Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 102
Filtrar
2.
Sci Rep ; 12(1): 1391, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-35082350

RESUMO

Transcranial magnetic stimulation (TMS)-evoked potentials (TEPs), recorded using electroencephalography (EEG), reflect a combination of TMS-induced cortical activity and multi-sensory responses to TMS. The auditory evoked potential (AEP) is a high-amplitude sensory potential-evoked by the "click" sound produced by every TMS pulse-that can dominate the TEP and obscure observation of other neural components. The AEP is peripherally evoked and therefore should not be stimulation site specific. We address the problem of disentangling the peripherally evoked AEP of the TEP from components evoked by cortical stimulation and ask whether removal of AEP enables more accurate isolation of TEP. We hypothesized that isolation of the AEP using Independent Components Analysis (ICA) would reveal features that are stimulation site specific and unique individual features. In order to improve the effectiveness of ICA for removal of AEP from the TEP, and thus more clearly separate the transcranial-evoked and non-specific TMS-modulated potentials, we merged sham and active TMS datasets representing multiple stimulation conditions, removed the resulting AEP component, and evaluated performance across different sham protocols and clinical populations using reduction in Global and Local Mean Field Power (GMFP/LMFP) and cosine similarity analysis. We show that removing AEPs significantly reduced GMFP and LMFP in the post-stimulation TEP (14 to 400 ms), driven by time windows consistent with the N100 and P200 temporal characteristics of AEPs. Cosine similarity analysis supports that removing AEPs reduces TEP similarity between subjects and reduces TEP similarity between stimulation conditions. Similarity is reduced most in a mid-latency window consistent with the N100 time-course, but nevertheless remains high in this time window. Residual TEP in this window has a time-course and topography unique from AEPs, which follow-up exploratory analyses suggest could be a modulation in the alpha band that is not stimulation site specific but is unique to individual subject. We show, using two datasets and two implementations of sham, evidence in cortical topography, TEP time-course, GMFP/LMFP and cosine similarity analyses that this procedure is effective and conservative in removing the AEP from TEP, and may thus better isolate TMS-evoked activity. We show TEP remaining in early, mid and late latencies. The early response is site and subject specific. Later response may be consistent with TMS-modulated alpha activity that is not site specific but is unique to the individual. TEP remaining after removal of AEP is unique and can provide insight into TMS-evoked potentials and other modulated oscillatory dynamics.


Assuntos
Biologia Computacional/métodos , Eletroencefalografia/métodos , Potenciais Evocados Auditivos/fisiologia , Córtex Motor/fisiologia , Estimulação Magnética Transcraniana/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Potencial Evocado Motor/fisiologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
3.
J Cancer ; 12(14): 4240-4246, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093824

RESUMO

Although tumor-derived exosomes play an important role in the process of metastasis, differences in exosomes secreted by the same cells at different stages or conditions have not been noticed by most of the relevant researchers. Here we developed a lung cancer model in nude mice, and the phenotype and inclusions of exosomes secreted by early and advanced tumors were analysed. The size distribution and surface topography of these two exosomes were not significantly different, but the expression of CD63 in early tumor exosome (E-exosome) was significantly lower than that in advanced tumor exosome (A-exosome). α-SMA expression on HELF cells treated with A-exosome was significantly higher than that treated with E-exosome. The ability of A-exosome to promote the migration of A549 cells was better than E-exosome. Furthermore, small RNA sequence showed that only 3 of the 171 detected-small RNAs were expressed simultaneously in both exosomes. These findings proved that there are significant differences in inclusions and functions between the early and late exosomes of the same tumor. The study highlights the importance of exosomes in cancer metastasis, and might suggest exosomes can be used as biomarkers and therapeutic targets for cancer metastasis.

