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1.
Theranostics ; 9(22): 6412-6423, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588226

RESUMO

Targeted delivery of therapeutic agents is of particular interest in the field of cancer treatment. However, there is an urgent need for developing clinically promising targeting approaches that can be readily administered in a green manner. Methods: Five phthalocyanine derivatives bearing different anionic and cationic groups were designed and synthesized. Then, their binding affinity with albumin were studied using gel assays, optical spectra and computational simulation. Finally, in vitro and in vivo fluorescence imaging and photodynamic therapy (PDT) evaluations were carried out. Results: The two positively charged compounds could selectively bind to albumin dimer over albumin monomer, while the three negatively charged phthalocyanines could bind to both albumin monomer and dimer. Following systemic administration, the phthalocyanines show improved tumor accumulation via transport by natural albumin. PDT evaluations indicate that one of the positively charged compounds, ZnPcN4, shows outstanding phototherapeutic efficacy against tumors in preclinical models. Conclusion: Our findings demonstrate that the use of water-soluble phthalocyanines as photosensitizers and in vivo albumin as a natural carrier may provide a green and efficient approach for tumor-targeted imaging and therapy.

2.
PeerJ ; 7: e7561, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31565558

RESUMO

A new species of ichthyosauriform is recognized based on 20 specimens, including nearly complete skeletons, and named Chaohusaurus brevifemoralis. A part of the specimens was previously identified as Chaohusaurus chaoxianensis and is herein reassigned to the new species. The new species differs from existing species of Chaohusaurus in a suite of features, such as the bifurcation of the caudal peak neural spine and a short femur relative to trunk length. The specimens include both complete and partially disarticulated skulls, allowing rigorous scrutiny of cranial sutures. For example, the squamosal does not participate in the margin of the upper temporal fenestra despite previous interpretations. Also, the frontal unequivocally forms a part of the anterior margin of the upper temporal fenestra, forming the most medial part of the anterior terrace. The skull of the holotype largely retains three-dimensionality with the scleral rings approximately in situ, revealing that the eyeball was uncovered in two different directions, that is, laterally and slightly dorsally through the main part of the orbit, and dorsally through the medial extension of the orbit into the skull roof. This skull construction is likely a basal feature of Ichthyosauromorpha. Phylogenetic analyses place the new species as a sister taxon of Chaohusaurus chaoxianensis.

3.
ACS Appl Mater Interfaces ; 11(40): 36435-36443, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31525892

RESUMO

Self-assembled phototheranostic nanomaterials used for photodynamic therapy (PDT) have attracted increasing attention owing to their several advantages. Herein, we developed a novel strategy for size-tunable self-assembled nanophotosensitizers for PDT through a simple method. A series of switchable self-assembled nanophotosensitizers (NanoPc90, NanoPc40, NanoPc20, and NanoPc10) of different particle sizes were readily prepared based on an amphiphilic silicon(IV) phthalocyanine (SiPc)-biotin conjugate by regulating the amount of the Cremophor EL surfactant used. The photoactivities, including fluorescence and reactive oxygen species (ROS), of the self-assemblies could be regulated by the particle size. The self-assemblies could be specifically disassembled by tumor-overexpressing biotin receptors, leading to the recovery of quenched photoactivities. Demonstrated by the competitive assay, the self-assemblies were able to enter HepG2 cells through a biotin-receptor-mediated pathway, followed by biotin-receptor-triggered fluorescence recovery at the cellular level. Moreover, the particle size could also affect the in vitro and in vivo PDT effects and tumor targeting. The photocytotoxicity of NanoPc20 against HepG2 cells was more potent compared to that of NanoPc90 because of its strong intracellular fluorescence, higher intracellular ROS generation, and different subcellular localization. In addition, NanoPc20 showed higher in vivo tumor targeting and photodynamic therapeutic efficacy than NanoPc90. This work would provide a valuable reference for the development of self-assembled nanophotosensitizers for cancer diagnosis and therapy.

