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1.
Angew Chem Int Ed Engl ; 59(8): 3226-3234, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-31756258

RESUMO

Pathogenesis hallmarks for tuberculosis (TB) are the Mycobacterium tuberculosis (Mtb) escape from phagolysosomal destruction and limited drug delivery into infected cells. Several nanomaterials can be entrapped in lysosomes, but the development of functional nanomaterials to promote phagolysosomal Mtb clearance remains a big challenge. Here, we report on the bactericidal effects of selenium nanoparticles (Se NPs) against Mtb and further introduce a novel nanomaterial-assisted anti-TB strategy manipulating Ison@Man-Se NPs for synergistic drug-induced and phagolysosomal destruction of Mtb. Ison@Man-Se NPs preferentially entered macrophages and accumulated in lysosomes releasing Isoniazid. Surprisingly, Ison@Man-Se/Man-Se NPs further promoted the fusion of Mtb into lysosomes for synergistic lysosomal and Isoniazid destruction of Mtb. Concurrently, Ison@Man-Se/Man-Se NPs also induced autophagy sequestration of Mtb, evolving into lysosome-associated autophagosomal Mtb degradation linked to ROS-mitochondrial and PI3K/Akt/mTOR signaling pathways. This novel nanomaterial-assisted anti-TB strategy manipulating antimicrobial immunity and Mtb clearance may potentially serve in more effective therapeutics against TB and drug-resistant TB.

2.
Mol Cancer ; 18(1): 182, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31830995

RESUMO

BACKGROUND: Chemotherapy is a widely used treatment for cancer. However, the development of acquired multidrug resistance (MDR) is a serious issue. Emerging evidence has shown that the extracellular vesicles (EVs) mediate MDR, but the underlying mechanism remains unclear, especially the effects of chemotherapeutic agents on this process. METHODS: Extracellular vesicles isolation was performed by differential centrifugation. The recipient cells that acquired ATP-binding cassette sub-family B member 1 (ABCB1) proteins were sorted out from co-cultures according to a stringent multi-parameter gating strategy by fluorescence-activated cell sorting (FACS). The transfer rate of ABCB1 was measured by flow cytometry. The xenograft tumor models in mice were established to evaluate the transfer of ABCB1 in vivo. Gene expression was detected by real-time PCR and Western blotting. RESULTS: Herein, we show that a transient exposure to chemotherapeutic agents can strikingly increase Rab8B-mediated release of extracellular vesicles (EVs) containing ABCB1 from drug-resistant cells, and accelerate these EVs to circulate back onto plasma membrane of sensitive tumor cells via the down-regulation of Rab5. Therefore, intercellular ABCB1 transfer is significantly enhanced; sensitive recipient cells acquire a rapid but unsustainable resistance to evade the cytotoxicity of chemotherapeutic agents. More fascinatingly, in the xenograft tumor models, chemotherapeutical drugs also locally or distantly increase the transfer of ABCB1 molecules. Furthermore, some Non-small-cell lung carcinoma (NSCLC) patients who are undergoing primary chemotherapy have a rapid increase of ABCB1 protein in their monocytes, and this is obviously associated with poor chemotherapeutic efficacy. CONCLUSIONS: Chemotherapeutic agents stimulate the secretion and recycling of ABCB1-enriched EVs through the dysregulation of Rab8B and Rab5, leading to a significant increase of ABCB1 intercellular transfer, thus assisting sensitive cancer cells to develop an urgent resistant phenotype. Our findings provide a new molecular mechanism of how chemotherapeutic drugs assist sensitive cancer cells in acquiring an urgent resistance.

