced by pathological stimuli such as ischemia. We previously reported that posttranslational modification of mTOR plays an important role in regulating cardiac mTOR expression. The aim of this study was to see if Tel2 (telomere maintenance 2), a protein that regulates the abundance of PIKKs, confers similar cardioprotective effects as mTOR. Tel2 is not well-characterized in cardiomyocytes, therefore we examined the effects of Tel2 on cardiomyocyte viability under ischemic stress conditions. MATERIALS AND METHODS: We overexpressed Tel2 or silenced Tel2 with siRNA in the HL-1 cardiomyocyte cell line to survey the effects of Tel2 overexpression and downregulation on cell survival during hypoxia. Adult mouse cardiomyocytes transfected with Tel2 adenoviruses were used to test whether Tel2 sufficiently prevented cardiomyocyte cell death against hydrogen peroxide (H2O2). KEY FINDINGS: Overexpressing Tel2 increased mTOR expression with a concomitant increase in mTOR Complex 1 (mTORC1) and mTORC2 activity in HL-1 cells. Tel2 deletion decreased mTOR expression, and mTORC1 and mTORC2 activity accordingly. In both HL-1 cells and adult mouse cardiomyocytes, Tel2 overexpression protected cardiomyocytes under ischemic stress. These effects were mTOR-dependent, as mTOR inhibitors blunted the effects of Tel2. While gene silencing of Tel2 did not affect cell survival under normoxia, Tel2 silencing made cardiomyocytes more vulnerable to cell death under hypoxia. SIGNIFICANCE: Upregulating Tel2 expression increases mTOR-mediated cardiomyocyte survival and targeting Tel2 could be another therapeutic strategy against ischemic heart disease.


Assuntos
Sobrevivência Celular/fisiologia , Miócitos Cardíacos/citologia , Proteínas de Ligação a Telômeros/fisiologia , Adenoviridae/genética , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Inativação Gênica , Peróxido de Hidrogênio/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Camundongos , Transdução de Sinais , Proteínas de Ligação a Telômeros/genética , Transfecção
16.
Int J Nanomedicine ; 14: 3893-3909, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239663

RESUMO

Background: Photothermal and chemotherapy treatment has been frequently studied for cancer therapy; however, chemotherapy is equally toxic to both normal and cancer cells. The clinical application value of most kinds of photothermal transforming agents remains limited, due to their poor degradation and minimal accumulation in tumors. Materials and methods: We reported the synthesis of photothermal transforming agents (MoS2) and chemotherapeutic (doxorubicin, DOX) co-loaded electrospun nanofibers using blend electrospinning for the treatment of postoperative tumor recurrence. Results: Under the irradiation of an 808 nm laser, the as-prepared chitosan/polyvinyl alcohol/MoS2/DOX nanofibers showed an admirable photothermal conversion capability with a photothermal conversion efficiency of 23.2%. These composite nanofibers are in vitro and in vivo biocompatible. In addition, they could control the sustained release of DOX and the generated heat can sensitize the chemotherapeutic efficacy of DOX via enhancing its release rate. Their chemo-/photothermal combined therapy efficiency was systematically studied in vitro and in vivo. Instead of circulating with the body fluid, MoS2 was trapped by the nanofibrous matrix in the tumor and so its tumor-killing ability was not compromised, thus rendering this composite nanofiber a promising alternative for future clinical translation within biomedical application fields. Conclusion: Chitosan/polyvinyl alcohol/MoS2/DOX nanofibers showed an excellent photothermal conversion capability with a photothermal conversion efficiency of 23.2% and can completely inhibit the postoperative tumor reoccurrence.


Assuntos
Dissulfetos/química , Doxorrubicina/uso terapêutico , Molibdênio/química , Nanofibras/química , Nanotecnologia/métodos , Neoplasias/terapia , Fototerapia , Animais , Materiais Biocompatíveis/farmacologia , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Reagentes para Ligações Cruzadas/química , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Células HT29 , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanofibras/ultraestrutura , Recidiva Local de Neoplasia/patologia , Neoplasias/sangue , Neoplasias/patologia , Neoplasias/cirurgia , Padrões de Referência , Resultado do Tratamento
17.
Int J Nanomedicine ; 14: 3967-3982, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239666

RESUMO

Background: The combination of chemotherapy with radiotherapy serves as a common therapeutic strategy in clinics. However, it is unsatisfactory due to its poor therapeutic efficiency and severe side-effects originating from chemotherapy-exerted systemic toxicity as well as radiation-induced injury. Purpose: Hence, Berberine (Ber), an isoquinolin alkaloid with low toxicity and protective effects against radiotherapy, was used as a novel chemotherapeutic agent for chemo-radiotherapy of liver cancer. Patients and methods: We preloaded Ber into folic acid targeting Janus gold mesoporous silica nanocarriers (FA-JGMSNs) for overcoming the poor bioavailability of Ber. Furthermore, FA-JGMSNs were not only employed as radiosensitizers for expanding radiotherapeutic effect, but also used as photothermal agents for supplementing chemo-radiotherapeutic effect by local photothermal therapy. Results: In vitro and in vivo experiemtal results demonstrated the highly efficient anti-tumor effect, good biosafety as well as the effective protection of normal tissue of this nanoplatform. Conclusion: Based on its superb performance, we believe our work provided a feasible strategy for triple-therapies of liver cancer.


