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1.
J Biomed Nanotechnol ; 17(5): 838-845, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34082870

RESUMO

Malignant melanoma has a poor prognosis because of its strong ability to invade tissues and metastasize. Immune checkpoint blockades significantly improve the clinical response in the development of melanoma. However, there are some obstacles to overcome, such as cost and limited application. Therefore, prospective approaches remain to be exploited. We designed cellular nanovesicles (NVs) expressing PD-1 to reactivate T cells by disrupting the PD-1/PD-L1 immunoinhibitory pathway. Furthermore, siNF90 was wrapped into PD-1 NVs to inhibit the proliferation of tumor cells. Such a dual target effect is helpful for the treatment of melanoma. In addition, our results showed that treatment with PD-1 @siNF90 NVs inhibited the growth of melanoma tumors and extended the survival time of mice, exhibiting a better effect than PD-1 NVs alone. The data also verified that the percentage of CD8+ T cells in tumors was highest after PD-1 @siNF90 NVs treatment. To sum up, PD-1 @siNF90 NVs could serve as safe and effective blockers in the treatment of melanoma.


Assuntos
Melanoma , Receptor de Morte Celular Programada 1 , Animais , Linfócitos T CD8-Positivos , Membrana Celular , Melanoma/tratamento farmacológico , Camundongos , Estudos Prospectivos
2.
EMBO Mol Med ; 13(3): e12834, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33555115

RESUMO

Herein, we demonstrate that NFAT, a key regulator of the immune response, translocates from cytoplasm to nucleolus and interacts with NF45/NF90 complex to collaboratively promote rDNA transcription via triggering the directly binding of NF45/NF90 to the ARRE2-like sequences in rDNA promoter upon T-cell activation in vitro. The elevated pre-rRNA level of T cells is also observed in both mouse heart or skin transplantation models and in kidney transplanted patients. Importantly, T-cell activation can be significantly suppressed by inhibiting NF45/NF90-dependent rDNA transcription. Amazingly, CX5461, a rDNA transcription-specific inhibitor, outperformed FK506, the most commonly used immunosuppressant, both in terms of potency and off-target activity (i.e., toxicity), as demonstrated by a series of skin and heart allograft models. Collectively, this reveals NF45/NF90-mediated rDNA transcription as a novel signaling pathway essential for T-cell activation and as a new target for the development of safe and effective immunosuppressants.


Assuntos
Proteína do Fator Nuclear 45 , Proteínas do Fator Nuclear 90 , Animais , DNA Ribossômico/genética , Humanos , Imunossupressores/farmacologia , Camundongos , Proteína do Fator Nuclear 45/genética , Proteína do Fator Nuclear 45/metabolismo , Proteínas do Fator Nuclear 90/genética , Proteínas do Fator Nuclear 90/metabolismo , Regiões Promotoras Genéticas
3.
Sci Rep ; 5: 14468, 2015 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-26446489

RESUMO

Natural products are a rich resource for the discovery of therapeutic substances. By directly using 504 fine fractions from isolated traditional Chinese medicine plants, we performed a transgenic zebrafish based screen for anti-angiogenesis substances. One fraction, DYVE-D3, was found to inhibit the growth of intersegmental vessels in the zebrafish vasculature. Bioassay-guided isolation of DYVE-D3 indicates that the flavonoid kaempferol was the active substance. Kaempferol also inhibited the proliferation and migration of HUVECs in vitro. Furthermore, we found that kaempferol suppressed angiogenesis through inhibiting VEGFR2 expression, which can be enhanced by FGF inhibition. In summary, this study shows that the construction of fine fraction libraries allows efficient identification of active substances from natural products.