3.
Mater Sci Eng C Mater Biol Appl ; 103: 109777, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349400

RESUMO

Tuberculosis (TB), caused by M.tuberculosis (Mtb), has become a top killer among infectious diseases. Enhancing the ability of anti-TB drugs to kill intracellular Mtb in host cells remains a big challenge. Here, an innovative nano-system was developed to increase drug delivery and Mtb-killing efficacy in Mtb-infected macrophages. We employed mannose surface decoration to develop mannosylated and PEGylated graphene oxide (GO-PEG-MAN). Such nano-platform exhibited increased uptake by macrophages via mannose receptor-mediated endocytosis in vitro. Interestingly, drug-loaded GO-PEG-MAN was preferentially up-taken by mannose receptor-expressing mucosal CD14+ macrophages isolated from Mtb-infected rhesus macaques than drug-loaded GO-PEG. Consistently, the drug concentration was also significantly higher in macrophages than that in T and B cells expressing no or low mannose receptor, implicating a useful macrophage/mannose receptor-targeted drug-delivery system relevant to the in vivo settings. Concurrently, rifampicin-loaded GO-PEG-MAN (Rif@GO-PEG-MAN) significantly increased rifampicin uptake, inducing long-lasting higher concentration of rifampicin in macrophages. Such innovative Rif@GO-PEG-MAN could readily get into the lysosomes of the Mtb host cells, where rifampicin underwent an accelerated release in acidic lysosomic condition, leading to explosive rifampicin release after cell entry for more effective killing of intracellular Mtb. Most importantly, Rif@GO-PEG-MAN-enhanced intracellular rifampicin delivery and pharmacokinetics significantly increased the efficacy of rifampicin-driven killing of intracellular BCG and Mtb bacilli in infected macrophages both in vitro and ex vivo. Such innovative nanocarrier approach may potentially enhance anti-TB drug efficacy and reduce drug side effects.


Assuntos
Sistemas de Liberação de Medicamentos , Grafite , Macrófagos , Manose , Mycobacterium tuberculosis/metabolismo , Nanopartículas , Rifampina , Tuberculose , Animais , Grafite/química , Grafite/farmacocinética , Grafite/farmacologia , Humanos , Macaca mulatta , Macrófagos/metabolismo , Macrófagos/microbiologia , Macrófagos/patologia , Manose/química , Manose/farmacocinética , Manose/farmacologia , Nanopartículas/química , Nanopartículas/uso terapêutico , Rifampina/química , Rifampina/farmacocinética , Rifampina/farmacologia , Células THP-1 , Tuberculose/tratamento farmacológico , Tuberculose/metabolismo , Tuberculose/patologia
4.
Int J Mol Sci ; 20(4)2019 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-30813425

RESUMO

Kaempferol (Kae) is a natural flavonoid with potent antioxidant activity, but its therapeutic use is limited by its low aqueous solubility. Here, a series of Kae derivatives were synthesized to improve Kae dissolution property in water and antioxidant activity. These compounds included sulfonated Kae (Kae-SO3), gallium (Ga) complexes with Kae (Kae-Ga) and Kae-SO3 (Kae-SO3-Ga). The compound structures were characterized by high-resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR) spectroscopy, ultraviolet-visible (UV-Vis) spectroscopy, Fourier transform infrared (FT-IR) spectroscopy and thermal methods (TG/DSC). The results showed that a sulfonic group (-SO3) was successfully tethered on the C3' of Kae to form Kae-SO3. And in the metal complexation, 4-CO and 3-OH of the ligand participated in the coordination with Ga(III). The metal-to-ligand ratio 1:2 was suggested for both complexes. Interestingly, Kae-SO3-Ga was obviously superior to other compounds in terms of overcoming the poor water-solubility of free Kae, and the solubility of Kae-SO3-Ga was about 300-fold higher than that of Kae-Ga. Furthermore, the evaluation of antioxidant activities in vitro was carried out for Kae derivatives by using α,α-diphenyl-ß-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid) diammonium salt (ABTS) free radical scavenging. The results showed that Kae-SO3-Ga was also optimal for scavenging free radicals in a dose-dependent manner. These data demonstrate that sulfonate kaempferol-gallium complex has a promising future as a potential antioxidant and as a potential therapeutic agent for further biomedical studies.


Assuntos
Antioxidantes/farmacologia , Depuradores de Radicais Livres/farmacologia , Quempferóis/síntese química , Quempferóis/farmacologia , Água/química , Compostos de Bifenilo/química , Varredura Diferencial de Calorimetria , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Espectrometria de Massas , Picratos/química , Espectroscopia de Prótons por Ressonância Magnética , Solubilidade , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Ácidos Sulfônicos/química , Temperatura , Termogravimetria
5.
Methods Mol Biol ; 1886: 99-113, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30374864

RESUMO

As a high-resolution imaging technique, AFM has been found to be a novel tool for cell topography and its quantitative imaging. This chapter is focused on the introduction of AFM cell topography and its quantitative imaging, which includes the basic principle of AFM imaging, basic operation modes of AFM imaging, AFM imaging of biological sample, critical tips for AFM cell topography and its quantitative imaging, applications of AFM cell topography and its quantitative imaging, and perspective. We believe that this work will help to promote the technological and methodological developments of AFM cell topography and its quantitative imaging, promoting further application of AFM in cell biology, immunology, and medicine.


