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1.
Cell Metab ; 33(10): 2059-2075.e10, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34536344

RESUMO

Myocardial ischemia-reperfusion (MIR) injury is a major cause of adverse outcomes of revascularization after myocardial infarction. To identify the fundamental regulator of reperfusion injury, we performed metabolomics profiling in plasma of individuals before and after revascularization and identified a marked accumulation of arachidonate 12-lipoxygenase (ALOX12)-dependent 12-HETE following revascularization. The potent induction of 12-HETE proceeded by reperfusion was conserved in post-MIR in mice, pigs, and monkeys. While genetic inhibition of Alox12 protected mouse hearts from reperfusion injury and remodeling, Alox12 overexpression exacerbated MIR injury. Remarkably, pharmacological inhibition of ALOX12 significantly reduced cardiac injury in mice, pigs, and monkeys. Unexpectedly, ALOX12 promotes cardiomyocyte injury beyond its enzymatic activity and production of 12-HETE but also by its suppression of AMPK activity via a direct interaction with its upstream kinase TAK1. Taken together, our study demonstrates that ALOX12 is a novel AMPK upstream regulator in the post-MIR heart and that it represents a conserved therapeutic target for the treatment of myocardial reperfusion injury.

2.
Biomaterials ; 213: 119218, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31136911

RESUMO

Efficient treatment of primary tumor and preventing cancer metastasis present intriguing alternatives to cancer therapy. Herein, for the first time, we reported the photo-triggered nano-gadofullerene (Gd@C82-Ala, abbreviated Gd-Ala) induced malignant tumor vascular disruption by shortening the light interval between Gd-Ala administration and light illumination, where oxygen in blood vessels was employed efficiently to produce cytotoxic reactive oxygen species (ROS). The produced ROS could not only destroy the tumor cells but also devastate the vascular endothelial cells corresponding to the loss of intercellular junctions and vessels disruption. Notably, the irradiated Gd-Ala could enhance dendritic cells (DCs) maturation, which further secreted tumor necrosis factor-α (TNF-α) and interleukin-12 (IL)-12, and then activated T lymphocytes by up-regulation of cluster of differentiation CD4+ and CD8+ T lymphocytes. Furthermore, the down-regulation of matrix metalloprotein 2 (MMP2) and MMP9 also reduce the rate of tumor metastasis. This work explored a new biomedical application of gadofullerene, thereby providing a smart carbon nanomaterial candidate for tumor ablation and inhibition of cancer metastasis.


Assuntos
Antineoplásicos/farmacologia , Fulerenos/farmacologia , Neoplasias/tratamento farmacológico , Neovascularização Patológica , Fármacos Fotossensibilizantes/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Linhagem Celular Tumoral , Células Dendríticas/metabolismo , Feminino , Fulerenos/química , Fulerenos/uso terapêutico , Células Endoteliais da Veia Umbilical Humana , Humanos , Sistema Imunitário , Interleucina-12/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Neoplasias/irrigação sanguínea , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
3.
J Am Chem Soc ; 140(24): 7373-7376, 2018 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-29799737

RESUMO

Reactive oxygen species (ROS) and glutathione (GSH) dual responsive nanoparticulate drug delivery systems (nano-DDSs) hold great promise to improve the therapeutic efficacy and alleviate the side effects of chemo drugs in cancer theranosis. Herein, hydrogen peroxide (H2O2) and GSH dual responsive thioketal nanoparticle (TKN) was rationally designed for paclitaxel (PTX) delivery. Compared to other stimuli-sensitive nano-DDSs, this dual responsive DDS is not only sensitive to biologically relevant H2O2 and GSH for on-demand drug release but also biodegradable into biocompatible byproducts after fulfilling its delivering task. Considering the heterogeneous redox potential gradient, the PTX loaded TKNs (PTX-TKNs) might first respond to the extracellular ROS and then to the intracellular GSH, achieving a programmable release of PTX at the tumor site. The selective toxicity of PTX-TKNs to tumor cells with high levels of ROS and GSH was verified both in vitro and in vivo.