Assuntos
Inibidores da Angiogênese/farmacologia , Berberidaceae/química , Quempferóis/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Inibidores da Angiogênese/isolamento & purificação , Animais , Animais Geneticamente Modificados , Bioensaio , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fracionamento Químico/métodos , Embrião não Mamífero , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Quempferóis/isolamento & purificação , Medicina Tradicional Chinesa , Extratos Vegetais/química , Plantas Medicinais , Bibliotecas de Moléculas Pequenas/isolamento & purificação , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
4.
Chem Biodivers ; 11(7): 1099-108, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25044595

RESUMO

Three new isocoumarin derivatives, mucorisocoumarins A-C (1-3, resp.), together with seven known compounds, 4-10, were isolated from the cold-adapted fungal strain Mucor sp. (No. XJ07027-5). The structures of the new compounds were identified by detailed IR, MS, and 1D- and 2D-NMR analyses. It was noteworthy that compounds 1, 2, 4, and 5 were successfully resolved by chiral HPLC, indicating that 1-7 should exist as enantiomers. In an embryonic developmental toxicity assay using a zebrafish model, compound 3 produced developmental abnormalities in the zebrafish embryos. This is the first report of isocoumarins with developmental toxicity to zebrafish embryos.


Assuntos
Embrião não Mamífero/anormalidades , Embrião não Mamífero/efeitos dos fármacos , Isocumarinas/química , Isocumarinas/toxicidade , Mucor/química , Peixe-Zebra/embriologia , Aclimatação , Animais , Temperatura Baixa , Embrião não Mamífero/embriologia , Desenvolvimento Embrionário/efeitos dos fármacos , Isocumarinas/isolamento & purificação , Mucor/fisiologia
5.
PLoS One ; 8(4): e53317, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23658603

RESUMO

Polo-like kinase 1 (PLK1), one of the key regulators of mitosis, is a target for cancer therapy due to its abnormally high activity in several tumors. Plk1 is highly conserved and shares a nearly identical 3-D structure between zebrafish and humans. The initial 10 mitoses of zebrafish embryonic cleavages occur every∼30 minutes, and therefore provide a rapid assay to evaluate mitosis inhibitors including those targeting Plk1. To increase efficiency and specificity, we first performed a computational virtual screen of∼60000 compounds against the human Plk1 3-D structure docked to both its kinase and Polo box domain. 370 candidates with the top free-energy scores were subjected to zebrafish assay and 3 were shown to inhibit cell division. Compared to general screen for compounds inhibiting zebrafish embryonic cleavage, computation increased the efficiency by 11 folds. One of the 3 compounds, named I2, was further demonstrated to effectively inhibit multiple tumor cell proliferation in vitro and PC3 prostate cancer growth in Xenograft mouse model in vivo. Furthermore, I2 inhibited Plk1 enzyme activity in a dose dependent manner. The IC50 values of I2 in these assays are compatible to those of ON-01910, a Plk1 inhibitor currently in Phase III clinic trials. Our studies demonstrate that zebrafish assays coupled with computational screening significantly improves the efficiency of identifying specific regulators of biological targets. The PLK1 inhibitor I2, and its analogs, may have potential in cancer therapeutics.


Assuntos
Acetanilidas/farmacologia , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Quinolinas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Peixe-Zebra/metabolismo , Acetanilidas/química , Animais , Antineoplásicos/química , Bioensaio , Proteínas de Ciclo Celular/química , Relação Dose-Resposta a Droga , Embrião não Mamífero , Glicina/análogos & derivados , Glicina/química , Glicina/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Camundongos , Camundongos Nus , Mitose/efeitos dos fármacos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/química , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas/química , Quinolinas/química , Bibliotecas de Moléculas Pequenas/química , Sulfonas/química , Sulfonas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Quinase 1 Polo-Like
6.
PLoS One ; 8(4): e60266, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23560085