Assuntos
Técnicas Citológicas , Processamento de Imagem Assistida por Computador , Microscopia de Força Atômica/métodos , Animais , Biomarcadores , Humanos , Processamento de Imagem Assistida por Computador/métodos , Microscopia de Força Atômica/normas
6.
J Cell Biochem ; 120(3): 3736-3746, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30229997

RESUMO

Oridonin, an active diterpenoid isolated from Rabdosia rubescens, has been reported for its antitumor activity on several cancers. However, its effect on human esophageal cancer remains unclear. In this study, we demonstrated that oridonin could inhibit the growth of human esophageal cancer cells both in vitro and in vivo. Oridonin not only suppressed the proliferation, but also induced cell cycle arrest and mitochondrial-mediated apoptosis in KYSE-30, KYSE-150, and EC9706 cells with dose-dependent manner. Further mechanism studies revealed that oridonin led cell cycle arrest in esophageal cancer cells via downregulating cell cycle-related proteins, such as cyclin B1 and CDK2, while upregulating p53 and p21. Oridonin also increased proapoptotic protein Bax and reduced antiapoptotic protein Bcl-2, as well as the increased expression of cleaved caspase-3, -8, and -9. In addition, oridonin treatment could significantly inhibit the PI3K/Akt/mTOR and Ras/Raf signaling pathway. In vivo results further demonstrated that oridonin treatment markedly inhibited tumor growth in the esophageal cancer xenograft mice model. Taken together, these results suggest that oridonin may be a potential anticancer agent for the treatment of esophageal cancer.

7.
Artif Cells Nanomed Biotechnol ; 46(sup3): S297-S307, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30183382

RESUMO

Graphene oxides (GO) is a promising building material to fabricate desired drug delivery system due to its excellent physicochemical properties. In this study, an innovative nano-drug (Ori@GE11-GO) was constructed based on GE11 peptide functionalized GO for targeted delivery of oridonin to realize the specific recognition of tumour cells and enhance anticancer efficiency. GE11 surface modification onto GO significantly increased the cellular uptake of GO in EGFR overexpressed oesophageal cancer cells (KYSE-30 and EC109 cells) than that of normal cells, indicating the EGFR targeting effects of Ori@GE11-GO. The internalized Ori@GE11-GO could accumulate into lysosomes and significantly inhibit the viability of cancer cells. Moreover, Ori@GE11-GO could effectively induce KYSE-30 and EC109 cells cycle arrest, apoptosis, mitochondrial membrane potential (△Ψm) disruption through the activation of apoptotic signalling pathways and the inhibition of EGFR/Ras/Raf/MEK/ERK signalling pathway, showing potential use of Ori@GE11-GO for cancer treatment. Taken together, this study demonstrates a good strategy for the construction of bio-functionalized GO drug delivery nanosystem to improve the cancer targeting efficiency of anticancer medicines.


Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Portadores de Fármacos , Neoplasias Esofágicas , Grafite , Nanopartículas , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Grafite/química , Grafite/farmacocinética , Grafite/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Nanopartículas/química , Nanopartículas/uso terapêutico
8.
Bioinorg Chem Appl ; 2018: 1062562, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30073019

RESUMO

Zinc oxide nanoparticles (ZnO NPs) are used in an increasing number of industrial products such as rubber, paint, coating, and cosmetics. In the past two decades, ZnO NPs have become one of the most popular metal oxide nanoparticles in biological applications due to their excellent biocompatibility, economic, and low toxicity. ZnO NPs have emerged a promising potential in biomedicine, especially in the fields of anticancer and antibacterial fields, which are involved with their potent ability to trigger excess reactive oxygen species (ROS) production, release zinc ions, and induce cell apoptosis. In addition, zinc is well known to keep the structural integrity of insulin. So, ZnO NPs also have been effectively developed for antidiabetic treatment. Moreover, ZnO NPs show excellent luminescent properties and have turned them into one of the main candidates for bioimaging. Here, we summarize the synthesis and recent advances of ZnO NPs in the biomedical fields, which will be helpful for facilitating their future research progress and focusing on biomedical fields.