4.
mSphere ; 4(5)2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484738

RESUMO

The demand for a prophylactic vaccine against methicillin-resistant Staphylococcus aureus (MRSA) has motivated numerous dedicated research groups to design and develop such a vaccine. In this study, we have developed a multivalent vaccine, Sta-V5, composed of five conserved antigens involved in three important virulence mechanisms. This prototype vaccine conferred up to 100% protection against multiple epidemiologically relevant S. aureus isolates in five different murine disease models. The vaccine not only elicits functional antibodies that mediate opsonophagocytic killing of S. aureus but also mounts robust antigen-specific T-cell responses. In addition, our data implied that γδ T cells contribute to the protection induced by Sta-V5 in a murine skin infection model.IMPORTANCE Staphylococcus aureus infections, especially MRSA infections, are becoming a major global health issue and are resulting in mortality rates that are increasing every year. However, an effective vaccine is lacking due to the complexity of the infection process of S. aureus In this study, we found that the addition of two novel protein components to three well-studied vaccine candidates significantly improved the efficacy of the combined vaccine. Furthermore, the five-component vaccine not only elicits a robust antibody response but also induces cytokine secretion by T cells, making it a promising vaccine candidate to fill the void.

5.
iScience ; 13: 82-97, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30826728

RESUMO

N-methyl-D-aspartate (NMDA) receptor (NMDAR) is highly compartmentalized in neurons, and its dysfunction has been implicated in various neuropsychiatric and neurodegenerative disorders. Recent failure to exploit NMDAR antagonization as a potential therapeutic target has driven the need to identify molecular mechanisms that regulate NMDAR compartmentalization. Here, we report that the reduction of Kif5b, the heavy chain of kinesin-1, protected neurons against NMDA-induced excitotoxicity and ischemia-provoked neurodegeneration. Direct binding of kinesin-1 to the GluN2B cytoplasmic tails regulated the levels of NMDAR at extrasynaptic sites and the subsequent influx of calcium mediated by extrasynaptic NMDAR by regulating the insertion of NMDARs into neuronal surface. Transient increase of Kif5b restored the surface levels of NMDAR and the decreased neuronal susceptibility to NMDA-induced excitotoxicity. The expression of Kif5b was repressed in cerebral ischemia preconditioning. Our findings reveal that kinesin-1 regulates extrasynaptic NMDAR targeting and signaling, and the reduction of kinesin-1 could be exploited to defer neurodegeneration.

6.
Antiviral Res ; 161: 125-133, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30503888

RESUMO

Human respiratory syncytial virus (HRSV) infection is a significant cause of morbidity and mortality, particularly among the children and the elderly. Despite extensive efforts, there is currently no formally approved vaccine and effective antiviral options against HRSV infection are limited. The development of vaccines and antiviral strategies for HRSV was partly hampered by the lack of an efficient lethal mouse model to evaluate the efficacy of the candidate vaccines or antivirals. In this study, we established a lethal HRSV mouse model by consecutively passaging a clinical HRSV isolate, GZ08-0. GZ08-18 was isolated from mouse bronchioalveolar lavage fluids at the 50th passage of GZ08-0. Importantly, all GZ08-18-inoculated mice succumbed to the infection by day 7 post infection, whereas all GZ08-0-inoculated mice recovered from the infection. Subsequent investigations demonstrated that GZ08-18 replicated to a higher titer in mouse lungs, induced more prominent lung pathology, and resulted in higher expression levels of a number of key pro-inflammatory cytokines including IFN-γ, MIP-1α, and TNF-α in comparison to that of GZ08-0. The cyclophosphamide pretreatment rendered the mice more susceptible to a lethal outcome with less rounds of virus inoculation. Full genome sequencing revealed 17 mutations in GZ08-18, some of which might account for the dramatically increased pathogenicity over GZ08-0. In addition, by using ribavirin as a positive control, we demonstrated the potential application of this lethal mouse model as a tool in HRSV investigations. Overall, we have successfully established a practical lethal mouse model for HRSV with a mouse-adapted virus, which may facilitate future in vivo studies on the evaluation of candidate vaccines and drugs against HRSV.

