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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(4): 1348-1352, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31418406

RESUMO

Abstract  Tumor xenograft model (PDTX) derived from leukemia patients is an animal model in which the leukemia cells or primary cell lines of patients are transplanted directly into immunodeficient mice.The emergence of nude mice and SCID mice opened early xenotransplantation, then the NSG, NOG mice and the improved model and humanized mice based on there mice significantly improves the success rate of transplantation. The late presented transplantation of leukemia LSC and transplantation of patient-derived and induced pluripotent stem cells obtained based on iPSC technology provide new insight for the anderstanding leukemia genesis and development, and the new type humanized mouse model with normal lymphatic hematopoietic reconstruction provides a new platform of leukemia cell therapy and immunotherapy for leukemia therapy. PDTX is an important platform for the study of the pathogenesis and drug resistance mechanism of leukemia, as well as the development of new drugs and individualized treatment. In this paper, the recent progress in the construction and application of models of immunodeficient mice and their models is reviewed.


Assuntos
Leucemia , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Transplante Heterólogo
2.
Chem Biol Interact ; 312: 108799, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31433961

RESUMO

Black seed (Nigella sativa) oil has been used in various dermatological applications, and its major constituent, thymoquinone (TQ) has been shown to exhibit antiproliferative activity against various cancer cells. In this study, we tried to provide a mechanistic basis of apoptosis induced by TQ. Skin squamous carcinoma A431 cells were treated with TQ to monitor the apoptosis induced by TQ. Western blot analysis was performed to detect expression of apoptotic or anti-apoptotic proteins. Cell viability and apoptosis were measured by using the MTT test and FACS analysis, respectively. The induction of intracellular reactive oxygen species (ROS) by TQ was evaluated by 2',7'-dichlorofluorescein diacetate staining. In vivo xenograft study was followed to confirm the antiproliferative effect of TQ. Treatment of A431 cells with TQ-induced apoptosis, which was associated with the induction of p53 and Bax, inhibition of Mdm2, Bcl-2, and Bcl-xl expression, and activation of caspase-9, -7, and -3. TQ inhibited the constitutive phosphorylation and DNA binding activity of signal transducer and activator of transcription-3 (STAT3) in A431 cells by blocking the phosphorylation of the upstream kinase, Src. Moreover, the expression of STAT3 target gene products, cyclin D1 and survivin, was attenuated by TQ treatment. The generation of ROS was increased during TQ-induced apoptosis, and the pretreatment of N-acetyl cysteine, a ROS scavenger, reversed the apoptotic effect of TQ. In vivo study with NOD scid gamma (NSG) mice confirmed the inhibitory effect of TQ on the growth of A431 cells. Our results provide the first demonstration that TQ induces the apoptosis of A431 cells through generation of ROS and inhibition of STAT3 signaling.


Assuntos
Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Regulação para Baixo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Antineoplásicos/uso terapêutico , Benzoquinonas/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos NOD , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transplante Heterólogo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
4.
Chem Commun (Camb) ; 55(63): 9363-9366, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31317136

RESUMO

We developed a biodegradable, oncosensitive, megamer-based delivery system for miRNA therapy. The miRNA nanotherapeutics, activatable by stepwise stimulation of acidity and reduction mimicking tumor microenvironment, efficiently improve liver-specific miR-122 expression, increasing the possibility of translational application of miR-122 therapy against liver cancer.


Assuntos
Portadores de Fármacos/química , MicroRNAs/química , Nanopartículas/química , Polietilenoglicóis/química , Animais , Linhagem Celular Tumoral , Dendrímeros/química , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , MicroRNAs/uso terapêutico , Transplante Heterólogo
5.
Cell Physiol Biochem ; 53(1): 141-156, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31237760