9.
Biomed Pharmacother ; 103: 1592-1601, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29864947

RESUMO

Atomic force microscopy (AFM) is appropriately applied to the examination of hard surfaces and soft samples with extremely high resolution and ultrasensitive force, which cannot be obtained by other imaging techniques, including optical and electron microscopy. In the current study, AFM was employed to evaluate the anti-arthritic effect of licochalcone A (LCA), a flavonoid isolated from the root of Chinese medicinal herb Glycyrrhiza inflate, on rheumatoid arthritis synovial fibroblasts (RASFs) at the nanoscale for the first time. The morphology, ultrastructure and stiffness of RASFs was modified by LCA as determined by AFM, suggesting that LCA most likely exerts an anti-arthritic effect based on the key role of RASFs in the progression of RA. Further studies showed that the inhibitory effect of LCA on IκBα phosphorylation and degradation as well as on p65 nuclear translocation and phosphorylation contributed to altering the morphology, ultrastructure and stiffness of the RASF membrane. Interestingly, IKKß phosphorylation was not detectable in RASFs, indicating that LCA altered the morphology, ultrastructure and stiffness of the RASF membrane by inhibiting NF-κB activation independent of IKKß phosphorylation. Antigen-induced arthritis (AIA) was established in Sprague Dawley (SD) rats to validate the anti-arthritic effect of LCA, and LCA significantly decreased both the arthritis scores and paw swelling in the AIA rats, suggesting that LCA inhibits the progression and development of arthritis in vivo. Collectively, AFM provides evidence at the nanoscale to predict the anti-arthritic effect of drugs on RASFs, and LCA should be further investigated as a candidate agent for the treatment of arthritis.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Chalconas/uso terapêutico , Microscopia de Força Atômica , NF-kappa B/metabolismo , Transdução de Sinais , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/patologia , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Chalconas/química , Chalconas/farmacologia , Módulo de Elasticidade , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibroblastos/ultraestrutura , Masculino , Inibidor de NF-kappaB alfa/metabolismo , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Ratos Sprague-Dawley , Membrana Sinovial/patologia
10.
Mikrochim Acta ; 185(6): 287, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29737406

RESUMO

The authors describe a dual-mode (colorimetric-fluorometric) nanoprobe for H2O2 that was fabricated by covering molybdenum disulfide nanosheets (MoS2 NS) with ortho-phenylenediamine (OPD). The probe (OPD-MoS2 NS) was applied to the optical determination of H2O2, to the quantitation of cell numbers, and to the detection of intracellular concentrations of H2O2. Oxidation by H2O2 leads to a colored and fluorescent product (oxidized OPD) with absorption/excitation/fluorescence peaks at 450/450/557 nm. The nanoprobe can detect H2O2 in down to 500 nM concentrations, and HeLa cells at levels of 100 cells mL-1. The detection limit for intracellular H2O2 is in the 5.5 to 12.6 µM concentration range when the method is applied to cells at levels of 102-106 cells mL-1. Due to its good biocompatibility and easy cell uptake, the nanoprobe also permits sensitive fluorometric imaging of intracellular H2O2. It can also comparatively discriminate the change of intracellular oxidation state in living cancerous and normal cells. Graphical abstract Editor, we provided image with high resolution. Please find it in a folder name "MIAC-D-18-00081" in the FTP site. A dual-mode (colorimetric-fluorometric) detection nanoplatform based on OPD-modified MoS2 nanosheets is used to quantitatively detect H2O2, cell numbers and intracellular H2O2. The MoS2 nanoprobes also permit sensitive fluorescence imaging of intracellular H2O2, and can discriminate intracellular oxide states in living cancerous and normal cells.