7.
J Am Chem Soc ; 141(3): 1366-1372, 2019 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-30565924

RESUMO

Albumin is a promising candidate as a biomarker for potential disease diagnostics and has been extensively used as a drug delivery carrier for decades. In these two directions, many albumin-detecting probes and exogenous albumin-based nanocomposite delivery systems have been developed. However, there are only a few cases demonstrating the specific interactions of exogenous probes with albumin in vivo, and nanocomposite delivery systems usually suffer from tedious fabrication processes and potential toxicity of the complexes. Herein, we demonstrate a facile "one-for-all" switchable nanotheranostic (NanoPcS) for both albumin detection and cancer treatment. In particular, the in vivo specific binding between albumin and PcS, arising from the disassembly of injected NanoPcS, is confirmed using an inducible transgenic mouse system. Fluorescence imaging and antitumor tests on different tumor models suggest that NanoPcS has superior tumor-targeting ability and the potential for time-modulated, activatable photodynamic therapy.

8.
Biomater Sci ; 7(1): 211-219, 2018 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-30426113

RESUMO

Development of a photosensitizer that can achieve tumor specificity, improve therapeutic efficacy, and reduce side effects remains a challenge for photodynamic therapy (PDT). In this work, a pH-sensitive activatable nanophotosensitizer (SMSN-ZnPc1) has been elaborately designed, which could be readily prepared by using a functionalized zinc(ii) phthalocyanine (ZnPc) to conjugate with stellate mesoporous silica nanoparticles (SMSNs) through an acid-sensitive hydrazone bond. Meanwhile, a non-activatable analogue SMSN-ZnPc2 has also been prepared as a negative control. The fluorescence emission and singlet oxygen generation of the photosensitizer are essentially quenched in the intact nanophotosensitizer. However, these properties of SMSN-ZnPc1 can be restored greatly both in acidic solutions and at the cellular level. More importantly, after intravenous administration, SMSN-ZnPc1 can also be selectively activated at the tumor site and exhibit efficient tumor growth inhibition in S180 rat ascitic tumor-bearing KM mice with negligible systemic toxicity. It thus may serve as a promising nanoplatform for cancer diagnosis and targeted PDT.


Assuntos
Preparações de Ação Retardada/química , Indóis/uso terapêutico , Nanoconjugados/uso terapêutico , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Compostos Organometálicos/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Dióxido de Silício/química , Animais , Preparações de Ação Retardada/administração & dosagem , Feminino , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Indóis/administração & dosagem , Indóis/química , Camundongos , Nanoconjugados/administração & dosagem , Nanoconjugados/química , Neoplasias/patologia , Imagem Óptica/métodos , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/química , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/química , Porosidade , Ratos , Dióxido de Silício/administração & dosagem
9.
Biomaterials ; 184: 20-30, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30195802

RESUMO

Successful immunogene therapy depends not only on the therapeutic gene but also on the gene delivery vector. In this study, we synthesized a novel copolymer consisting of low-molecular-weight polyethylenimine (PEI) cross-linked by myo-inositol (INO) and conjugated with a galactose-grafted PEG chain, named LA-PegPI. We characterized the chemical structure and molecular weight of the copolymer and particle properties of LA-PegPI/pDNA. Furthermore, we showed that LA-PegPI/pDNA polyplexes possessed excellent stability in physiological salt solution, low cytotoxicity, and high transfection efficiency in the asialoglycoprotein receptor (ASGPR)-positive liver cells in vitro. Importantly, we also showed that through intraperitoneal injection of LA-PegPI/pDNA nanoparticles, the reporter gene was forcefully expressed in the liver hepatocytes of mice. Finally, we documented that intraperitoneal injection of LA-PegPI/pIL15 nanoparticles effectively suppressed tumor growth and prolonged survival time of tumor-bearing mice via activation of CD8+ T cells and NK cells and upregulation of the cytokines IFN-γ, TNF, and IL12 in an orthotopic hepatocellular carcinoma mouse model. Interestingly, LA-PegPI/pluc nanoparticles could effectively stimulate the proliferation of NK cells and inhibit tumor growth in this model. In summary, LA-PegPI is a useful gene vector for immunogene therapy of hepatocellular carcinoma, and its potential for clinical application warrants further study.