RESUMO

BACKGROUND/AIMS: Previous research has indicated that the currently available histone deacetylase inhibitors (HDACis) are not effective as monotherapies against oral squamous cell carcinoma (OSCC). However, HDACis act synergistically with other therapeutic agents to exert significant antitumor activities. Thus, a strategy to develop chemotherapeutic agents by combining several active groups based on histone deacetylase (HDAC) into a single molecule as a conjugate that modulates multiple cellular pathways may be useful for the treatment of OSCC. METHODS: The novel inhibitor Roxyl-ZR was prepared by organic synthesis and its anticancer effects on OSCC were investigated by cell metabolism (n=5), colony formation (n=3), cell cycle (n=3), cell apoptosis (n=3), wound healing (n=3), transwell migration (n=3), and 5-bromo-2'-deoxyuridine staining (n=3) assays in vitro and in in vivo xenograft mice models (4 mice/group for subcutaneous xenograft and 3 mice/group for orthotopic xenograft ). The abundance of Ki67, Bcl-2, and p-STAT3 was detected by immunohistochemistry staining (n=4). Apoptotic cells in the tumor tissues of mice were detected by terminal deoxynucleotidyl transferase dUTP nickend labeling assay (n=3). The abundance of related proteins levels were evaluated by western blot (n=3). E-cadherin expression was detected by an immunofluorescence assay (n=3). RESULTS: Compared with the approved HDACi, conjugated Roxyl-ZR exhibited significantly higher antitumor effects in OSCC cells. Roxyl-ZR suppressed OSCC cell proliferation by inducing the reduction of S phase and inducing caspase-dependent apoptosis by down-regulating Bcl-2 expression. Moreover, Roxyl-ZR attenuated the epithelial-mesenchymal transition, which is closely associated with migration and invasion. In addition, Roxyl-ZR inhibited OSCC xenograft mice models and showed low toxicity. The mechanism underlying the Roxyl-ZR-enhanced sensitivity to HDACi may be attributed to the inhibition of key regulators of JAK1-STAT3 signaling pathway. CONCLUSION: HDAC-cyclin-dependent kinase conjugates represent a novel approach to the development of OSCC treatment. Our findings may open a new avenue for the development of novel inhibitors for the treatment of OSCC.


Assuntos
Apoptose/efeitos dos fármacos , Benzimidazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Benzimidazóis/síntese química , Benzimidazóis/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Janus Quinase 1/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transplante Heterólogo
6.
Cell Physiol Biochem ; 53(1): 157-171, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31251006

RESUMO

BACKGROUND/AIMS: Dysregulation of deubiquitinating enzymes (DUBs), which regulate the stability of key proteins, has been implicated in many human diseases, including cancers. Thus, DUBs can be considered as potential therapeutic targets for many diseases. Among them, USP4 has been proposed as a promising target for colon cancer drugs since USP4 controls the stability of ß-catenin, a key factor in the Wnt signaling involved in the tumorigenesis of colorectal cancer. However, developing potential DUB inhibitors has been hindered because many DUBs harbor similar active site structures and show broad substrate specificities. METHODS: By performing in vitro deubiquitinating activity assays using a chemical library, we identified several potential DUB inhibitors. Among them, only neutral red (NR) showed selective inhibitory activity on USP4 in a cell-based assay system. In colon cancer cells, NR affected the protein stability of ß-catenin, as shown by immunoblotting, and it affected the target gene expression of ß-catenin, as shown by quantitative real-time PCR. NR's potential as an anticancer drug was further estimated by colony formation and cell migration assays and by using a mouse xenograft model. RESULTS: We identified NR as an uncompetitive inhibitor of USP4 and validated its effects in colorectal cancer. NR-treated cells showed decreased ß-catenin stability and reduced expression of ß-catenin target genes. Additionally, treating colon cancer cells with NR significantly reduced colony formation and cell migration, and injecting NR into a mouse xenograft model reduced the tumor volume. CONCLUSION: The current results suggest that NR could be developed as an anticancer drug targeting USP4, and they support the possibility of developing specific DUB inhibitors as therapeutic agents.