4.
J Control Release ; 331: 404-415, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33485883

RESUMO

Each type of cancer has its own specific metastatic route developed by disseminating circulating tumor cells (CTCs) and related extracellular vesicles to the target organ, i.e., metastasis organotropism. Tumor-derived small extracellular vesicles (herein exosomes, EXO) play an important role in determining cancer organotropic metastases to pre-metastasis niches. We therefore hypothesized that drug-loaded EXO may mix well with their companion small extracellular vesicles to specifically target the aimed metastatic organ via organotropism. Here, we demonstrate that the circulating breast-cancer-derived EXO loaded with doxorubicin (EXO-DOX) can mingled with their original companion EXO and inhibit breast cancer metastasis to lungs. The CD47 on the EXO-DOX prevented EXO-DOX from immune attack and prolonged their circulation in blood. The tissue distribution ratio of EXO-DOX is identical to the ratio of their companion EXO due to the specific affinity of EXO to integrins in targeted tissues. Quantitative accumulation of EXO-DOX in the mouse lungs is proportional to the organotropism of the circulating breast cancer cells that disseminate from subcutaneously-implanted human breast cancer cells in mice. EXO-DOX inhibited angiogenesis and cancer cell proliferation, resulting in prevention of breast cancer metastasis to the lungs. This study opens a novel path to use Trojan small extracellular vesicles for specifically controlled release of active components by small extracellular vesicles organotropism mechanism to the targeted organ for disease chemoprevention.


Assuntos
Exossomos , Células Neoplásicas Circulantes , Preparações Farmacêuticas , Animais , Linhagem Celular Tumoral , Proliferação de Células , Doxorrubicina , Humanos , Camundongos
5.
Environ Sci Pollut Res Int ; 27(27): 33732-33742, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32535820

RESUMO

Anaerobic digested residue (DR) is the main by-product from biogas plants, and it is predominantly used as organic fertilizer after composting. To resolve the problems of long duration and nitrogen loss in conventional composting, bulking agents are always added during the composting process. In this study, oyster shell (OS) was used as a bulking agent for DR composting. Four treatments were conducted by mixing DR and OS at different concentrations (0%, 10%, 20% and 30%, based on wet weight) and then composting the mixtures for 40 days. The results showed that the organic matter (OM) degradation efficiency was enhanced by 5.62%, 12.15% and 16.98% with increasing amounts of OS addition. The increased content of microbial biomass carbon in the compost indicated a suitable living environment for aerobic microbes with added OS, which could explain the increased OM degradation efficiency. Compared with the control, the NH3 emissions in the treatments with 10%, 20% and 30% OS were decreased by 13.81%, 33.33% and 53.76%, respectively. The increase in total nitrogen content in the compost is probably due to the absorption of NH3 by OS. Results indicated that OS is a suitable bulking agent for DR composting and that the addition of 20-30% OS can significantly enhance composting performance.


Assuntos
Compostagem , Ostreidae , Anaerobiose , Animais , Fertilizantes , Esterco , Nitrogênio/análise , Solo
6.
J Dig Dis ; 21(3): 189-194, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31953907

RESUMO

OBJECTIVE: To evaluate the efficacy of living-donor liver transplantation (LDLT) in children with tyrosinemia type I. METHODS: Altogether 10 patients diagnosed with tyrosinemia type I underwent LDLT between June 2013 and April 2019. Cirrhosis was the indication for LDLT in all 10 patients, and hepatocellular carcinoma (HCC) was suspected in nine. Patients' outcomes, including liver function, restoration of metabolism, quality of life and physical development, were analyzed after LDLT. RESULTS: All recipients were alive with a normal liver function after a median follow-up period of 49 months. Pathological examinations detected HCC in one patient, dysplasia in five and cirrhosis in all. Nine patients were found to have elevated alpha-fetoprotein level, and their median alpha-fetoprotein level dropped from 2520 ng/mL to a normal level after LDLT, with no recurrence of HCC detected during the follow-up. Tyrosine metabolism was restored to its normal level with normalized plasma tyrosine and succinylacetone concentrations. Moreover, urinary succinylacetone excretion decreased significantly during the follow up. LDLT improved patients' renal tubular function, as evidenced by the normalized plasma phosphate concentration and improved glomerular filtration rate. Severe rickets symptoms, including spontaneous fractures and bone pain, were also ameliorated. Improved motor function was reported by all patients' parents during the follow-up. Dietary restriction was no longer required, which was associated with a favorable catch-up in growth and improved quality of life. Complete resolution of hypertrophic cardiomyopathy was observed one year after LDLT in one patient. CONCLUSION: LDLT is an effective treatment for patients with end-stage liver disease resulting from tyrosinemia type I.