RESUMO

The Hedgehog (Hh) pathway inhibitors have shown great promise in cancer therapeutics. SANT75, a novel compound we previously designed to specially inhibit the Smoothened (SMO) protein in the Hh pathway, has greater inhibitory potency than many of commonly used Hh inhibitors. However, preclinical studies of SANT75 revealed water insolubility and acute toxicity. To overcome these limitations, we developed a liposomal formulation of SANT75 and investigated its antitumor efficacy in vitro and in vivo. We encapsulated SANT75 into PEGylated liposome and the mean particle size distribution and zeta-potential (ZP) of liposomes were optimized. Using the Shh-light2 cell and Gli-GFP or Flk-GFP transgenic reporter zebrafish, we confirmed that liposome-encapsulated SANT75 inhibited Hh activity with similar potency as the original SANT75. SANT75 encapsulated into liposome exerted strong tumor growth-inhibiting effects in vitro and in vivo. In addition, the liposomal SANT75 therapy efficiently improved the survival time of tumor-bearing mice without obvious systemic toxicity. The pathological morphology and immunohistochemistry staining revealed that liposomal SANT75 induced tumor cell apoptosis, inhibited tumor angiogenesis as assessed by CD31 and down-regulated the expression of Hh target protein Gli-1 in tumor tissues. Our findings suggest that liposomal formulated SANT75 has improved solubility and bioavailability and should be further developed as a drug candidate for treating tumors with abnormally high Hh activity.


Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lipossomos/química , Proteínas Oncogênicas/antagonistas & inibidores , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transativadores/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Composição de Medicamentos , Embrião não Mamífero , Feminino , Genes Reporter , Proteínas de Fluorescência Verde , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Polietilenoglicóis/química , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptor Smoothened , Transativadores/genética , Transativadores/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra , Proteína GLI1 em Dedos de Zinco
7.
ACS Comb Sci ; 15(4): 202-7, 2013 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-23441930

RESUMO

One-pot and efficient syntheses of structurally diverse isoquinolin-3-ones and isoquinolin-3-one-based benzo-1,4-diazepin-2,5-diones have been developed. The notable features of the process include the Ugi condensation of monomasked phthalaldehydes with amines, carboxylic acids, and isonitriles, followed by HClO4-mediated intramolecular condensation of the carbonyl with amide.


Assuntos
Benzodiazepinas/síntese química , Técnicas de Química Combinatória/métodos , Isoquinolinas/síntese química , Amidas/química , Ácidos Carboxílicos/química , Ciclização , Isoquinolinas/química , Nitrilas/química , o-Ftalaldeído/química
8.
Yi Chuan ; 34(9): 1144-52, 2012 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-23017455

RESUMO

Due to its small size, fast external development, transparent embryos, and amenability to genetic analysis, zebrafish has become an ideal vertebrate animal model. In addition to studies in genetics and developmental biology, zebrafish has also been widely used in human disease modeling and drug screening. As a small whole-organism model, zebrafish can be used to comprehensively test and evaluate the activity and side effect of a compound at the same time, fulfilling high content screening. Recently, new zebrafish disease models and screening technologies have been developed. A number of active compounds were identified and most of them have similar functions in mammal models. One compound prostaglandin E2 has been subjected to clinical trial to test if it can promote the growth of umbilical cord blood units after transplantation. Another compound leflunomide has also been approved in clinical trial to cure melanoma in combination with vemurafenib. These findings demonstrate that zebrafish model is appropriate for drug screening. This review summarizes the unique features of zebrafish model and the recent progresses of zebrafish based drug screening.


Assuntos
Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos
9.
Beilstein J Org Chem ; 8: 841-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23015832

RESUMO

Sant-75 is a newly identified potent inhibitor of the hedgehog pathway. We designed a diversity-oriented synthesis program, and synthesized a series of Sant-75 analogues, which lays the foundation for further investigation of the structure-activity relationship of this important class of hedgehog-pathway inhibitors.

10.
PLoS One ; 6(6): e20630, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21698186

RESUMO

Mutations in LRRK2 are genetically linked to Parkinson's disease (PD) but its normal biological function is largely unknown. Sheng et al. recently reported that deletion of the WD40 domain of LRRK2 in zebrafish specifically causes PD-like loss of neurons and behavior defect. However, our similar early study and recent confirming experiments using the same reagents reported by Sheng et al. failed to reproduce the phenotype of the loss of dopaminergic neurons, although the mRNA of LRRK2 was molecularly disrupted. Our study suggests that function of LRRK2 and its usefulness to generate zebrafish PD model needs further evaluation.