Assuntos
Vermelho Neutro/farmacologia , Proteases Específicas de Ubiquitina/antagonistas & inibidores , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Ciclina D1/genética , Ciclina D1/metabolismo , Progressão da Doença , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Vermelho Neutro/química , Vermelho Neutro/uso terapêutico , Transplante Heterólogo , Proteases Específicas de Ubiquitina/metabolismo
7.
Zhonghua Zhong Liu Za Zhi ; 41(5): 338-345, 2019 May 23.
Artigo em Chinês | MEDLINE | ID: mdl-31137166

RESUMO

Objective: To detect the effect and regulatory mechanism of human ether à go-go related gene 1 (Herg 1) knockdown on the proliferation and invasion of osteosarcoma (OS). Methods: We constructed a recombinant adenovirus vector (Ad5-Herg1-shRNA) expressing short hair RNA (shRNA) against Herg1 and tested the knockdown efficiency. Then, the effects of Herg 1 knockdown on the proliferation, growth and invasion of osteosarcoma were measured by using cell counting kit-8 (CCK-8), wound healing assay, Transwell assay and xenograft model of nude mice, respectively. Tandem affinity purification, mass spectrometry and dual luciferase reporter assay were used to find out the molecules interacted with Herg1. Western blot was used to detect the expressions of large tumor suppressor gene (LATS1), p-LATS1, Yes-associated protein (YAP) and p-YAP in cells after infection of Ad5-Herg1-shRNA. Results: Compared to Ad5-control-shRNA, Ad5-Herg1-shRNA dramatically inhibited the expression of Herg1 in OS cells. The result of CCK8 array demonstrated that 143B cell vitalities of Ad5-Herg1-shRNA1 and Ad5-Herg1-shRNA2 group were (65.47±3.90)% and (79.90±1.52)%, significantly lower than (100.00±6.14)% of Ad5-control-shRNA group. Meanwhile, U2OS cell vitality of Ad5-Herg1-shRNA1 and Ad5-Herg1-shRNA2 group were (69.69±1.36)% and (76.72±2.75)%, significantly lower than (100.00±3.01)% of Ad5-control-shRNA group (all P<0.001). The results of wound healing array showed that 143B cell migration rates of Ad5-Herg1-shRNA1 and Ad5-Herg1-shRNA2 group were (33.03±2.88)% and (36.47±4.16)%, significantly lower than (97.78±2.28)% of Ad5-control-shRNA group. Meanwhile, U2OS cell migration rates of Ad5-Herg1-shRNA1 and Ad5-Herg1-shRNA2 group were (68.07±0.90)% and (73.97±1.25)%, significantly lower than (96.50±1.12)% of Ad5-control-shRNA group (all P<0.001). The results of Transwell showed that 143B cell invasion numbers of Ad5-Herg1-shRNA1 and Ad5-Herg1-shRNA2 group were 36.50±12.15 and 44.83±7.62, significantly lower than 195.33±19.68 of Ad5-control-shRNA group. Meanwhile, U2OS cell migration rates of Ad5-Herg1-shRNA1 and Ad5-Herg1-shRNA2 group were 21.83±7.99 and 22.85±7.08, significantly lower than 83.33±12.36 of Ad5-control-shRNA group (all P<0.001). The results of xenograft model of OS showed that the tumor volume and weight of Ad5-Herg1-shRNA group were significantly smaller than of Ad5-control-shRNA group after 14 days and 5 weeks of inoculation, respectively (P<0.001). Moreover, knockdown of Herg1 inhibited the metastasis of OS cells. In mechanism, Herg1 protein interacted with NF2 protein. Knockdown of Herg1 significantly suppressed the expression levels of LATS1 and YAP protein, and promoted the phosphorylation of LATS1 and YAP in OS cells (all P<0.001). Conclusion: Our findings suggest that Herg1 participates in the proliferation and motility of OS cells and may serve as a potential therapeutic target for osteosarcoma patients.