Assuntos
Doença Hepática Terminal/cirurgia , Transplante de Fígado/métodos , Doadores Vivos , Tirosinemias/cirurgia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/cirurgia , Criança , Pré-Escolar , Doença Hepática Terminal/genética , Feminino , Humanos , Lactente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirurgia , Masculino , Qualidade de Vida , Resultado do Tratamento , Tirosinemias/complicações
7.
Nat Commun ; 11(1): 243, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913267

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

8.
Chem Commun (Camb) ; 56(6): 916-919, 2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31850457

RESUMO

Efficient biomimetic catalases have been broadly explored for free-radical scavenging and antioxidative stress. Herein, we introduce a non-toxic Se-modified carbon nitride (CN) nanosheet for this bioapplication, and it presents efficient catalase activity, high fluorescence properties, and good biocompatibility. These properties indicate that this material has potential for use as an artificial enzyme against oxidative stress.

9.
Nat Commun ; 10(1): 5476, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792209

RESUMO

There are disease-causing biohazards in the blood that cannot be treated with modern medicines. Here we show that an intelligently designed safe biomaterial can precisely identify, tow and dump a targeted biohazard from the blood into the small intestine. Positively charged mesoporous silica nanoparticles (MSNs) functionalized with EGFR-targeting aptamers (MSN-AP) specifically recognize and bind blood-borne negatively charged oncogenic exosomes (A-Exo), and tow A-Exo across hepatobiliary layers and Oddi's sphincter into the small intestine. MSN-AP specifically distinguish and bind A-Exo from interfering exosomes in cell culture and rat and patient blood to form MSN-AP and A-Exo conjugates (MSN-Exo) that transverse hepatocytes, cholangiocytes, and endothelial monolayers via endocytosis and exocytosis mechanisms, although Kupffer cells have been shown to engulf some MSN-Exo. Blood MSN-AP significantly decreased circulating A-Exo levels, sequentially increased intestinal A-Exo and attenuated A-Exo-induced lung metastasis in mice. This study opens an innovative avenue to relocate blood-borne life-threatening biohazards to the intestine.


Assuntos
Sangue/metabolismo , Exossomos/metabolismo , Intestino Delgado/metabolismo , Nanopartículas/metabolismo , Células A549 , Animais , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/metabolismo , Análise Química do Sangue , Endocitose , Receptores ErbB/genética , Receptores ErbB/metabolismo , Exossomos/química , Hepatócitos/metabolismo , Humanos , Cinética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Ratos , Dióxido de Silício/química , Dióxido de Silício/metabolismo
10.
Onco Targets Ther ; 12: 9105-9114, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31806995

