Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 43
Filtrar
Filtros adicionais











Intervalo de ano
1.
J Nanobiotechnology ; 17(1): 76, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31217009

RESUMO

BACKGROUND: Molybdenum disulfide (MoS2) has been widely explored for biomedical applications due to its brilliant photothermal conversion ability. In this paper, we report a novel multifunctional MoS2-based drug delivery system (MoS2-SS-HA). By decorating MoS2 nanosheets with hyaluronic acid (HA), these functionalized MoS2 nanosheets have been developed as a tumor-targeting chemotherapeutic nanocarrier for near-infrared (NIR) photothermal-triggered drug delivery, facilitating the combination of chemotherapy and photothermal therapy into one system for cancer therapy. RESULTS: The nanocomposites (MoS2-SS-HA) generated a uniform diameter (ca. 125 nm), exhibited great biocompatibility as well as high stability in physiological solutions, and could be loaded with the insoluble anti-cancer drug erlotinib (Er). The release of Er was greatly accelerated under near infrared laser (NIR) irradiation, showing that the composites can be used as responsive systems, with Er release controllable through NIR irradiation. MTT assays and confocal imaging results showed that the MoS2-based nanoplatform could selectively target and kill CD44-positive lung cancer cells, especially drug resistant cells (A549 and H1975). In vivo tumor ablation studies prove a better synergistic therapeutic effect of the joint treatment, compared with either chemotherapy or photothermal therapy alone. CONCLUSION: The functionalized MoS2 nanoplatform developed in this work could be a potent system for targeted drug delivery and synergistic chemo-photothermal cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Dissulfetos/química , Portadores de Fármacos/química , Cloridrato de Erlotinib/farmacologia , Hipertermia Induzida , Molibdênio/química , Nanocompostos/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Cloridrato de Erlotinib/química , Feminino , Humanos , Ácido Hialurônico/química , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fototerapia
2.
EBioMedicine ; 42: 281-295, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30878596

RESUMO

BACKGROUND: Treatment multiple tumors by immune therapy can be achieved by mobilizing both innate and adaptive immunity. The programmed death ligand 1 (PD-L1; or CD274, B7-H1) is a critical "don't find me" signal to the adaptive immune system. Equally CD47 is a critical "don't eat me" signal to the innate immune system and a regulator of the adaptive immune response. METHOD: Both of CD47 and PD-L1 are overexpressed on the surface of cancer cells to enable to escape immune-surveillance. We designed EpCAM (epithelial cell adhesion molecule)-targeted cationic liposome (LPP-P4-Ep) containing si-CD47 and si-PD-L1 could target high-EpCAM cancer cells and knockdown both CD47 and PD-L1 proteins. FINDINGS: Efficient silencing of CD47 and PD-L1 versus single gene silencing in vivo by systemic administration of LPP-P4-Ep could significantly inhibited the growth of solid tumors in subcutaneous and reduced lung metastasis in lung metastasis model. Target delivery of the complexes LPP-P4-Ep increased anti-tumor T cell and NK cell response, and release various cytokines including IFN-γ and IL-6 in vivo and in vitro. INTERPRETATION: This multi-nanoparticles showed significantly high-EpCAM tumor targeting and lower toxicity, and enhanced immune therapeutic efficacy. Our data indicated that dual-blockade tumor cell-specific innate and adaptive checkpoints represents an improved strategy for tumor immunotherapy. FUND: This research supported by the Ministry of Science and Technology of the People's Republic of China (grant number 2015CB931804); the National Natural Science Foundation of China (NSFC, grant numbers 81703555, U1505225 and 81773063), and the China Postdoctoral Science Foundation (grant number 2017 M620268).