Assuntos
Receptor de Asialoglicoproteína/genética , Carcinoma Hepatocelular/terapia , Galactose/química , Interleucina-15/metabolismo , Neoplasias Hepáticas/terapia , Polietilenoglicóis/química , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Reagentes para Ligações Cruzadas/química , DNA/administração & dosagem , Portadores de Fármacos , Feminino , Genes Reporter , Hepatócitos/patologia , Humanos , Imunoterapia , Inositol/química , Interleucina-15/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Camundongos Endogâmicos BALB C , Peso Molecular , Nanopartículas/química , Plasmídeos , Polietilenoimina/química
10.
Oncogene ; 37(49): 6299-6315, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30038266

RESUMO

Cancer stem cell (CSC)-dictated intratumor heterogeneity accounts for the majority of drug-resistance and distant metastases of breast cancers. Here, we identify a SIRT1-PRRX1-KLF4-ALDH1 circuitry, which couples CSCs, chemo-resistance, metastasis and aging. Pro-longevity protein SIRT1 deacetylates and stabilizes the epithelial-to-mesenchymal-transition (EMT) inducer PRRX1, which inhibits the transcription of core stemness factor KLF4. Loss of SIRT1 destabilizes PRRX1, disinhibits KLF4, and activates the transcription of ALDH1, which induces and functionally marks CSCs, resulting in chemo-resistance and metastatic relapse. Clinically, the level of PRRX1 is positively linked to SIRT1, whereas KLF4 is reversely correlated. Importantly, KLF4 inhibitor Kenpaullone sensitizes breast cancer cells and xenograft tumors to Paclitaxel and improves therapeutic effects. Our findings delineate a SIRT1-centered circuitry that regulates CSC origination, and targeting this pathway might be a promising therapeutic strategy.


Assuntos
Neoplasias da Mama/patologia , Células-Tronco Neoplásicas/patologia , Transdução de Sinais/fisiologia , Sirtuína 1/metabolismo , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Proteínas de Homeodomínio/metabolismo , Humanos , Isoenzimas/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Camundongos Nus , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Células-Tronco Neoplásicas/metabolismo , Retinal Desidrogenase/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Eur J Med Chem ; 155: 24-33, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29852329

RESUMO

A series of novel symmetric or unsymmetric silicon (IV) phthalocyanines axially substituted with cyclic Arg-Gly-Asp (cRGD) ligands through different ethylene glycol chains have been synthesized by a facile and mild "click" reaction. All the compounds show efficient photosensitizing activities in N,N-dimethylformamide, and are essentially non-aggregated in RPMI 1640 medium with 0.05% Cremophor EL. Owing to the presence of two cRGD ligands, the conjugate 6b exhibits highest selectivity toward αvß3+ HT-29 cells in photocytotoxicities. It shows higher cellular uptake and ROS generation efficiency toward the αvß3+ HT-29 cells compared with that of αvß3- MCF-7 cells. The competitive cellular uptake and subcellular localization indicate that 6b is internalized mainly through integrin-mediated endocytosis. In addition, the in vivo studies showed that 6b can mainly accumulate in tumor sites and show a significant PDT effect resulting in 75% tumor growth inhibition. The results indicate that 6b is a highly promising photosensitizer for targeted photodynamic therapy.


Assuntos
Indóis/farmacologia , Integrinas/antagonistas & inibidores , Peptídeos Cíclicos/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Silício/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Indóis/química , Integrinas/metabolismo , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Peptídeos Cíclicos/química , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Silício/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
12.
Angew Chem Int Ed Engl ; 57(31): 9885-9890, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-29927036

RESUMO

Owing to their unique, nanoscale related optical properties, nanostructures assembled from molecular photosensitizers (PSs) have interesting applications in phototheranostics. However, most nanostructured PS assemblies are super-quenched, thus, preventing their use in photodynamic therapy (PDT). Although some of these materials undergo stimuli-responsive disassembly, which leads to partial recovery of PDT activity, their therapeutic potentials are unsatisfactory owing to a limited ability to promote generation reactive oxygen species (ROS), especially via type I photoreactions (i.e., not by 1 O2 generation). Herein we demonstrate that a new, nanostructured phthalocyanine assembly, NanoPcA, has the ability to promote highly efficient ROS generation via the type I mechanism. The results of antibacterial studies demonstrate that NanoPcA has potential PDT applications.