Assuntos
Neoplasias Ósseas/genética , Canal de Potássio ERG1/genética , Osteossarcoma/genética , Proteínas Serina-Treonina Quinases/metabolismo , Adenoviridae , Animais , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Modelos Animais de Doenças , Regulação para Baixo , Vetores Genéticos , Humanos , Camundongos , Camundongos Nus , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Osteossarcoma/patologia , Transdução de Sinais , Transplante Heterólogo
8.
BMC Cancer ; 19(1): 400, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035951

RESUMO

BACKGROUND: Oral squamous cell carcinoma (OSCC) is an oral and maxillofacial malignancy with a high incidence worldwide. Accumulating evidence indicates that circular RNAs (circRNAs) play a vital role in modulating tumor development. However, the mechanism of circRNA action in human OSCC remains largely unknown. METHODS: By using high-throughput transcriptome sequencing technology, we conducted a comprehensive study of circRNAs in human OSCC. The effect of circRNA hsa_circ_0005379 on OSCC tissues and cell lines was monitored by qRT-PCR, Transwell assay, flow cytometry, and western blot analysis. Xenograft mouse models were used to assess tumor growth and animal survival. RESULTS: We found that circRNA hsa_circ_0005379 expression is significantly lower in OSCC tissue compared to paired non-cancerous matched tissue and is associated with tumor size and differentiation. Overexpression of hsa_circ_0005379 effectively inhibits migration, invasion, and proliferation of OSCC cells in vitro and suppresses OSCC growth in nude mice in vivo. Mechanistic studies revealed that hsa_circ_0005379 may be involved in the regulation of the epidermal growth factor receptor (EGFR) pathway. Furthermore, we found that high expression of hsa_circ_0005379 could significantly enhance the sensitivity of OSCC to the cetuximab drug. CONCLUSIONS: Our findings provide evidence that hsa_circ_0005379 regulates OSCC malignancy and may be a new therapeutic target for OSCC treatment.


Assuntos
Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Bucais/genética , RNA/genética , Animais , Antineoplásicos Imunológicos/farmacologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Cetuximab/farmacologia , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Transdução de Sinais/genética , Transplante Heterólogo , Carga Tumoral/genética
9.
Fish Shellfish Immunol ; 90: 109-117, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31051240

RESUMO

The immune response after allograft or xenograft transplantation in the pearl oyster is a major factor that cause its nucleus rejection and death. To determine the mechanism underlying the immune response after allograft and xenograft transplantations in the pearl oyster Pinctada fucata martensii, we constructed two sets of transcriptomes of hemocytes at different times (6 and 12 h; 1, 3, 6, 12, and 30 d) after allograft and xenograft transplantations, in which the xenografted mantle tissue was from Pinctada maxima. The transcriptomic analysis reveals many genes are involved in the immune response to transplantation, such as transient receptor potential cation channel (TRP), calmodulin (CaM), DNA replication-related genes, and sugar and lipid metabolism-related genes. The expression of these identified genes was higher in the host pearl oyster transplanted with xenograft than that by allograft. The histological analysis of the pearl sac also confirmed that many hemocytes were still gathered around the transplanted nucleus, and no pearl sac was formed in the host pearl oysters at 30 d after xenograft transplantation. The genomic analysis indicated that pearl oysters evolved many copies of genes, such as TRP, CaM, and GST, to sense and cope with the immune response after transplantation. "Ribosome" and "Cytosolic DNA-sensing pathway" were specifically induced in the xenograft group, whereas "Notch signaling pathway" specifically responded to the allograft transplantation. These results can improve our understanding of the mechanism underlying the immune response of pearl oysters after allograft and xenograft transplantations.