Assuntos
Materiais Biomiméticos/química , Dissulfetos/química , Peróxido de Hidrogênio/metabolismo , Espaço Intracelular/metabolismo , Molibdênio/química , Nanoestruturas/química , Imagem Óptica/métodos , Peroxidases/metabolismo , Células HeLa , Humanos , Peróxido de Hidrogênio/química , Limite de Detecção , Modelos Moleculares , Conformação Molecular , Oxirredução
11.
Pathol Res Pract ; 214(5): 691-699, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29567333

RESUMO

Matrine, as a natural alkaloid isolated from the traditional herb medicine sophora flavescens, has been proved to possess excellent biological activities, including anticancer effects. Now, this research aims to assess the anticancer activities and the mechanism of matrine against esophageal cancer cells, we investigated the proliferative inhibition, apoptosis induction, as well as the underlying mechanism of matrine on esophageal cancer KYSE-150 cells. It was found that matrine could suppress KYSE-150 cell proliferation and significantly mediate cell apoptosis in a dose-dependent relation by increasing intracellular reactive oxygen species level and triggering mitochondrial membrane potential disruption. More precise mechanism studies demonstrated that matrine could up-regulate the expression of Bax proteins and down-regulate the expression of Bcl-2 proteins, as well as the activation about caspase-3, 8 and 9 in KYSE-150 cells. The morphological analysis of KYSE-150 cells exhibited that matrine could destroy the F-actin and nuclei structures and induce morphological damage with increased surface height distribution and roughness of cell membrane. These results not only demonstrated the potential anticancer activity mechanism of matrine at nanoscale, but also provide preliminary guidance for the treatment of esophageal cancer using matrine.


Assuntos
Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Alcaloides , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Quinolizinas , Proteína X Associada a bcl-2/metabolismo
12.
Drug Deliv ; 24(1): 1549-1564, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29019267

RESUMO

Selenium nanoparticles (Se NPs) have attracted increasing interest in recent decades because of their anticancer, immunoregulation, and drug carrier functions. In this study, GE11 peptide-conjugated Se NPs (GE11-Se NPs), a nanosystem targeting EGFR over-expressed cancer cells, were synthesized for oridonin delivery to achieve enhanced anticancer efficacy. Oridonin loaded and GE11 peptide conjugated Se NPs (GE11-Ori-Se NPs) were found to show enhanced cellular uptake in cancer cells, which resulted in enhanced cancer inhibition against cancer cells and reduced toxicity against normal cells. After accumulation into the lysosomes of cancer cells and increase of oridonin release under acid condition, GE11-Ori-Se NPs were further transported into cytoplasm after the damage of lysosomal membrane integrity. GE11-Ori-Se NPs were found to induce cancer cell apoptosis by inducting reactive oxygen species (ROS) production, activating mitochondria-dependent pathway, inhibiting EGFR-mediated PI3K/AKT and inhibiting Ras/Raf/MEK/ERK pathways. GE11-Se NPs were also found to show active targeting effects against the tumor tissue in esophageal cancer bearing mice. And in nude mice xenograft model, GE11-Ori-Se NPs significantly inhibited the tumor growth via inhibition of tumor angiogenesis by reducing the angiogenesis-marker CD31 and activation of the immune system by enhancing IL-2 and TNF-α production. The selenium contents in mice were found to accumulate into liver, tumor, and kidney, but showed no significant toxicity against liver and kidney. This cancer-targeted design of Se NPs provides a new strategy for synergistic treating of cancer with higher efficacy and reduced side effects, introducing GE11-Ori-Se NPs as a candidate for further evaluation as a chemotherapeutic agent for EGFR over-expressed esophageal cancers.


Assuntos
Antineoplásicos/farmacologia , Diterpenos de Caurano/farmacologia , Receptores ErbB/antagonistas & inibidores , Peptídeos/farmacologia , Selênio/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Diterpenos de Caurano/administração & dosagem , Diterpenos de Caurano/farmacocinética , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Interleucina-2/biossíntese , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Nanopartículas/química , Peptídeos/administração & dosagem , Peptídeos/farmacocinética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Selênio/farmacocinética , Fator de Necrose Tumoral alfa/biossíntese
13.
Nanoscale ; 9(42): 16365-16374, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29052674