Assuntos
Antibacterianos/farmacologia , Indóis/farmacologia , Nanoestruturas/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Indóis/síntese química , Indóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Tamanho da Partícula , Processos Fotoquímicos , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/metabolismo , Propriedades de Superfície
13.
Drug Discov Today ; 23(10): 1791-1800, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29803933

RESUMO

In recent years, photodynamic therapy has been applied in cancer treatment because of its high selectivity and marginal invasion properties. However, the excitation light used has limited ability to penetrate tissue, which creates a stumbling block for its future development. To overcome this, X-rays have been introduced to transmit energy to deeper tissues. Given that a large number of X-ray-induced sensitizers have been designed to facilitate X-ray excitation and generate reactive oxygen species (ROS), this has led to the concept of X-ray-induced photodynamic therapy (X-PDT). After 10 years of development, this treatment now shows good therapeutic effects as well as shortcomings. Going forward, it will be important to improve tumor targeting and a standard deep-seated tumor model should be established.


Assuntos
Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Animais , Desenvolvimento de Medicamentos/métodos , Humanos , Terapia de Alvo Molecular , Neoplasias/patologia , Espécies Reativas de Oxigênio/metabolismo , Raios X
14.
Chem Sci ; 9(8): 2098-2104, 2018 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-29675251

RESUMO

Phthalocyanine (Pc) molecules exhibit high extinction coefficients in near-infrared region, rendering them well-suited for phototherapies, but most of their applications are limited to the field of photodynamic therapy (PDT). Herein, for the first time, we illustrate that Pc molecules can be endowed with excellent photothermal properties by means of structural regulation rather than formation of aggregates. Three representative Pc derivatives show efficient activities of photothermal therapy (PTT) against human hepatocellular carcinoma cells. Among them, copper phthalocyanine (PcC1) exhibits a high in vivo PTT efficacy against mice bearing S180 tumors. The unique investigation in this article should light up a perspective of Pc's new applications for PTT, which enable to make up the inherent defects of PDT.

15.
BMC Infect Dis ; 18(1): 195, 2018 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-29699491

RESUMO

BACKGROUND: Staphylococcus aureus (S. aureus) causes a wide range of infectious diseases in human and animals. The emergence of antibiotic-resistant strains demands novel strategies for prophylactic vaccine development. In this study, live attenuated S. enterica subsp. enterica serotype Typhimurium (S. Typhimurium) vaccine against S. aureus infection was developed, in which Salmonella Pathogenesis Island-1 Type 3 Secretion System (SPI-1 T3SS) was employed to deliver SaEsxA and SaEsxB, two of ESAT-6-like (Early Secreted Antigenic Target-6) virulence factors of S. aureus. METHODS: Antigens SaEsxA and SaEsxB were fused with the N-terminal secretion and translocation domain of SPI-1 effector SipA. And cytosolic delivery of Staphylococcal antigens into macrophages was examined by western blot. BALB/c mice were orally immunized with S. Typhimurium-SaEsxA and S. Typhimurium-SaEsxB vaccines. Antigen-specific humoral and Th1/Th17 immune responses were examined by ELISA and ELISPOT assays 7-9 days after the 2nd booster. For ELISPOT assays, the statistical significance was determined by Student's t test. The vaccine efficacy was evaluated by lethal challenge with two S. aureus clinical isolates Newman strain and USA 300 strain. Statistical significance was determined by Log rank (Mantel-Cox) analysis. And a P value of < 0.05 was considered statistically significant. RESULTS: Oral administration of S. Typhimurium-SaEsxA and S. Typhimurium-SaEsxB vaccines induced antigen-specific humoral and Th1/Th17 immune responses, which increased the survival rate for vaccinated mice when challenged with S. aureus strains. CONCLUSIONS: The newly developed S. Typhimurium-based vaccines delivering SaEsxA and SaEsxB by SPI-1 T3SS could confer protection against S. aureus infection. This study provides evidence that translocation of foreign antigens via Salmonella SPI-1 T3SS into the cytosol of antigen presenting cells (APCs) could induce potent immune responses against pathogens.