Assuntos
Antineoplásicos/uso terapêutico , Portadores de Fármacos/química , Nanopartículas/química , Paclitaxel/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Plásticos Biodegradáveis/síntese química , Plásticos Biodegradáveis/química , Plásticos Biodegradáveis/toxicidade , Células CHO , Linhagem Celular Tumoral , Cricetulus , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Glutationa/química , Química Verde/métodos , Humanos , Peróxido de Hidrogênio/química , Masculino , Camundongos , Nanopartículas/toxicidade , Paclitaxel/química , Paclitaxel/farmacologia , Polímeros/síntese química , Polímeros/química , Polímeros/toxicidade , Sulfetos/síntese química , Sulfetos/química , Sulfetos/toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Biomaterials ; 163: 142-153, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29459323

RESUMO

The tumor vasculature with unique characteristics offers an attractive target for anti-cancer therapy. Herein, we put forward a novel antitumor therapeutic mechanism based on the gadofullerene nanocrystals (GFNCs), the agent we have previously shown to efficiently disrupt tumor vasculature by size-expansion with assistance of radiofrequency (RF). However, the tumor vascular disrupting mechanism of RF-assisted GFNCs treatment was not further studied. In the present work, a rapid tumor blood flow shutdown has been observed by the vascular perfusion imaging in vivo and vascular damages were evident 6 h after the RF-assisted GFNCs treatment. Importantly, a significant down-expression of tumor vascular endothelial cadherin (VE-cadherin) treated by RF-assisted GFNCs was further investigated, which caused vascular collapse, blood flow shut-down and subsequent tumor hemorrhagic necrosis. These findings set forth a systematic mechanism on the superior anti-tumor efficiency by RF-assisted GFNCs treatment.


Assuntos
Antineoplásicos/administração & dosagem , Vasos Sanguíneos/metabolismo , Fulerenos/administração & dosagem , Gadolínio/química , Nanopartículas/química , Animais , Antígenos CD/metabolismo , Antineoplásicos/química , Caderinas/metabolismo , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Fulerenos/química , Células Hep G2 , Xenoenxertos , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/uso terapêutico , Tamanho da Partícula , Ondas de Rádio
5.
Biomaterials ; 133: 107-118, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28433934

RESUMO

Researchers have been puzzled of the therapy of malignant tumors and the current therapeutic strategies are always accompanied by toxicity or side effects. Developing efficient nanodrugs could reduce the dosage and greatly improve the therapeutic effects in cancer treatments. Here we initially reported a novel kind of gadofullerene nanoparticles functionalized with amino acid (ß-alanine), which exhibited a superior antitumor activity in hepatoma H22 models via a novel therapeutic mechanism. The involvement of ß-alanine improved the tumor inhibition rate up to 76.85% for a single treatment by strengthening the interaction with radiofrequency (RF) and extending blood circulation time. It realized a highly antivascular treatment to cut off the nutrient supply of tumor cells by physically destroying the abnormal tumor blood vessels assisted by RF. In situ and real-time observation of the vascular change was conducted using the dorsal skin fold chamber model, which corresponded to the erythrocyte diapedesis in histopathological examination. The ultrastructural changes of vascular endothelial cells were further investigated by environmental scanning electron microscopy and transmission electron microscopy. Long-term toxicity evaluation showed that the GF-Ala nanoparticles could be eliminated from the mice after several days and no obvious toxicity was found to the main organs. All these encouraging results suggest GF-Ala nanoparticles are valuable for the significant therapeutic potential with high-efficacy and low-toxicity.


Assuntos
Alanina/química , Antinematódeos/química , Antinematódeos/uso terapêutico , Fulerenos/química , Gadolínio/química , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Nanopartículas/química , Animais , Linhagem Celular Tumoral , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Neovascularização Patológica/tratamento farmacológico
6.
Biomaterials ; 103: 75-85, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27376559

RESUMO

A novel phototheranostic platform based on tri-malonate derivative of fullerene C70 (TFC70)/photosensitizer (Chlorin e6, Ce6) nanovesicles (FCNVs) has been developed for effective tumor imaging and treatment. The FCNVs were prepared from amphiphilic TFC70-oligo ethylene glycol -Ce6 molecules. The developed FCNVs possessed the following advantages: (i) high loading efficiency of Ce6 (up to ∼57 wt%); (ii) efficient absorption in near-infrared light region; (iii) enhanced cellular uptake efficiency of Ce6 in vitro and in vivo; (iv) good biocompatibility and total clearance out from the body. These unique properties suggest that the as-prepared FCNVs could be applied as an ideal theranostic agent for simultaneous imaging and photodynamic therapy of tumor. This finding may provide a good solution to highly efficient phototheranostic applications based on fullerene derivatives fabricated nanostructures.