RESUMO

Poor bioavailability and non-specificity of chemotherapeutic agents are major challenges in breast cancer treatment. Antibodies and small molecules that block cell signaling pathways have shown promise in the clinic, but their application is also limited by the high costs and treatment dosages required. Novel therapies that aim to rapidly and specifically target malignant cells with long-lasting impact in the tumor microenvironment may ultimately improve clinical outcome in cancer patients. Here, we demonstrate that epidermal growth factor receptor (EGFR)-targeting GE11 peptides conjugated with PEGylated polylactic-co-glycolic acid (PLGA) nanoparticles can be used to effectively deliver an anti-cancer agent, curcumin, into EGFR-expressing MCF-7 cells in vitro and in vivo. Treatment of breast cancer cells and tumor-bearing mice with these curcumin-loaded nanoparticles gave rise to reduced phosphoinositide 3-kinase signaling, decreased cancer cell viability, attenuated drug clearance from the circulation, and suppressed tumor burden compared with free curcumin or non-EGFR targeting nanoparticles. The targeted nanoscale drug delivery system we describe here may provide a new strategy for the design of targeted cancer therapy vectors. Our study provides evidence that the efficacy of pharmacologic anti-cancer agents can be enhanced through their delivery in the form of modified nanoparticles that effectively target specific malignant cell types.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Curcumina/administração & dosagem , Portadores de Fármacos , Receptores ErbB/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas , Fosfatidilinositol 3-Quinases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Pharmacol Res ; 119: 479-489, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28411855

RESUMO

As the active anticancer component of Rabdosia Rubescens, oridonin has been proved to show strong anticancer activity in cancer cells, which is also found to be closely related to its specific inhibition effects on the EGFR tyrosine kinase activity. In this study, atomic force microscopy based single molecule force spectroscopy (AFM-SMFS) was used for real-time and in-situ detection of EGF-EGFR interactions in living esophageal cancer KYSE-150 cells to evaluate the anticancer activity of oridonin for the first time. Oridonin was found to induce apoptosis and also reduce EGFR expression in KYSE-150 cells. AFM-SMFS results demonstrated that oridonin could inhibit the binding between EGF and EGFR in KYSE-150 cells by decreasing the unbinding force and binding probability for EGF-EGFR complexes, which was further proved to be closely associated with the intracellular ROS level. More precise mechanism studies based on AFM-SMFS demonstrated that oridonin treatment could decrease the energy barrier width, increase the dissociation off rate constant and decrease the activation energy of EGF-EGFR complexes in ROS dependent way, suggesting oridonin as a strong anticancer agent targeting EGF-EGFR interactions in cancer cells through ROS dependent mechanism. Our results not only suggested oridonin as a strong anticancer agent targeting EGF-EGFR interactions in ROS dependent mechanism, but also highlighted AFM-SMFS as a powerful technique for pharmacodynamic studies by detecting ligand-receptor interactions, which was also expected to be developed into a promising tool for the screening and mechanism studies of drugs.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Diterpenos de Caurano/farmacologia , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Diterpenos de Caurano/química , Neoplasias Esofágicas/metabolismo , Esôfago/efeitos dos fármacos , Esôfago/metabolismo , Humanos , Isodon/química , Microscopia de Força Atômica
15.
Biochem Biophys Res Commun ; 486(2): 245-251, 2017 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-28274875

RESUMO

Acute myocardial infarction (AMI) initiation and progression follow complex molecular and structural changes in the nanoarchitecture of platelets. However, it remains poorly understood how the transformation from health to AMI alters the ultrastructural and biomechanical properties of platelets within the platelet activation microenvironment. Here, we show using an atomic force microscope (AFM) that platelet samples, including living human platelets from the healthy and AMI patient, activated platelets from collagen-stimulated model, show distinct ultrastructural imaging and stiffness profiles. Correlative morphology obtained on AMI platelets and collagen-activated platelets display distinct pseudopodia structure and nanoclusters on membrane. In contrast to normal platelets, AMI platelets have a stiffer distribution resulting from complicated pathogenesis, with a prominent high-stiffness peak representative of platelet activation using AFM-based force spectroscopy. Similar findings are seen in specific stages of platelet activation in collagen-stimulated model. Further evidence obtained from different force measurement region with activated platelets shows that platelet migration is correlated to the more elasticity of pseudopodia while high stiffness at the center region. Overall, ultrastructural and nanomechanical profiling by AFM provides quantitative indicators in the clinical diagnostics of AMI with mechanobiological significance.