Assuntos
Imunidade Adaptativa , Antígeno B7-H1/metabolismo , Antígeno CD47/metabolismo , Citocinas/metabolismo , Imunidade Inata , Neoplasias/imunologia , Neoplasias/metabolismo , Biomarcadores , Citotoxicidade Imunológica , Humanos , Imuno-Histoquímica , Neoplasias/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
3.
Mol Pharm ; 16(5): 2235-2248, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-30896172

RESUMO

Dual-targeted nanoparticles are gaining increasing importance as a more effective anticancer strategy by attacking double key sites of tumor cells, especially in chemophotodynamic therapy. To retain the nuclei inhibition effect and enhance doxorubicin (DOX)-induced apoptosis by mitochondrial pathways simultaneously, we synthesized the novel nanocarrier (HKH) based on hollow carbon nitride nanosphere (HCNS) modified with hyaluronic acid (HA) and the mitochondrial localizing peptide D[KLAKLAK]2 (KLA). DOX-loaded HKH nanoparticles (HKHDs) showed satisfactory drug-loading efficiency, excellent solubility, and very low hemolytic effect. HA/CD44 binding and electrostatic attraction between positively charged KLA and A549 cells facilitated HKHD uptake via the endocytosis mechanism. Acidic microenvironment, hyaluronidase, and KLA targeting together facilitate doxorubicin toward the mitochondria and nuclei, resulting in apoptosis, DNA intercalation, cell-cycle arrest at the S phase, and light-induced reactive oxygen species production. Intravascular HKHD inhibited tumor growth in A549-implanted mice with good safety. The present study, for the first time, systemically reveals biostability, targetability, chemophotodynamics, and safety of the functionalized novel HKHD.

4.
Sci Rep ; 9(1): 4532, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30872703

RESUMO

Carcinoma metastasis is triggered by a subpopulation of circulating tumor cells (CTCs). And single immune checkpoint therapy is not good enough to inhibit CTC-induced metastasis. Here, we demonstrate that simultaneously blocking CD274 (programmed death ligand 1, PD-L1 or B7-H1) and CD47 checkpoints which were respectively signal of "don't find me" and "don't eat me" on CTCs by corresponding antibodies could enhance the inhibition tumor growth than single CD274 or CD47 antibody alone. In vitro flow cytometry data proved that CD47 and CD274 were overexpressed on the tested mouse tumor cell lines. The antibodies could effectively block the expressions of CD47 and CD274 on the cell surface and stably attached to tumor cell surface for several hours. The simultaneous blockade on both CD47 and CD274 checkpoints inhibited tumor growth and CTCs metastasis more potently than a single antibody inhibition or blank control on 4T1 tumor mouse model in vivo. Our results demonstrated that simultaneous dual targeting immune checkpoints, i.e., CD47 and CD274, by using specific antibodies may be more effective as an immunotherapeutics on CTCs than a CD47 or CD274 alone.

5.
Exp Cell Res ; 375(1): 62-72, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578764

RESUMO

Despite the recognition of the lethality of cancer metastasis and the importance of developing specific anti-metastasis therapies directed at the cancer metastatic cascade, the dynamics of cancer metastasis remains poorly understood. In this study, we examined the dynamics of circulating tumor cell (CTC) survival in the bloodstream using experimental mouse models. CTCs were arrested in the capillaries by adhesion to vascular endothelium within a few minutes after injection into the bloodstream. The loss of CTCs from the circulation followed a bi-phasic decay pattern, with the number of CTCs in the bloodstream being closely associated with the number of blood circulation cycles. The calculated in vivo Vd (apparent volume of distribution) of the CTC revealed organ specific binding of the CTCs. Moreover, confocal microscopy, in vivo fluorescence imaging in syngeneic mouse metastatic models and analysis of blood circulation patterns support the notion of organ-specific tumor metastasis. The present study suggests that organ-specific tumor metastasis is influenced by cooperation between blood circulation patterns and 'seed-soil' compatibility factors. These new findings provide further insights for optimized cancer metastatic prevention strategies such as by creating a hostile circulation microenvironment and targeting the organ-specific 'seed-soil' compatibility factors.