RESUMO

The success of cancer immunotherapy on recognition checkpoints for killing cancer cells has raised a great interest of scientists in understanding new and old methods of immunotherapeutic. CD47 (cluster of differentiation 47) is a cell surface glycoprotein and widely expressed on cells, which belongs to the immunoglobulin (Ig) superfamily as a cell membrane receptor which serves in immune therapy. CD47 is an inhibitory receptor expressed on tumor cell surface and interacts with signal receptor protein-alpha (SIPR-α, also named CD172a or SHPS-1) which may escape from immune cells such as macrophage and T cells. Meanwhile, tumor cells express high CD47 protein which may secrete exosomes with high CD47 expression. The high CD47 expression-exosomes could serve the tumor metastasis process and provide transfer convenience for tumors on the microenvironment. CD47 on cancer cells can also affect the migration and invasion of cells. The high CD47 expression on tumor or CTC (circulating tumor cell) surface means the stronger migration and invasion and makes them escape from immune cells for phagocytosis such as T cells, NK (natural killer) cells and macrophage, which could be used for diagnosis and prognosis on cancer patients. Meanwhile, targeting CD47 combined with other biomarkers such as EpCAM (epithelial cell adhesion molecule), CD44, etc on cancer surface could be used to isolate CTCs from patients' blood. In terms of treatment, anti-CD47 antibody combined with another antibody such as anti-PD-L1 (programmed death-ligand 1) antibody or drugs such as rituximab, DOX or oxaliplatin also has better therapeutic effects and antitumor function to tumors. Using nanomaterials as an intermediary for CD47-related immune therapy could greatly increase the therapeutic effect and overcome multiple biological barriers for anti-CD47 antibody in vivo. In this review, we discuss the important role and the function of CD47 in tumor metastasis and also provide a reference for related research.

11.
Luminescence ; 34(6): 595-601, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31074200

RESUMO

In this paper, the interactions of pepsin with fluoroquinolones, including norfloxacin (NFX) or ofloxacin (OFX), were investigated using fluorescence spectroscopy. The effects of NFX or OFX on pepsin showed that the molecular conformation of pepsin and the microenvironment of tryptophan residues were changed under mimicked physiological conditions. Static quenching was suggested as a factor. Quenching constants and binding constants were determined and thermodynamic parameters were calculated at three temperatures (25°C, 31°C and 37°C). Molecular interaction distances (binding distance r) were obtained. Binding was enthalpy driven and the process was spontaneous. Synchronous fluorescence, three-dimensional fluorescence spectroscopy and molecular simulation were used for analysis. Interactions were further tested using molecular modelling. Quenching and binding constants of NFX with pepsin were the highest when testing NFX/OFX/fleroxacin/gatifloxacin with pepsin combinations. NFX was the strongest quencher, and affinity of NFX for pepsin was higher than that of OFX/fleroxacin/gatifloxacin.


Assuntos
Antibacterianos/química , Fluoroquinolonas/química , Pepsina A/química , Fleroxacino/química , Fluorescência , Cinética , Conformação Molecular , Simulação de Acoplamento Molecular , Norfloxacino/química , Ligação Proteica , Espectrometria de Fluorescência
12.
Sci Rep ; 9(1): 4532, 2019 03 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.


Assuntos
Anticorpos/imunologia , Antígeno B7-H1/imunologia , Antígeno CD47/imunologia , Neoplasias/terapia , Células Neoplásicas Circulantes/imunologia , Animais , Antígeno B7-H1/metabolismo , Antígeno CD47/metabolismo , Linhagem Celular Tumoral , Feminino , Imunoterapia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Células Neoplásicas Circulantes/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transplante Homólogo
13.
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
14.
Mol Pharm ; 16(5): 2235-2248, 2019 05 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.


Assuntos
Núcleo Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Mitocôndrias/efeitos dos fármacos , Nanosferas/química , Nitrilas/química , Fotoquimioterapia/métodos , Células A549 , Animais , Peptídeos Catiônicos Antimicrobianos/química , Apoptose/efeitos dos fármacos , Núcleo Celular/metabolismo , Doxorrubicina/química , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Solubilidade , Distribuição Tecidual , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Acta Pharmacol Sin ; 40(2): 279-287, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29872134