Assuntos
Fulerenos/química , Nanocápsulas/química , Neoplasias Experimentais/química , Neoplasias Experimentais/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Porfirinas/administração & dosagem , Células A549 , Absorção Fisico-Química , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Difusão , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Nanocápsulas/administração & dosagem , Nanocápsulas/ultraestrutura , Neoplasias Experimentais/patologia , Tamanho da Partícula , Fármacos Fotossensibilizantes/química , Porfirinas/química , Distribuição Tecidual , Resultado do Tratamento
7.
Adv Healthc Mater ; 5(17): 2283-94, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27385651

RESUMO

Nanocarbons such as carbon nanotubes, graphene derivatives, and carbon nanohorns have illustrated their potential uses as cancer theranostics owing to their intrinsic fluorescence or NIR absorbance as well as superior cargo loading capacity. However, some problems still need to be addressed, such as the fates and long-term toxicology of different nanocarbons in vivo and the improvement of their performance in various biomedical imaging-guided cancer therapy systems. Herein, a versatile and clearable nanocarbon theranostic based on carbon dots (CDs) and gadolinium metallofullerene nanocrystals (GFNCs) is first developed, in which GFNCs enhance the tumor accumulation of CDs, and CDs enhance the relaxivity of GFNCs, leading to an efficient multimodal imaging-guided photodynamic therapy in vivo without obvious long-term toxicity. Furthermore, biochemical analysis reveals that the novel nanotheranostic can harmlessly eliminate from the body in a reasonable period of time after exerting diagnostic and therapeutic function.


Assuntos
Carbono/química , Fulerenos/química , Nanopartículas/química , Fotoquimioterapia/métodos , Pontos Quânticos/química , Nanomedicina Teranóstica/métodos , Linhagem Celular , Humanos
8.
ACS Appl Mater Interfaces ; 8(18): 11246-54, 2016 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-27097822

RESUMO

A macromolecular magnetic resonance imaging (MRI) contrast agent was successfully synthesized by conjugating the gadolinium/1,4,7,10-tetraazacyclododecane-1,4,7-tetracetic acid complex (Gd-DO3A) with 6,6-phenyl-C61 butyric acid (PC61BA) and upon further modification with human serum albumin (HSA). The final product, PC61BA-(Gd-DO3A)/HSA, has a high stability and exhibits a much higher relaxivity (r1 = 89.1 mM(-1) s(-1) at 0.5 T, 300 K) than Gd-DO3A (r1 = 4.7 mM(-1) s(-1)) does under the same condition, producing the synergistic positive effect of HSA and C60 on the relaxivity of Gd-DO3A. The in vivo MR images of PC61BA-(Gd-DO3A)/HSA-treated tumor-bearing mice show strong signal enhancement for the tumor area due to the enhanced permeability and retention effect. The maximum accumulation of PC61BA-(Gd-DO3A)/HSA at the tumor site was achieved at 4 h postinjection, which may guide surgery. The results from the hematology and histological observations indicate that PC61BA-(Gd-DO3A)/HSA has no obvious toxicity in vivo. These unique properties of PC61BA-(Gd-DO3A)/HSA enable them to be highly efficient for tumor-targeting MRI in vivo, possibly providing a good solution for tumor diagnosis.


Assuntos
Neoplasias , Animais , Meios de Contraste , Fulerenos , Gadolínio , Humanos , Imageamento por Ressonância Magnética , Camundongos , Compostos Organometálicos , Albumina Sérica
9.
Dalton Trans ; 44(19): 9114-9, 2015 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-25899301

RESUMO

Manganese-porphyrin compounds as MRI contrast agents have drawn particular attention due to high relaxivities and unique biodistribution. It has been reported that the charge density of the metal center and steric decompression of the substituents, rather than rotational correlation time, were the key factors to determine the relaxivities of manganese(III) porphyrins. In this study, [6,6]-phenyl-C61-butyric acid (PC61BA) was introduced into 5-(4-aminophenyl)-10,15,20-tris (4-sulfonatophenyl) porphyrin (APTSPP) to investigate the influence on water proton relaxation. The obtained PC61BA-APTSPP-Mn possesses a relaxivity of 19.2 mM(-1) s(-1), which is greater than that of Mn-APTSPP (11.2 mM(-1) s(-1)) and clinically used Gd-DTPA (4.1 mM(-1) s(-1)) at 0.5 T, and even more effective compared with those binding manganese(III) porphyrins to certain macromolecules. It was reasonably speculated that the high relaxivity of PC61BA-APTSPP-Mn should ascribe to the charge density variation of Mn(III) and steric decompression induced by PC61BA. Both fluorescence emission spectra and cyclic voltammetry results verified the presence of electronic communication between PC61BA and APTSPP-Mn. In addition, the hydrodynamic diameter of PC61BA-APTSPP-Mn aggregates was much smaller than that of APTSPP-Mn aggregates, which may contribute to the higher relaxivity by inhibiting the formation of dimers of APTSPP-Mn. Therefore, the introduction of fullerene derivatives is suggested to be a good strategy for the improvement of the relaxivities of manganese(III) porphyrins.


Assuntos
Fulerenos/química , Metaloporfirinas/química , Compostos Organometálicos/química , Prótons , Água/química , Estrutura Molecular , Compostos Organometálicos/síntese química , Tamanho da Partícula , Propriedades de Superfície
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