6.
Waste Manag ; 80: 10-16, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30454988

RESUMO

Severe nitrogen (N) loss is a barrier for composting treatment. Since N transformation during composting is closely related to nitrogen loss, the impacts of adding sulphur and Thiobacillus thioparus 1904 to N transformation during composting were investigated in this work. Physicochemical properties and the expression of genes encoding N-related proteins were analysed to evaluate microbiological processes associated with N dynamics. The results indicated that (1) sulphur addition reduced the pH and cumulative NH3 emission, and decreased N losses by 44.23%, while no significant differences were observed in the expression of N cycle-associated genes compared with the control treatment; (2) the application of T. thioparus 1904 increased NO3--N content, reduced N loss by 28.20%, and significantly enhanced the expression of ammonia monooxygenase A (archaeal amoA; AOA) and nitrite oxidoreductase A (nxrA) during the mature phase; (3) the combined application of sulphur and T. thioparus 1904 significantly affected the expression of functional genes related to nitrification and denitrification, which contributed to a reduction in accumulated NH3 emission, an increase in NO4+-N content, and a decrease in N losses by 70.94%. Expression of ammonia monooxygenase A (bacterial amoA; AOB), nxrA and nitrous oxide reductase Z (nosZ) genes in the combined treatment was positively correlated with NO3--N, whereas expression of AOA and accumulation of NH3 were negatively correlated with NO3--N. These results indicate that the combined application of sulphur and T. thioparus 1904 had a significant regulatory effect on N cycle genes and effectively reduced the N loss during composting.

7.
Int J Oncol ; 53(6): 2590-2604, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30280201

RESUMO

Metastasis accounts for the majority of cancer-related mortalities, and the complex processes of metastasis remain the least understood aspect of cancer biology. Metabolic reprogramming is associated with cancer cell survival and metastasis in a hostile envi-ronment with a limited nutrient supply, such as solid tumors. Little is known regarding the differences of bioenergetic adaptation between primary tumor cells and metastatic tumor cells in unfavorable microenvironments; to clarify these differences, the present study aimed to compare metabolic reprogramming of primary tumor cells and metastatic tumor cells. SW620 metastatic tumor cells exhibited stronger bioenergetic adaptation in unfavorable conditions compared with SW480 primary tumor-derived cells, as determined by the sustained elevation of glycolysis and regulation of the cell cycle. This remarkable glycolytic ability of SW620 cells was associated with high expression levels of hexokinase (HK)1, HK2, glucose transporter type 1 and hypoxia-inducible factor 1α. Compared with SW480 cells, the expression of cell cycle regulatory proteins was effectively inhibited in SW620 cells to sustain cell survival when there was a lack of energy. Furthermore, SW620 cells exhibited a stronger mesenchymal phenotype and stem cell characteristics compared with SW480 cells; CD133 and CD166 were highly expressed in SW620 cells, whereas expression was not detected in SW480 cells. These data may explain why metastatic cancer cells exhibit greater microenvironmental adaptability and survivability; specifically, this may be achieved by upregulating glycolysis, optimizing the cell cycle and reprogramming cell metabolism. The present study may provide a target metabolic pathway for cancer metastasis therapy.

8.
Pharmacol Res ; 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30366102

RESUMO

A perfect microenvironment facilitates the activated circulating tumor cells (CTCs) to spark the adhesion-invasion-extravasation metastatic cascade in their premetastatic niche. Platelet-CTC interaction contributes to the progression of tumor malignancy by protecting CTCs from shear stress and immunological assault, aiding CTCs entrapment in the capillary bed, enabling CTCs to successfully exit the bloodstream and enter the tissue, inducing epithelial-mesenchymal-like transition (EMT), and assisting in the establishment of metastatic foci. To prevent the cascade from sparking, we show that, the multifunctional S-nitrosocaptopril (CapNO) acts on both CTCs and platelets to interrupt platelet/CTCs interplay and adhesion to endothelium, thus inhibiting CTC-based pulmonary metastasis in vivo. The activated platelets cloak cancer HT29 cells, resulting in HT29-exhibiting platelet biomarkers CD61 and P-selectin positive. CapNO inhibits both sialyl Lewisx (Slex) expression on HT29 and ADP-induced activation of platelets through P-selectin- and GPIIb/IIIa-dependent mechanisms, confirmed by the corresponding antibody assay. CapNO inhibits platelet- or interleukin (IL)-1ß-mediated adhesion between HT29 and endothelial cells, and micrometastatic formation in the lungs of immunocompetent syngeneic mouse models. CapNO have also shown the effects of vasodilation, anticoagulation, inhibition of matrix metalloproteinase-2 (MMP2) expression on cancer cells, and inhibition of cell adhesion molecules (CAMs) expression on vascular endothelium. Due to a series of the beneficial effects of CapNO, CTCs remain exposed to the hostile bloodstream environment and are vulnerable to death induced by shear stress and immune elimination. This new discovery provides a basis for CapNO used for cancer metastatic chemoprevention, and might suggest regulation of the CTCs bloodstream microenvironment as a new avenue for cancer metastatic prevention.