Assuntos
Genoma/imunologia , Imunidade Inata/genética , Pinctada/genética , Pinctada/imunologia , Transcriptoma/imunologia , Aloenxertos/imunologia , Animais , Perfilação da Expressão Gênica , Hemócitos/imunologia , Xenoenxertos/imunologia , Transplante Heterólogo/veterinária , Transplante Homólogo/veterinária
10.
Nat Commun ; 10(1): 1634, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30967552

RESUMO

Gene correction in human long-term hematopoietic stem cells (LT-HSCs) could be an effective therapy for monogenic diseases of the blood and immune system. Here we describe an approach for X-linked sSevere cCombined iImmunodeficiency (SCID-X1) using targeted integration of a cDNA into the endogenous start codon to functionally correct disease-causing mutations throughout the gene. Using a CRISPR-Cas9/AAV6 based strategy, we achieve up to 20% targeted integration frequencies in LT-HSCs. As measures of the lack of toxicity we observe no evidence of abnormal hematopoiesis following transplantation and no evidence of off-target mutations using a high-fidelity Cas9 as a ribonucleoprotein complex. We achieve high levels of targeting frequencies (median 45%) in CD34+ HSPCs from six SCID-X1 patients and demonstrate rescue of lymphopoietic defect in a patient derived HSPC population in vitro and in vivo. In sum, our study provides specificity, toxicity and efficacy data supportive of clinical development of genome editing to treat SCID-Xl.


Assuntos
DNA Complementar/genética , Edição de Genes/métodos , Transplante de Células-Tronco Hematopoéticas , Subunidade gama Comum de Receptores de Interleucina/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia , Animais , Antígenos CD34/metabolismo , Sistemas CRISPR-Cas/genética , Linhagem Celular , Códon de Iniciação/genética , Éxons/genética , Sangue Fetal/citologia , Vetores Genéticos/genética , Voluntários Saudáveis , Células-Tronco Hematopoéticas/metabolismo , Humanos , Masculino , Camundongos , Mutação , Parvovirinae/genética , Cultura Primária de Células , Fatores de Tempo , Transdução Genética/métodos , Quimeras de Transplante/genética , Transplante Heterólogo/métodos , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética
11.
Transplant Proc ; 51(3): 987-992, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30979492

RESUMO

BACKGROUND: To explore the adsorption of heterologous antibodies in 6 xenotransplants of Landrace piglet kidneys into rhesus monkeys. METHODS: The Landrace piglets and rhesus monkeys were used as donors and recipients, respectively. The donor kidney was the left kidney excised from each Landrace piglet and lavaged with University of Wisconsin solution through the renal artery and vein ex vivo. The renal arteriovenous end of the recipient was preserved. After anastomosis of the renal artery and vein with the arteriovenous end of the recipient for reperfusion, a cross-lymphocyte cytotoxicity test of the heterogeneous kidney was performed. RESULTS: All 6 Landrace piglet kidneys absorbed heterologous antibodies that were pre-existing in the rhesus macaques' kidneys. The cross-lymphocyte toxicity test was performed after the kidney were completely blackened. The cross-lymphocyte toxicity in all each heterogeneous kidney changed from strong positive to weak positive. CONCLUSIONS: Heterologous antibodies were adsorbed in xenotransplants of Landrace piglet kidneys into rhesus monkeys. Xenotransplanted kidney can adsorb heterologous antibodies and consume relevant complements, which is a good model for research of hyperacute rejection in xenotransplantation.


Assuntos
Anticorpos Heterófilos/imunologia , Rejeição de Enxerto/imunologia , Transplante de Rim , Rim/imunologia , Adenosina , Adsorção , Alopurinol , Animais , Anticorpos Heterófilos/metabolismo , Modelos Animais de Doenças , Feminino , Glutationa , Insulina , Macaca mulatta , Soluções para Preservação de Órgãos , Rafinose , Suínos , Doadores de Tecidos , Transplante Heterólogo
12.
Neurochem Res ; 44(6): 1475-1493, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30989481