Assuntos
Berberina/uso terapêutico , Ouro/química , Hipertermia Induzida , Neoplasias Hepáticas/terapia , Nanopartículas/química , Fototerapia , Lesões por Radiação/prevenção & controle , Dióxido de Silício/química , Animais , Berberina/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Camundongos Nus , Nanopartículas/ultraestrutura , Tamanho da Partícula , Porosidade , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Lesões por Radiação/terapia , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Temperatura Ambiente
18.
Int J Nanomedicine ; 14: 4017-4028, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239667

RESUMO

Background: The design of novel nanoparticles with higher therapeutic efficacy and lower side effects, is still difficult but encouraging in cancer therapy. Specifically, for upconversion nanoparticles (UCNP)-based drug release, a high intensity of NIR light (1.4~5.0 W/cm2) above the maximum permissible exposure (0.33 W/cm2 for 980 nm) is commonly used and severely limits its practical application. Methods: The highly emissive UCNP is first synthesized and then coated with mesoporous silica (MS) shell (UCMS). Next, the surface of UCMS is modified with the thioether (-S-BP) linker, leading to UCMS-S-BP nanoparticles. Finally, after the drug doxorubicin (Dox) is loaded into the pore channels of UCMS, the pore openings are blocked by the ß-cyclodextrin (ß-CD) gatekeeper through the association with the -S-BP linker (UCMS(Dox)-S-BP@ß-CD). Results: Upon 980 nm NIR light irradiation with an ultralow intensity of 0.30 W/cm2, it is found that the loaded Dox can be released through the cleavage of thioether linkers triggering dissociation of ß-CD gatekeepers. The in vitro results exhibited significantly therapeutic efficacy with 85.2% of HeLa cells killed in this study. Conclusions: An ultralow-intensity NIR light triggered on-demand drug release system has been developed by employing highly emissive UCNP and photocleavable linker with low bond dissociation energy to avoid the potential photodamage on healthy neighbor cells.


Assuntos
Liberação Controlada de Fármacos , Raios Infravermelhos , Nanopartículas/química , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Teoria da Densidade Funcional , Doxorrubicina/farmacologia , Endocitose/efeitos dos fármacos , Fluorescência , Células HeLa , Humanos , Nanopartículas/ultraestrutura , Espectrofotometria Ultravioleta , Termodinâmica
19.
Int J Nanomedicine ; 14: 4105-4121, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239670

RESUMO

Purpose: Doxorubicin (DOX) encapsulated O-succinyl chitosan graft Pluronic® F127 (OCP) copolymer nanoparticles conjugated with an anti-HER2 monoclonal antibody were developed as targeted drug delivery vehicles for the treatment of HER2-overexpressing breast cancer. Methods: Five percent and 10% (w/w) of O-succinyl chitosan was grafted onto Pluronic® F127 using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) as mediated cross-linking agents. DOX was added to the copolymer solution to form DOX-nanoparticles before conjugation with anti-HER2 on the surface of the nanoparticles. Results: DOX was encapsulated within the NP matrices at an encapsulation efficiency of 73.69 ± 0.53% to 74.65 ± 0.44% (the initial DOX concentration was 5 µg/mL). Anti-HER2 was successfully conjugated onto the surface of the nanoparticles at a moderately high conjugation efficiency of approximately 57.23 ± 0.38% to 61.20 ± 4.42%. In the in vitro DOX dissolution study, the nanoparticle formulations exhibited a biphasic drug release with an initial burst release followed by a sustained release profile at both pH 5.0 and pH 7.4. The drug was rapidly and completely released from the nanoparticles at pH 5.0. In the in vitro cytotoxicity, the anti-HER2 conjugated OCP copolymer nanoparticles showed the lowest IC50, which indicated an increase in the therapeutic efficacy of DOX to treat human breast cancer cells with the HER2 overexpression. Conclusion: Our study shows that anti-HER2 conjugated OCP copolymer nanoparticles have the potential for the development of anticancer drug carriers.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quitosana/análogos & derivados , Doxorrubicina/uso terapêutico , Nanopartículas/química , Receptor ErbB-2/metabolismo , Animais , Neoplasias da Mama/patologia , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cercopithecus aethiops , Quitosana/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Feminino , Humanos , Ligantes , Células MCF-7 , Micelas , Tamanho da Partícula , Células Vero
20.
Int J Nanomedicine ; 14: 4167-4186, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239675

RESUMO

Engineered nanomaterials (ENMs) have been widely used in various fields due to their novel physicochemical properties. However, the use of ENMs has led to an increased exposure in humans, and the safety of ENMs has attracted much attention. It is universally acknowledged that ENMs could enter the human body via different routes, eg, inhalation, skin contact, and intravenous injection. Studies have proven that ENMs can cross or bypass the blood-brain barrier and then access the central nervous system and cause neurotoxicity. Until now, diverse in vivo and in vitro models have been developed to evaluate the neurotoxicity of ENMs, and oxidative stress, inflammation, DNA damage, and cell death have been identified as being involved. However, due to various physicochemical properties of ENMs and diverse study models in existing studies, it remains challenging to establish the structure-activity relationship of nanomaterials in neurotoxicity. In this paper, we aimed to review current studies on ENM-induced neurotoxicity, with an emphasis on the molecular and cellular mechanisms involved. We hope to provide a rational material design strategy for ENMs when they are applied in biomedical or other engineering applications.


Assuntos
Nanoestruturas/toxicidade , Nanotecnologia , Neurotoxinas/toxicidade , Morte Celular/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Dano ao DNA , Humanos , Nanoestruturas/química
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