9.
Biomed Res Int ; 2018: 7093691, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29977915

RESUMO

Clausena lansium (Lour.) Skeels, commonly known as "wampee," is an excellent food ingredient of medicinal value. Effects of leaf developmental stages on the composition of phenolics, flavonoids, and antioxidant activity were investigated. Phenolics composition was studied using HPLC-PAD, whereas antioxidant activity was estimated by oxygen radical absorbance capacity (ORAC) and cellular antioxidant activity (CAA) assays. Increase in bound flavonoids, quercetin, and cellular antioxidant activity was observed in bound and free fractions at different stages of leaf development. Predominantly, quercetin and ferulic acid contents were high in free and bound fractions of old leaves. In addition, phenolic components depicted highly significant positive association (p < 0.05) with antioxidant activity. Overall, old leaves of wampee have utility value similar to leaf buds, so they could be a more sustainable and economical source of bioactive compounds for commercial application in nutraceutical and pharmaceutical industries.

10.
Forensic Sci Med Pathol ; 14(4): 469-477, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30058014

RESUMO

We report on a novel method for saliva identification by reverse transcription-loop-mediated isothermal amplification (RT-LAMP). In our previous report, real-time RT-LAMP was used for blood identification by using HBB detection as a model but in this advanced study, this method was refined for the identification of the more challenging body fluid of saliva. Expression of the18S rRNA gene was used as the internal control and the Statherin (STATH) gene as the saliva-specific marker. A turbidimeter was used for real-time detection of the RT-LAMP products, and confirmation was obtained that the real products were generated using: agarose gel electrophoresis, calcein fluorescence detection and/or enzymatic digestion. The specificity of the test was performed using 42 samples including 7 different body fluids, and the expression of STATH was only observed in all the saliva samples (6) with a threshold time of 39.4 ± 2.9 min. Sensitivity testing showed that RT-LAMP products for STATH were stably detected when the RNA template was not less than 6.25 ng. When the primer concentrations for STATH were two times that of 18S rRNA, saliva could be identified in the body fluid mixtures even at a ratio (saliva:semen) of 1:3 (without loop primer)/1:5 (with loop primer). A multiplex RT-LAMP was established to simultaneously amplify the 18S rRNA and STATH genes, and applied to the identification of saliva on ten non-probative cigarette butts. A positive result for saliva was obtained from all ten butts, even for those that returned a negative or ambiguous result using the amylase test. A direct RT-LAMP test is also reported where the RNA extraction step was omitted to speed the collection of data and all tests using either the simplex or multiplex RT-LAMP resulted in a positive response if saliva was present. Our data provide a simple and effective means to detect the presence of saliva.

11.
Nanoscale ; 10(18): 8870-8871, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29707724

RESUMO

Correction for 'A novel nanomissile targeting two biomarkers and accurately bombing CTCs with doxorubicin' by Yu Gao et al., Nanoscale, 2017, 9, 5624-5640.

12.
Bioresour Technol ; 249: 254-260, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29049984

RESUMO

The effects of sulphur and Thiobacillus thioparus 1904 on odour emissions during composting were studied. Results indicated that the sulphur addition reduced the pH and decreased cumulative emission of ammonia and the nitrogen loss by 47.80% and 44.23%, respectively, but the amount of volatile sulphur compounds (VSCs) and the sulphur loss increased. The addition of T. thioparus 1904 effectively reduced the cumulative emissions of H2S, methyl sulphide, methanethiol, dimethyl disulphide and the sulphur loss by 33.24%, 81.24%, 32.70%, 54.22% and 54.24%, respectively. T. thioparus 1904 also limited the nitrogen loss. The combined application of sulphur and T. thioparus 1904 resulted in the greatest amount of nitrogen retention. The accumulation of ammonia emissions was reduced by 63.33%, and the nitrogen loss was reduced by 71.93%. The combined treatment did not increase the emission of VSCs. The application of sulphur and T. thioparus 1904 may help to control the odour of compost.