RESUMO

Mucolipidosis II α/ß, mucolipidosis III α/ß, and mucolipidosis III γ are autosomal recessive disorders belonging to the family of lysosomal storage disorders caused by deficiency of the UDP-N-acetylglucosamine, a lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) localized in the Golgi apparatus, which is essential for normal processing and packaging of soluble lysosomal enzymes with initiating the first step of tagging lysosomal enzymes with mannose-6-phosphate (M6P). Mucolipidosis II and III are caused by mutations in the GNPTAB and GNPTG genes, and patients with these diseases are characterized by short stature, skeletal abnormalities, and developmental delay. In this study we report 38 patients with mucolipidosis II and III enrolled in Eastern China during the past 8 years. The diagnosis was made based on clinical characteristics and measurement of plasma lysosomal enzyme activity. Sanger sequencing of GNPTAB and/or GNPTG for all patients and real-time quantitative PCR were performed to confirm the diagnosis. In addition, 11 cases of prenatal mucolipidosis II were diagnosed based on measurement of the enzyme activity in amniotic fluid supernatant and genetic testing of cultured amniotic cells. Based on molecular genetic tests, 30 patients were diagnosed with mucolipidosis II α/ß, 6 were diagnosed with III α/ß and 2 were diagnosed with III γ. Thirty-seven different GNPTAB gene mutations were identified in 29 patients with mucolipidosis II α/ß and six patients with III α/ß. These mutations included 22 new mutations (p.W44X, p.E279X, p.W416X, p.W463X, p.Q802X, p.Q882X, p.A34P, p.R334P, p.D408N, p.D534N, p.Y997C, p.D1018V, p.L1025S, p.L1033P, c.88_89delAC, c.890_891insT, c.1150_1151insTTA, c.1523delG, c.2473_2474insA, c.2980_2983delGCCT, c.3094delA, and deletion of exon 9). Four new GNPTG gene mutations were identified (c.13delC, p.Y81X, p.G126R and c.609+1delG) in two mucolipidosis III γ patients. Among the 11 cases of prenatal diagnosis, four were mucolipidosis II fetuses, three were heterozygous, and the remaining four were normal fetuses. This study expands the mutation spectrum of the GNPTAB and GNPTG genes and contributes to specific knowledge of mucolipidosis II/III in a population from Eastern China.


Assuntos
Mucolipidoses/diagnóstico , Mucolipidoses/genética , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Adolescente , Criança , Pré-Escolar , China , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mucolipidoses/classificação , Mutação de Sentido Incorreto , Gravidez , Diagnóstico Pré-Natal
16.
Pharmacol Res ; 139: 535-549, 2019 01.
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.


Assuntos
Antineoplásicos/uso terapêutico , Captopril/análogos & derivados , Neoplasias/tratamento farmacológico , Células Neoplásicas Circulantes/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Captopril/farmacologia , Captopril/uso terapêutico , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/metabolismo , Neoplasias/patologia , Selectina-P/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo
17.
World J Pediatr ; 15(1): 66-71, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30443829

RESUMO

BACKGROUND: This study aimed to explore the value of applying a new pterin marker (isoxanthopterin) to the traditional urine pterin analysis to reduce the rate of mis-diagnosis of 6-pyruvoyltetrahydropterin synthase deficiency (PTPSD) and improve the accuracy of diagnosis. METHODS: We compared the urine neopterin (N), biopterin (B), isoxanthopterin (Iso), B% and Iso% levels between patients with phenylalanine hydroxylase deficiency and those with PTPSD, and found the most specific pterin biomarkers by ROC analysis. A positive cut-off value of urine pterins was determined. The effect of combined Iso% + B + B% in reducing PTPSD mis-diagnosis was evaluated, and the different urine pterin levels in PTPSD and false PTPSD (FPTPSD) were compared. The concordance of PTPSD diagnosis by the new pterin scheme and gene mutation analysis was determined. RESULTS: (1) Urinary B, B%, Iso and Iso% were significantly lower in PTPSD than those in phenylalanine hydroxylase-deficiency group (P < 0.01); (2) Iso%, B%, and B were the most specific markers; (3) The positive cut-off values of B, B%, Iso% for PTPSD were < 0.17 mmoL/moLCr, < 5.0%, and < 9.5%, respectively; (4) urinary B + B% + Iso% scheme significantly reduced the false-positive rate of PTPSD compared to traditional ones. The Iso% levels in FPTPSD group were higher than the ones in PTPSD group; (5) an accuracy of diagnosis for PTPSD was increased by 9-19% when Iso% was introduced to urinary pterin scheme. CONCLUSIONS: Iso% is helpful to reduce the rate of misdiagnosis of PTPSD in the diagnosis by urinary pterin analysis for hyperphenylalaninemias and improve the accuracy of diagnosis. This approach is worthy of further development and increased utilization.