Assuntos
Células RAW 264.7/efeitos dos fármacos , Salmonella typhimurium/imunologia , Infecções Estafilocócicas/prevenção & controle , Sistemas de Secreção Tipo III/imunologia , Vacinas Atenuadas/administração & dosagem , Animais , Imunização , Camundongos , Camundongos Endogâmicos BALB C , Fatores de Virulência/imunologia
16.
Arterioscler Thromb Vasc Biol ; 38(5): 1037-1051, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29519941

RESUMO

OBJECTIVE: Platelet secretion is crucial for many physiological platelet responses. Even though several regulators of the fusion machinery for secretory granule exocytosis have been identified in platelets, the underlying mechanisms are not yet fully characterized. APPROACH AND RESULTS: By studying a mouse model (cKO [conditional knockout]Kif5b) lacking Kif5b (kinesin-1 heavy chain) in its megakaryocytes and platelets, we evidenced unstable hemostasis characterized by an increase of blood loss associated to a marked tendency to rebleed in a tail-clip assay and thrombus instability in an in vivo thrombosis model. This instability was confirmed in vitro in a whole-blood perfusion assay under blood flow conditions. Aggregations induced by thrombin and collagen were also impaired in cKOKif5b platelets. Furthermore, P-selectin exposure, PF4 (platelet factor 4) secretion, and ATP release after thrombin stimulation were impaired in cKOKif5b platelets, highlighting the role of kinesin-1 in α-granule and dense granule secretion. Importantly, exogenous ADP rescued normal thrombin induced-aggregation in cKOKif5b platelets, which indicates that impaired aggregation was because of defective release of ADP and dense granules. Last, we demonstrated that kinesin-1 interacts with the molecular machinery comprising the granule-associated Rab27 (Ras-related protein Rab-27) protein and the Slp4 (synaptotagmin-like protein 4/SYTL4) adaptor protein. CONCLUSIONS: Our results indicate that a kinesin-1-dependent process plays a role for platelet function by acting into the mechanism underlying α-granule and dense granule secretion.


Assuntos
Plaquetas/enzimologia , Hemostasia , Cinesina/metabolismo , Megacariócitos/enzimologia , Ativação Plaquetária , Vesículas Secretórias/enzimologia , Trombose/enzimologia , Trifosfato de Adenosina/sangue , Animais , Plaquetas/ultraestrutura , Modelos Animais de Doenças , Humanos , Cinesina/sangue , Cinesina/deficiência , Cinesina/genética , Megacariócitos/ultraestrutura , Camundongos Endogâmicos C57BL , Camundongos Knockout , Selectina-P/sangue , Agregação Plaquetária , Fator Plaquetário 4/sangue , Via Secretória , Vesículas Secretórias/genética , Vesículas Secretórias/ultraestrutura , Transdução de Sinais , Trombose/sangue , Trombose/genética , Trombose/patologia , Proteínas de Transporte Vesicular/sangue , Proteínas rab27 de Ligação ao GTP/sangue
17.
Eur J Med Chem ; 145: 86-95, 2018 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-29324346

RESUMO

Sono-Photodynamic therapy (SPDT) utilizing ultrasound and light has been demonstrated that this novel approach can lower dosage resulting in reduction of the potential side effects caused by sensitizers. Recently, a new formulation of rose bengal (RB) as an intralesional injection has completed clinical trials phase II for PDT treatment of melanoma cancer. However, the inherent unfavorable pharmacological properties of RB hindered its extensive clinical development. With the aim to identify new RB derivatives (RBDs) with enhanced photodynamic and sonodynamic anticancer efficiency, a series of amphiphilic RBDs have been designed, synthesized and biological characterized. Among them, RBD4 significantly improved cellular uptake and enhanced intracellular ROS generation efficiency upon light and ultrasound irradiation, resulting in dramatically improved anticancer potency. Notably, RBD4 has a relative potency similar to sinoporphyrin sodium (DVDMS), indicating its further potential application for SPDT.