Assuntos
Compostagem , Odorantes , Thiobacillus , Enxofre , Compostos de Enxofre
13.
Sci Rep ; 7(1): 17190, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29215040

RESUMO

Metapristone is the primary metabolite of the abortifacient mifepristone (RU486), and is being developed as a safe and effective cancer metastatic chemopreventive agent for both sexes. Here, we systematically investigated the sex-related pharmacokinetics of metapristone in both rats and dogs, and explored the related mechanisms of actions. Administration of metapristone to rats and dogs showed that plasma concentrations of metapristone (AUC, C max ) were significantly higher in female dogs and rats than in males. The sex-related differences in pharmacokinetics become more significant after ten consecutive days of oral administration. Female liver microsomes metabolized metapristone significantly slower than the male ones. The results from P450 reaction phenotyping using recombinant cDNA-expressed human CYPs in conjunction with specific CYP inhibitors suggested that CYP1A2 and CYP3A4 are the predominant CYPs involved in the metapristone metabolism, which were further confirmed by the enhanced protein levels of CYP1A2 and CYP3A4 induced by 1-week oral administration of metapristone to rats. The highest tissue concentration of metapristone was found in the liver. The study demonstrates, for the first time, the sex-related pharmacokinetics of metapristone, and reveals that activities of liver microsomal CYP1A2 and CYP3A4 as well as the renal clearance are primarily responsible for the sex-related pharmacokinetics.

14.
Oncotarget ; 8(45): 78351-78364, 2017 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-29108234

RESUMO

Therapies targeting epidermal growth factor receptor (EGFR) can effectively treat with non-small cell lung cancer (NSCLC), but NSCLC's drug resistance makes it intractable. Herein, we showed that RU486 metabolite metapristone inhibited the proliferation of various NSCLC cell lines with either wild (A549, H1299, H520) or mutated EGFR (H1975, HCC827). The suppression was resulted from inhibition by metapristone of EGFR signaling pathways through down-regulating the EGFR, PTEN, as well as AKT and ERK proteins. In addition, metapristone inhibited anti-apoptotic marker Bcl-2, and activated pro-apoptotic key signaling proteins caspase-3, and poly (ADP-ribose) polymerase. Metapristone induced A549 and H1975 cell cycle via arrest at the G0-G1 stage. What's more, metapristone inhibited the growth of NSCLC xenografts in BALB/c nude mice through decreasing the expression of tumor growth biomarkers PCNA and EGFR. Taken together, the present study demonstrated that metapristone suppressed NSCLC proliferation by promoting apoptosis via decrease the cellular EGFR-mediated PI3K/AKT pathways. The results suggest metapristone a new treatment for EGFR-overexpressed NSCLC.

15.
Bioresour Technol ; 239: 447-453, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28538200

RESUMO

The Dirichlet multinomial mixtures mode was used to analyse illumina sequencing data to reveal both temporal and spatial variations of the fungi community present in the aerobic composting. Results showed that 670 operational taxonomic units (OTUs) were detected, and the dominant phylum was Ascomycota. There were four types of samples fungi communities during the composting process. Samples from the early composting stage were mainly grouped into type I and Saccharomycetales sp. was dominant. Fungi community in the medium composting stage were fallen into type II and III, Sordariales sp. and Acremonium alcalophilum, Saccharomycetales sp. and Scedosporium minutisporum were the dominant OTUs respectively. Samples from the late composting stage were mainly grouped into type IV and Scedosporium minutisporum was the dominant OTU; Scedosporium minutisporum was significantly affected by depth (P<0.05). Results indicate that time and depth both are factors that influence fungi distribution and variation in c waste during static aerobic composting.


Assuntos
Ascomicetos , Esterco , Solo , Animais , Galinhas , Fungos , Microbiologia do Solo
16.
Nanoscale ; 9(17): 5624-5640, 2017 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-28422250