Assuntos
Plaquetas/efeitos dos fármacos , Colágeno/farmacologia , Infarto do Miocárdio/patologia , Ativação Plaquetária/efeitos dos fármacos , Pseudópodes/efeitos dos fármacos , Fenômenos Biomecânicos , Coagulação Sanguínea , Plaquetas/patologia , Plaquetas/ultraestrutura , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Elasticidade , Hemorreologia , Humanos , Microscopia de Força Atômica , Pseudópodes/patologia , Pseudópodes/ultraestrutura
16.
Scanning ; 38(6): 901-912, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27487564

RESUMO

Dihydromyricetin (DMY) a flavonoid derived from medicinal plant Ampelopsis grossedentata, possesses anti-oxidative and anti-inflammatory effects in vitro, however, the in vivo anti-inflammatory action of DMY remains unknown. In the current study, carrageenan-induced paw edema in rat, an acute inflammation model, and RAW264.7 macrophages activated by LPS were employed to evaluate the anti-inflammatory potency of DMY in vivo and in vitro. Results showed that DMY significantly attenuated rat paw edema induced by carrageenan. Also, DMY markedly inhibited NO secretion, iNOS, and COX-2 protein expression, as well as p65 phosphorylation via suppression of IKKß activity and IKKα/ß phosphorylation in RAW264.7 cells. And using high resolution Atomic Force Microscope (AFM), we also proved that DMY prevented morphological change and membrane alterations of RAW 264.7 macrophages caused by LPS stimulation. As activation of macrophages is one of major factors in carrageenan-induced paw edema of rats, the anti-inflammatory action of DMY is suggested to be closely associated with suppression of macrophage activation. These findings indicate that DMY is valuable of being further investigated as a candidate new agent for treating inflammatory conditions, and suggest that AFM could be a powerful nanotool for anti-inflammatory investigations. SCANNING 38:901-912, 2016. © 2016 Wiley Periodicals, Inc.


Assuntos
Anti-Inflamatórios/farmacologia , Flavonóis/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , Animais , Feminino , Células HEK293 , Humanos , Macrófagos/imunologia , Camundongos , Microscopia de Força Atômica , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Células RAW 264.7 , Ratos , Ratos Wistar , Fator de Transcrição RelA/antagonistas & inibidores
17.
Sci Rep ; 6: 30782, 2016 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-27469490

RESUMO

Ursolic acid (UA) has proved to have broad-spectrum anti-tumor effects, but its poor water solubility and incompetent targeting property largely limit its clinical application and efficiency. Here, we synthesized a nanoparticle-based drug carrier composed of chitosan, UA and folate (FA-CS-UA-NPs) and demonstrated that FA-CS-UA-NPs could effectively diminish off-target effects and increase local drug concentrations of UA. Using MCF-7 cells as in vitro model for anti-cancer mechanistic studies, we found that FA-CS-UA-NPs could be easily internalized by cancer cells through a folate receptor-mediated endocytic pathway. FA-CS-UA-NPs entered into lysosome, destructed the permeability of lysosomal membrane, and then got released from lysosomes. Subsequently, FA-CS-UA-NPs localized into mitochondria but not nuclei. The prolonged retention of FA-CS-UA-NPs in mitochondria induced overproduction of ROS and destruction of mitochondrial membrane potential, and resulted in the irreversible apoptosis in cancer cells. In vivo experiments showed that FA-CS-UA-NPs could significantly reduce breast cancer burden in MCF-7 xenograft mouse model. These results suggested that FA-CS-UA-NPs could further be explored as an anti-cancer drug candidate and that our approach might provide a platform to develop novel anti-cancer drug delivery system.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quitosana/química , Ácido Fólico/administração & dosagem , Nanopartículas/química , Triterpenos/administração & dosagem , Animais , Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Ácido Fólico/farmacologia , Humanos , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Triterpenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Pharmacol Res ; 111: 374-383, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27339828

RESUMO

The degranulation of mast cells and basophils is often initiated by a number of pathophysiological responses, especially in allergic and inflammatory conditions. Efficient techniques and methods for determining the level of such degranulation are highly demanded for laboratory and clinical studies. In this work, a rapid and sensitive assay based on the particle analysis of granules in RBL-2H3 cells, a cell line widely used as a convenient model system to study the degranulation of mast cells and basophils, was developed to detect cell degranulation using a Nanosight NS300 in light scatter mode and dynamic light scattering (DLS) on a Malvern Zetasizer Nano-ZS instrument. Using this method, drug-induced mast cell degranulation and systemic anaphylaxis were efficiently determined both in cell culture medium and blood samples from animals in the current study. This promising method is expected to be widely used for screening anti-allergic and anti-inflammatory drugs both in vitro and in vivo models, as well as for determining the level of mast cell degranulation of the patients in the clinic.