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disorder. We have previously developed a disease-in-a-dish model for familial PD using induced pluripotent stem cells (iPSCs) from two patients carrying the p.A53T α-synuclein (αSyn) mutation. By directed differentiation, we generated a model that displays disease-relevant phenotypes, including protein aggregation, compromised neurite outgrowth, axonal neuropathology and synaptic defects. Here we investigated the in vivo phenotypes of iPSCs, derived from one patient, after transplantation in a lesion mouse model established by unilateral intrastriatal 6-hydroxydopamine injection in the immunosuppressed NOD/SCID strain. Immunohistochemistry revealed that despite the disease-related characteristics that mutant cells displayed when maintained up to 70 days in vitro, they could survive and differentiate in vivo over a 12-week period. However, some differences were noted between patient-derived and control grafts, including a significant rise in αSyn immunoreactivity that might signal a first step towards pathology. Moreover, control-derived grafts appeared to integrate better than PD grafts within the host tissue extending projections that formed more contacts with host striatal neurons. Our data suggest that the distinct disease-related characteristics which p.A53T cells develop in vitro, may be attenuated or take longer to emerge in vivo after transplantation within the mouse brain. Further analysis of the phenotypes that patient cells acquire over longer periods of time as well as the use of multiple iPSC clones from different patients should extend our current proof-of-concept study and provide additional evidence for in vivo disease modeling.


Assuntos
Células-Tronco Pluripotentes Induzidas/transplante , Doença de Parkinson , Fenótipo , Animais , Encéfalo/citologia , Encéfalo/cirurgia , Neurônios Dopaminérgicos/citologia , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Estudo de Prova de Conceito , Transplante Heterólogo , alfa-Sinucleína/genética
13.
Nanoscale ; 11(18): 9008-9014, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31020984

RESUMO

An abnormal pH microenvironment results from the development of tumors, and also affects the therapeutic efficiency of anti-tumor drugs. In this work, a Förster resonance energy transfer (FRET)-based theranostic fluorescent nanoprobe was constructed for simultaneous ratiometric pH sensing and tumor-targeted photodynamic therapy. Based on the FRET process between rhodamine B and protoporphyrin IX (PpIX), the fabricated nanoprobe exhibited excellent pH responsiveness in both solutions and live cells with the ratiometric fluorescence changes. Moreover, this ratiometric pH fluorescent nanoprobe also possessed the capability for pH-responsive singlet oxygen (1O2) generation under light irradiation, guiding robust photodynamic therapy in a pH-dependent manner. Benefiting from the enhanced permeability and retention (EPR) effect, the nanoprobe could significantly inhibit tumor growth and metastasis via targeted photodynamic therapy in vivo. This work presents a novel paradigm for precise tumor theranostics by ratiometric pH fluorescence imaging-guided photodynamic therapy.


Assuntos
Nanoestruturas/química , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Nanomedicina Teranóstica/métodos , Animais , Linhagem Celular Tumoral , Transferência Ressonante de Energia de Fluorescência , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Microscopia Confocal , Neoplasias/diagnóstico por imagem , Imagem Óptica , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Protoporfirinas/química , Rodaminas/química , Oxigênio Singlete/metabolismo , Transplante Heterólogo
15.
Nanoscale ; 11(16): 7600-7608, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30968107

RESUMO

The treatment of malignant glioblastoma is a huge challenge due to the existence of the blood-brain barrier. Herein, we report the treatment of orthotopic malignant glioblastoma with imaging guided second near-infrared (NIR-II) photodynamic therapy and chemotherapy by using drug-loaded ultra-small Cu2-xSe theranostic nanoparticles (NPs). Ultra-small Cu2-xSe NPs possess a strong absorbance in the NIR-II window, and their absorption at 1064 nm is around 2 times that at 808 nm. Their strong NIR-II absorbance and the deeper-tissue penetration of NIR-II light ensure excellent photodynamic therapy performance under irradiation with a 1064 nm laser. We also demonstrate that ultra-small Cu2-xSe NPs can produce vast amounts of reactive oxygen species via electron transfer (for ˙OH generation) and energy transfer (for 1O2 generation) mechanisms under irradiation. In addition, these NPs can be effectively and locally transported into orthotopic malignant glioblastoma with the assistance of focused ultrasound. The deposited Cu2-xSe NPs can be used for photoacoustic imaging to guide the combined NIR-II photodynamic therapy and chemotherapy. The results show that the tumor growth can be significantly suppressed. This work demonstrates the great potential of drug-loaded ultra-small Cu2-xSe NPs as a promising therapeutic agent for the treatment of orthotopic malignant glioblastoma.