Assuntos
Fenilcetonúrias/diagnóstico , Fósforo-Oxigênio Liases/deficiência , Xantopterina/urina , Biomarcadores/urina , Biopterina/urina , Cromatografia Líquida , Diagnóstico Diferencial , Erros de Diagnóstico/prevenção & controle , Humanos , Lactente , Neopterina/urina , Curva ROC
18.
Exp Cell Res ; 375(1): 62-72, 2019 02 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.


Assuntos
Carcinoma Pulmonar de Lewis/genética , Melanoma Experimental/genética , Metástase Neoplásica/genética , Células Neoplásicas Circulantes , Animais , Carcinoma Pulmonar de Lewis/patologia , Adesão Celular/genética , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Humanos , Melanoma Experimental/patologia , Camundongos , Metástase Neoplásica/patologia , Especificidade de Órgãos/genética , Microambiente Tumoral/genética
19.
Int J Nanomedicine ; 13: 7457-7472, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30532533

RESUMO

Background: Gefitinib (Gef), an important epidermal growth factor receptor (EGFR), is used to treat lung cancer, but low water solubility and poor bioavailability severely limit its application in cancer therapy. Methods: In this study, nanographene oxide (NGO) was decorated with hyaluronic acid (HA) by a linker cystamine dihydrochloride containing disulfide bonds (-SS-), followed by the incorporation of gefitinib, thus, constructing a HA-functionalized GO-based gefitinib delivery system (NGO-SS-HA-Gef). Subsequently, studies of biological experiments in vitro and in vivo were performed to investigate the therapeutic effect of the system in lung cancer. Results: The HA-grafted GO nanosheets possessed enhanced physiological stability, admirable biocompatibility, and no obvious side effects in mice and could act as a nanocarrier for the delivery of gefitinib to tumor. Cellular uptake and intracellular cargo release assays showed that the uptake of NGO-SS-HA by A549 cells was facilitated via CD44 receptor-mediated endocytosis, and that more drug was released from NGO-SS-HA in the presence of GSH than in the absence of GSH. The target-specific binding of NGO-SS-HA to cancer cells with redox-responsive cargo release significantly enhanced the abilities of gefitinib-loaded GO nanosheets to induce cell apoptosis, suppress cell proliferation, and inhibit tumor growth in lung cancer cell-bearing mice. Conclusion: The results demonstrated the potential utility of NGO-SS-HA-Gef for therapeutic applications in the treatment of lung cancer.


Assuntos
Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Grafite/química , Ácido Hialurônico/química , Nanopartículas/química , Água/química , Células A549 , Animais , Apoptose/efeitos dos fármacos , Materiais Biocompatíveis/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dissulfetos/química , Liberação Controlada de Fármacos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oxirredução , Solubilidade , Distribuição Tecidual
20.
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.


Assuntos
Trifosfato de Adenosina/metabolismo , Neoplasias do Colo/patologia , Glicólise , Células-Tronco Neoplásicas/metabolismo , Animais , Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Metabolismo Energético , Regulação Neoplásica da Expressão Gênica , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Hexoquinase/genética , Hexoquinase/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Potencial da Membrana Mitocondrial , Camundongos , Metástase Neoplásica , Transplante de Neoplasias
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...