Assuntos
Teste de Degranulação Basófila/métodos , Basófilos/metabolismo , Técnicas Biossensoriais , Degranulação Celular , Mastócitos/metabolismo , Animais , Teste de Degranulação Basófila/instrumentação , Basófilos/efeitos dos fármacos , Basófilos/imunologia , Cálcio/metabolismo , Degranulação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Difusão Dinâmica da Luz , Desenho de Equipamento , Exocitose/efeitos dos fármacos , Feminino , Ionomicina/farmacologia , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Morfinanos/farmacologia , Valor Preditivo dos Testes , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Fatores de Tempo , p-Metoxi-N-metilfenetilamina/farmacologia
19.
Scanning ; 38(6): 792-801, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27280953

RESUMO

Polysaccharide compounds (PCs), which composed of different kinds of polysaccharides always isolated from different kinds of traditional Chinese medicine, are now attracting more and more attentions due to their strong immunomodulatory activities beyond the corresponding one-component polysaccharides. In this study, we demonstrated for the first time that PCs-1 and PCs-2 had strong immunomodulatory effects on macrophages both in in vitro and in vivo models by atomic force microscopy (AFM). By high resolution AFM imaging, PCs-1 and PCs-2 were found to inhibit LPS induced cell surface particle size and roughness increase in RAW264.7 macrophages, demonstrating the anti-inflammatory effects of PCs-1 and PCs-2 on macrophages. PCs-1 and PCs-2 were also proved to increase the particle size and roughness of resting RAW264.7 macrophages, which suggested that PCs could activate resting RAW264.7 macrophages. And additionally, PCs-1 and PCs-2 were also found to reverse the surface particle size and roughness decrease of peritoneal macrophages isolated from cyclophosphamide induced immunosuppressive mice, suggesting the activation effects of PCs-1 and PCs-2 on immunosuppressive macrophages. These results further enhanced our understanding of macrophage activations by direct imaging of cell surface ultrastructure and also highlighted AFM as a novel nanotool for macrophage detections. And most importantly, these results also indicated the outstanding immunomodulatory effects of PCs on macrophages, which therefore suggested that PCs could be served as a kind of novel immunomodulatory agents that would benefit human health. SCANNING 38:792-801, 2016. © 2016 Wiley Periodicals, Inc.


Assuntos
Fatores Imunológicos/farmacologia , Macrófagos/efeitos dos fármacos , Polissacarídeos/farmacologia , Animais , Células Cultivadas , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Microscopia de Força Atômica
20.
Bioorg Med Chem Lett ; 26(11): 2730-4, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27080177

RESUMO

According to the previous studies, the anticancer activity of flavonoids could be enhanced when they are coordinated with transition metal ions. In this work, kaempferol-zinc(II) complex (kaempferol-Zn) was synthesized and its chemical properties were characterized by UV-VIS, FT-IR, (1)H NMR, elemental analysis, electrospray mass spectrometry (ES-MS) and fluorescence spectroscopy, which showed that the synthesized complex was coordinated with a Zn(II) ion via the 3-OH and 4-oxo groups. The anticancer effects of kaempferol-Zn and free kaempferol on human oesophageal cancer cell line (EC9706) were compared. MTT results demonstrated that the killing effect of kaempferol-Zn was two times higher than that of free kaempferol. Atomic force microscopy (AFM) showed the morphological and ultrastructural changes of cellular membrane induced by kaempferol-Zn at subcellular or nanometer level. Moreover, flow cytometric analysis indicated that kaempferol-Zn could induce apoptosis in EC9706 cells by regulating intracellular calcium ions. Collectively, all the data showed that kaempferol-Zn might be served as a kind of potential anticancer agent.


Assuntos
Antineoplásicos/farmacologia , Quempferóis/farmacologia , Compostos Organometálicos/farmacologia , Zinco/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Quempferóis/química , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Espectrometria de Fluorescência , Relação Estrutura-Atividade , Zinco/química
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