Assuntos
Cobre/química , Raios Infravermelhos , Nanopartículas/química , Selênio/química , Animais , Encéfalo/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Nus , Nanopartículas/uso terapêutico , Nanopartículas/toxicidade , Fotoquimioterapia , Oxigênio Singlete/química , Oxigênio Singlete/metabolismo , Taxa de Sobrevida , Transplante Heterólogo
16.
Nanoscale ; 11(16): 7996-8011, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30969294

RESUMO

Despite the functions of anti-PD-1 antibodies as immune checkpoint regulators, less than 30% of patients exhibit durable therapeutic responses to anti-PD-1 antibodies. Studies have shown that insufficient infiltration of immune cells might limit the outcome of anti-PD-1 therapy. Therefore, we synthesized an immune cell-recruiting liposomal system (FN-nps) to improve this therapeutic strategy. The FN-nps could generate cell debris and expose heat shock protein 70, which could recruit immune cells to tumor sites to assist in anti-PD-1 treatment. In vivo experiments revealed that the FN-nps could assist in anti-PD-1 therapy by increasing the number of lymphocytes in the peripheral blood and tumor site by generating tumor antigens, and this effect was accompanied by an increase in cytokine expression. The number of CTLs increased and mRNA expression levels of cytokines were regulated when the FN-nps were combined with anti-PD-1 therapy. The revealed properties of the liposomal system make it highly promising for assisting in anti-PD-1 antibody immunotherapy in different cancers.


Assuntos
Anticorpos Monoclonais/metabolismo , Lipossomos/química , Receptor de Morte Celular Programada 1/imunologia , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocinas/sangue , Feminino , Proteínas de Choque Térmico HSP72/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Microscopia de Fluorescência , Nanopartículas/química , Nanopartículas/metabolismo , Nanopartículas/toxicidade , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Taxa de Sobrevida , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Distribuição Tecidual , Transplante Heterólogo , Ultrassonografia
17.
Nanoscale ; 11(17): 8102-8109, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-30982841

RESUMO

The proof-of-concept strategy in this study based on biodegradable and biocompatible self-assembling fluorescent virus-like particle/RNAi nanocomplexes (VLP/RNAi) produced in Escherichia coli (E. coli) followed by surface modification with a cell-penetrating peptide (CPP) and an apolipoprotein E peptide (ApoEP) (dP@VLP/RNAi), which can cross the blood-brain barrier (BBB) to inhibit the DNA repair mechanism and act synergistically with temozolomide (TMZ) for promoting clinical chemotherapy has achieved good therapeutic effects towards malignant brain tumors. The synergistic value of this study's design was verified in intracranial mouse models of glioblastomas (GBMs). Intravenous administration of this formulation enhanced the curative efficacy of TMZ by downregulating the hepatocyte growth factor receptor (c-MET) gene in GBM U87 cells. Furthermore, upon gene-chemotherapy, the methylated DNA in GBM U87 cells was significantly enhanced by inhibiting the DNA repair mechanism, leading to significant brain tumor suppression. The results of this study could be critical for the design of RNAi-based genetic therapeutics for promoting chemotherapy against brain tumors.


Assuntos
Portadores de Fármacos/química , Nanoestruturas/química , RNA Interferente Pequeno/química , Animais , Apolipoproteínas E/química , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/química , Reparo do DNA , Sinergismo Farmacológico , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Estimativa de Kaplan-Meier , Camundongos , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , RNA Interferente Pequeno/uso terapêutico , Temozolomida/química , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Transplante Heterólogo
18.
Cancer Sci ; 110(6): 2063-2074, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30972853