RESUMO

Rare circulating tumor cells (CTCs) cause >50% of primary colorectal cancer survivors to develop deadly metastasis at 3-5 years after surgery; the current chemotherapies can do nothing about these cells. Herein, we synthesized a novel doxorubicin (DOX)-entrapped mesoporous silica nanoparticle (MSN), covalently-conjugated with two aptamers, for simultaneously targeting EpCAM and CD44, the typical surface biomarkers of colorectal CTCs. The nanomissile can specifically capture the metastasis-prone CTCs spiked in healthy human blood in a competitive-binding manner. The binding not only accurately delivers DOX into the cancer cells via the biomarker-mediated endocytosis to inhibit CTC viability through the DOX-dependent mechanism, but also inhibits the adhesion of cancer cells to the endothelium and the consequent transmembrane migration through the DOX-independent mechanism. The molecular entity of the conjugate and its pharmaceutical DOX encapsulation-releasing capacity are well-demonstrated via various physiochemical characterizations including gel electrophoresis, which proves the >8-hour biostability of the nanomissile in blood, long enough for it to chase CTCs in mice and synergistically inhibit the CTC-induced lung metastasis more potently than its single aptamer-conjugated counterparts and DOX itself. The present strategy may pave a new avenue for safe and effective cancer metastasis chemoprevention.


Assuntos
Doxorrubicina/administração & dosagem , Portadores de Fármacos , Nanopartículas , Células Neoplásicas Circulantes/efeitos dos fármacos , Dióxido de Silício , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
17.
Front Plant Sci ; 7: 1165, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27540387

RESUMO

While glycolate oxidase (GLO) is well known as a key enzyme for the photorespiratory metabolism in plants, its physiological function and mechanism remains to be further clarified. Our previous studies have shown that suppression of GLO in rice leads to stunted growth and inhibited photosynthesis (Pn) which is positively and linearly correlated with decreased GLO activities. It is, therefore, of interest to further understand whether Pn can be improved when GLO is up-regulated? In this study, four independent overexpression rice lines, with gradient increases in GLO activity, were generated and functionally analyzed. Phenotypic observations showed that the growth could be improved when GLO activities were increased by 60 or 100%, whereas reduced growth was noticed when the activity was further increased by 150 or 210%. As compared with WT plants, all the overexpression plants exhibited significantly improved Pn under conditions of high light and high temperature, but not under normal conditions. In addition, the overexpression plants were more resistant to the MV-induced photooxidative stress. It was further demonstrated that the antioxidant enzymes, and the antioxidant metabolite glutathione was not significantly altered in the overexpression plants. In contrast, H2O2 and salicylic acid (SA) were correspondingly induced upon the GLO overexpression. Taken together, the results suggest that GLO may play an important role for plants to cope with high light and high temperature, and that H2O2 and SA may serve as signaling molecules to trigger stress defense responses but antioxidant reactions appear not to be involved in the defense.

18.
Eur J Pharmacol ; 791: 62-71, 2016 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-27565222

RESUMO

Inflammatory cytokines can induce the expression of cell adhesion molecules (CAMs) in endothelial cells. The induction may play an important role in attracting circulating tumor cells (CTCs) to endothelial cells. S-nitrosocaptopril (CapNO) is known to produce vasorelaxation and interfere the hetero-adhesion of CTCs to vascular endothelium via down-regulating the expression of CAMs. To elucidate the mechanisms underlying the inhibition of CapNO on CAMs, in this study, we examined the relationship between cytokines and CAMs expression and investigated the effects of CapNO on cytokine-induced NF-кB and JAK/STAT signal pathways. The activation of CAMs by cytokines was dependent on concentrations and reaction time of cytokines, and the combination of cytokines could produce a strong synergistic effect. IL-1ß induced the expression of CAMs on endothelial cells by activating NF-кB and JAK/STAT pathways. CapNO inhibited IL-1ß-stimulated NF-кB pathway by down-regulating IKK-α and inducing IкB-α directly. CapNO also inhibited JAK/STAT pathway by inhibiting JAK2 and STAT3 expressions. These effects bring about down-regulating CAMs expression on endothelial cells. These results suggest that CapNO may interrupt adhesion of cancer cells to endothelium by suppressing CAMs via inhibiting the NF-кB and JAK/STAT pathways in endothelial cells.