Assuntos
Antineoplásicos/farmacologia , Fotoquimioterapia , Rosa Bengala/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Estrutura Molecular , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Rosa Bengala/síntese química , Rosa Bengala/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
18.
ACS Nano ; 12(1): 681-688, 2018 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29232105

RESUMO

Supramolecular chemistry provides a "bottom-up" method to fabricate nanostructures for biomedical applications. Herein, we report a facile strategy to directly assemble a phthalocyanine photosensitizer (PcS) with an anticancer drug mitoxantrone (MA) to form uniform nanostructures (PcS-MA), which not only display nanoscale optical properties but also have the capability of undergoing nucleic-acid-responsive disassembly. These supramolecular assemblies possess activatable fluorescence emission and singlet oxygen generation associated with the formation of free PcS, mild photothermal heating, and a concomitant chemotherapeutic effect associated with the formation of free MA. In vivo evaluations indicate that PcS-MA nanostructures have a high level of accumulation in tumor tissues, are capable of being used for cancer imaging, and have significantly improved anticancer effect compared to that of PcS. This study demonstrates an attractive strategy for overcoming the limitations of photodynamic cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Indóis/uso terapêutico , Mitoxantrona/uso terapêutico , Nanoestruturas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Nanomedicina Teranóstica/métodos , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Humanos , Indóis/química , Indóis/farmacocinética , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitoxantrona/química , Mitoxantrona/farmacocinética , Modelos Moleculares , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Neoplasias/metabolismo , Ácidos Nucleicos/metabolismo , Imagem Óptica/métodos , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética
19.
Cell Discov ; 4: 65, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30603101

RESUMO

Kif5b-driven anterograde transport and clathrin-mediated endocytosis (CME) are responsible for opposite intracellular trafficking, contributing to plasma membrane homeostasis. However, whether and how the two trafficking processes coordinate remain unclear. Here, we show that Kif5b directly interacts with clathrin heavy chain (CHC) at a region close to that for uncoating catalyst (Hsc70) and preferentially localizes on relatively large clathrin-coated vesicles (CCVs). Uncoating in vitro is decreased for CCVs from the cortex of kif5b conditional knockout (mutant) mouse and facilitated by adding Kif5b fragments containing CHC-binding site, while cell peripheral distribution of CHC or Hsc70 keeps unaffected by Kif5b depletion. Furthermore, cellular entry of vesicular stomatitis virus that internalizes into large CCV is inhibited by Kif5b depletion or introducing a dominant-negative Kif5b fragment. These findings showed a new role of Kif5b in regulating large CCV-mediated CME via affecting CCV uncoating, indicating Kif5b as a molecular knot connecting anterograde transport to CME.

20.
J Cancer ; 8(9): 1609-1618, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28775780

RESUMO

Purpose Neuroblastoma is an embryonic solid tumor derived from the progenitors of the sympathetic nervous system. More than half of the patients developed metastatic disease at the time of initial diagnosis and had poor outcome with current therapeutic approaches. In recent years, some obligate and facultative anaerobic bacteria were reported to target the hypoxic and necrotic region of solid tumor models and caused tumor regression. We recently successfully constructed an "obligate" anaerobic Salmonella strain YB1 that was applied in breast cancer nude mice model by us. Here, we report the application of YB1 in neuroblastoma treatment. Methods The anti-cancer effect and side-effects of YB1 was examined in both in vitro and in vivo experiment. Previous established orthotopic neuroblastoma SCID/beige murine model using SK-NLP/luciferase cell line was adopted. ResultsIn vitro, YB1 induced apoptosis for up to 31.4% of the neuroblastoma cells under anaerobic condition, three times more than that under aerobic condition (10.9%). The expression of both Toll like Receptor 4 and 5 (TLR4 and TLR5) in cancer cells were significantly up-regulated (p<0.05, p<0.01 respectively) after the treatment of YB1 under anaerobic condition. In mouse model, YB1 preferentially accumulated inside the core of the tumors, rather than in normal tissues as our previous reported. This is suggestive of the hypoxic nature of tumor core. Tumor growth was significantly retarded in YB1 treatment group (n=6, P<0.01). Furthermore, there was no long-term organ damage noted in all the organs examined including heart, lung, liver, spleen and brain in the YB1 treated mice. Conclusion The genetic modified Salmonella strain YB1 is a promising anti-tumor strategy against the tumor bulk for neuroblastoma. Future study can be extended to other common cancer types to verify the relative efficacy on different neoplastic cells.

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