RESUMO

Although transforming growth factor beta (TGF-ß) is known to be involved in the pathogenesis and progression of many cancers, its role in renal cancer has not been fully investigated. In the present study, we examined the role of TGF-ß in clear cell renal carcinoma (ccRCC) progression in vitro and in vivo. First, expression levels of TGF-ß signaling pathway components were examined. Microarray and immunohistochemical analyses showed that the expression of c-Ski, a transcriptional corepressor of Smad-dependent TGF-ß and bone morphogenetic protein (BMP) signaling, was higher in ccRCC tissues than in normal renal tissues. Next, a functional analysis of c-Ski effects was carried out. Bioluminescence imaging of renal orthotopic tumor models demonstrated that overexpression of c-Ski in human ccRCC cells promoted in vivo tumor formation. Enhancement of tumor formation was also reproduced by the introduction of a dominant-negative mutant TGF-ß type II receptor into ccRCC cells. In contrast, introduction of the BMP signaling inhibitor Noggin failed to accelerate tumor formation, suggesting that the tumor-promoting effect of c-Ski depends on the inhibition of TGF-ß signaling rather than of BMP signaling. Finally, the molecular mechanism of the tumor-suppressive role of TGF-ß was assessed. Although TGF-ß signaling did not affect tumor angiogenesis, apoptosis of ccRCC cells was induced by TGF-ß. Taken together, these findings suggest that c-Ski suppresses TGF-ß signaling in ccRCC cells, which, in turn, attenuates the tumor-suppressive effect of TGF-ß.


Assuntos
Carcinoma de Células Renais/genética , Proteínas de Ligação a DNA/genética , Neoplasias Renais/genética , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais/genética , Fator de Crescimento Transformador beta/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Transplante Heterólogo
19.
Microbiol Spectr ; 7(2)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30953434

RESUMO

Human immune system (HIS) mice are created by transplanting human immune cells or their progenitor cells into highly immunodeficient recipient mouse hosts, thereby "humanizing" their immune systems. Over past decades, the field of HIS mice has evolved rapidly, as modifications of existing immunodeficient mouse strains have been developed, resulting in increasing levels of human tissue engraftment as humanization is optimized. Current HIS mouse models not only permit elevated levels of human cell engraftment but also demonstrate graft stability. As such, HIS mice are being extensively used to study the human innate and adaptive immune response against microbial infections in vivo. Compared to nonhumanized animal models, which are frequently infected with surrogate or adapted microbes, the HIS mouse models allow the analysis of interactions between human immune cells and bona fide pathogenic microbes, making them a more clinically relevant model. This article reviews the development of HIS mice and covers the different strategies used to humanize mice, as well as discussing the use of HIS mice for studying bacterial infections that cause human disease.


Assuntos
Doenças Transmissíveis/imunologia , Sistema Imunitário/imunologia , Imunidade Adaptativa , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos SCID , Transplante Heterólogo
20.
ACS Appl Mater Interfaces ; 11(17): 15426-15435, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30945838

RESUMO

High specificity detection and site-specific therapy are still the main challenges for theranostic anticancer prodrugs. In this work, we reported two smart activatable theranostic molecules based on a thermally activated delayed fluorescence fluorescein derivative. Nitroreductase induced by a mild hypoxia microenvironment of a solid tumor was used to activate the fluorescence and photodynamic therapy (PDT) efficiency by employing the intramolecular photoinduced electron transfer mechanism. A high PDT efficiency under 10% oxygen concentration was achieved, which is better than that of porphyrin (PpIX), a traditional photosensitizer. Such an excellent PDT efficiency can be attributed to lysosome disruption because the theranostic molecule can specifically enter the lysosomes of cells. Importantly, the strategy of targeting the mild hypoxic cells in the edge of tumor tissue could heal the "Achilles' heel" of traditional PDT. We believe that this theranostic molecule has a high potential to be applied in clinical investigation as a theranostic anticancer prodrug.


Assuntos
Fluoresceína/química , Nitrorredutases/metabolismo , Fármacos Fotossensibilizantes/química , Animais , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , Humanos , Hipóxia , Luz , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Nitrorredutases/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Oxigênio Singlete/metabolismo , Temperatura Ambiente , Nanomedicina Teranóstica , Transplante Heterólogo
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