Assuntos
Dopamina/metabolismo , Neurônios/citologia , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas de Peixe-Zebra/fisiologia , Animais , Sequência de Bases , Primers do DNA , Técnicas de Silenciamento de Genes , Hibridização In Situ , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/genética
11.
Mol Biosyst ; 6(8): 1463-8, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20625580

RESUMO

During the preclinical drug discovery process it remains a challenge to enable early elimination of candidate molecules that may have non-specific, off-target activities. Here, we use whole zebrafish embryo assays coupled with genetic analysis to address this issue. PLK1 (Polo-like kinase 1) is one of the key regulators that control mitotic entry, spindle assembly, chromosome segregation, and cytokinesis in the cell cycle. Since plk1 expression is abnormally up-regulated in several tumors, it is regarded as a good target for cancer therapy. A number of small-molecule inhibitors targeting PLK1 have been developed as reagents and anticancer drug candidates. It will be interesting to determine if these inhibitors indeed specifically target PLK1 in vivo. Bioinformatics analysis revealed that the zebrafish and human genomes share high homology across all PLK family members. In particular, PLK1 has a nearly identical 3-D structure between zebrafish and human. We selected three published PLK1 inhibitors, LFM-A13, ON01910, and thiazole-carboxamide 10A in our assay. When added at 2-cell stage, all of these inhibitors prevented embryos from dividing and caused cells to fuse into one large cell. When added at the later stage during zygotic mRNA transcription program initiation, embryos survived for 3 days but showed different phenotypes for each compound. Embryos treated with LFM-A13 appeared relatively normal. Embryos treated with ON01910 failed to properly develop trunk and tail regions while the head structure was unaffected. Embryos treated with thiazole-carboxamide 10A had a shorter body axis and deformed head structure. To determine which inhibitor is more selectively targeting PLK1, we inhibited PLK1 activity using anti-sense morpholino. Comparative analysis indicated that thiazole-carboxamide 10A could faithfully phenocopy zebrafish embryos genetically deficient of plk1. These findings demonstrate that these three PLK1 inhibitors, although well established by in vitro studies, have different off-target activities in vivo, and that thiazole-carboxamide 10A appears most specific to PLK1. Our studies suggest that zebrafish should be generally useful as an efficient in vivo model to evaluate specificity of small molecules designed to regulate any conserved target proteins through comparative analysis of genetic phenotypes.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Técnicas Genéticas , Inibidores de Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Peixe-Zebra/genética , Animais , Técnicas de Química Combinatória , Sequência Conservada , Avaliação Pré-Clínica de Medicamentos/métodos , Embrião não Mamífero , Desenvolvimento Embrionário/efeitos dos fármacos , Modelos Biológicos , Filogenia , Inibidores de Proteínas Quinases/análise , Bibliotecas de Moléculas Pequenas/análise , Especificidade por Substrato , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Quinase 1 Polo-Like
12.
Yao Xue Xue Bao ; 41(10): 933-8, 2006 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-17184109

RESUMO

AIM: To study a new way to prepare high-dosage paclitaxel entrapped magnetic targeted nanoparticles and evaluate its quality. METHODS: Fe3O4 nanoparticles are prepared by co-depositing, at the same time ultrasonic is used to decrease soft agglomerate of nanoparticles and increase disperse level of it. The property of nanoparticles surface is improved to make the integrating of liposome and nanoparticle to be tighter. At last, paclitaxel entrapped magnetic solid liposome nanoparticles have been prepared by microemulsion-curing under low-temperature. The loading efficiency and encapsulating rate were determined by reverse-phase high-perfomance chromatography. RESULTS: The nanoparticles have spherical shape. Diameter of nanoparticle ranged from 150 nm to 170 nm. 98.29% of the drug is entrapped in the particle. CONCLUSION: Magnetic susceptibility of nanoparticles is high, and the nanoparticles meet with the demand of targeted delivery system.


Assuntos
Composição de Medicamentos/métodos , Óxido Ferroso-Férrico/química , Nanopartículas/química , Paclitaxel/química , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Sistemas de Liberação de Medicamentos , Emulsões , Concentração de Íons de Hidrogênio , Lipossomos , Nanopartículas/administração & dosagem , Paclitaxel/administração & dosagem , Tamanho da Partícula , Temperatura , Ultrassom
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