Assuntos
Captopril/análogos & derivados , Moléculas de Adesão Celular/metabolismo , Endotélio Vascular/patologia , Células Endoteliais da Veia Umbilical Humana/citologia , Janus Quinases/metabolismo , NF-kappa B/metabolismo , Fatores de Transcrição STAT/metabolismo , Animais , Captopril/farmacologia , Adesão Celular/efeitos dos fármacos , Citocinas/farmacologia , Sinergismo Farmacológico , Endotélio Vascular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HT29 , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Metástase Neoplásica , Segurança , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
19.
Small ; 12(19): 2595-608, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27027489

RESUMO

The circulating tumor cells (CTCs) existing in cancer survivors are considered the root cause of cancer metastasis. To prevent the devastating metastasis cascade from initiation, we hypothesize that a biodegradable nanomaterial loaded with the abortifacient mifepristone (MIF) and conjugated with the epithelial cell adhesion molecule antibody (aEpCAM) may serve as a safe and effective cancer metastatic preventive agent by targeting CTCs and preventing their adhesion-invasion to vascular intima. It is demonstrated that MIF-loaded mesoporous silica nanoparticles (MSN) coated with aEpCAM (aE-MSN-M) can specifically target and bind colorectal cancer cells in either cell medium or blood through EpCAM recognition proven by quantitative flow cytometric detection and free aEpCAM competitive assay. The specific binding results in downregulation of the captured cells and drives them into G0/G1 phase primarily attributed to the effect of aEpCAM. The functional nanoparticles significantly inhibit the heteroadhesion between cancer cells and endothelial cells, suggesting the combined inhibition effects of aEpCAM and MIF on E-selectin and ICAM-1 expression. The functionalized nanoparticles circulate in mouse blood long enough to deliver MIF and inhibit lung metastasis. The present proof-of-concept study shows that the aE-MSN-M can prevent cancer metastasis by restraining CTC activity and their adhesion-invasion to vascular intima.


Assuntos
Anticorpos Monoclonais/imunologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/secundário , Molécula de Adesão da Célula Epitelial/imunologia , Mifepristona/administração & dosagem , Nanocápsulas/química , Dióxido de Silício/química , Abortivos Esteroides/administração & dosagem , Abortivos Esteroides/química , Absorção Fisico-Química , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/química , Apoptose/efeitos dos fármacos , Neoplasias Colorretais/imunologia , Difusão , Sistemas de Liberação de Medicamentos/métodos , Reposicionamento de Medicamentos , Células HT29 , Humanos , Camundongos , Mifepristona/química , Nanocápsulas/ultraestrutura , Nanoconjugados/administração & dosagem , Nanoconjugados/química , Nanoporos/ultraestrutura , Resultado do Tratamento
20.
Sci Rep ; 6: 22388, 2016 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-26932781

RESUMO

Metapristone is the most predominant biological active metabolite of mifepristone, and being developed as a novel cancer metastasis chemopreventive agent by us. Despite its prominent metastasis chemopreventive effect, the underlying mechanism remains elusive. Our study, for the first time, demonstrated that metapristone had the ability to prevent breast cancer cells from migration, invasion, and interfere with their adhesion to endothelial cells. To explore the underlying mechanism of metapristone, we employed the iTRAQ technique to assess the effect of metapristone on MDA-MB-231 cells. In total, 5,145 proteins were identified, of which, 311 proteins showed significant differences in metapristone-treated cells compared to the control group (P-value < 0.05). Bioinformatic analysis showed many differentially expressed proteins (DEPs) functionally associated with post-translational modification, chaperones, translation, transcription, replication, signal transduction, etc. Importantly, many of the DEPs, such as E-cadherin, vimentin, TGF-ß receptor I/II, smad2/3, ß-catenin, caveolin, and dystroglycan were associated with TGF-ß and Wnt signaling pathways, which were also linked to epithelial-to-mesenchymal transition (EMT) process. Further validation of the epithelial marker "E-caderin" and mesenchymal marker "vimetin" were carried out using immunoblot and immunofluorescence. These results have revealed a novel mechanism that metapristone-mediated metastasis chemoprevention is through intervening the EMT-related signaling pathways.


Assuntos
Caderinas/metabolismo , Quimioprevenção , Mifepristona/análogos & derivados , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/prevenção & controle , Proteômica/métodos , Vimentina/metabolismo , Antígenos CD , Western Blotting , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Ontologia Genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Marcação por Isótopo , Metaboloma/efeitos dos fármacos , Mifepristona/farmacologia , Mifepristona/uso terapêutico , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismo , Reprodutibilidade dos Testes , Regulação para Cima/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA