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1.
Nat Commun ; 12(1): 6145, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34686685

RESUMO

Tumor response to radiotherapy or ferroptosis is closely related to hydroxyl radical (•OH) production. Noninvasive imaging of •OH fluctuation in tumors can allow early monitoring of response to therapy, but is challenging. Here, we report the optimization of a diene electrochromic material (1-Br-Et) as a •OH-responsive chromophore, and use it to develop a near-infrared ratiometric fluorescent and photoacoustic (FL/PA) bimodal probe for in vivo imaging of •OH. The probe displays a large FL ratio between 780 and 1113 nm (FL780/FL1113), but a small PA ratio between 755 and 905 nm (PA755/PA905). Oxidation of 1-Br-Et by •OH decreases the FL780/FL1113 while concurrently increasing the PA755/PA905, allowing the reliable monitoring of •OH production in tumors undergoing erastin-induced ferroptosis or radiotherapy.


Assuntos
Radical Hidroxila/metabolismo , Imagem Molecular/métodos , Sondas Moleculares/metabolismo , Neoplasias/diagnóstico por imagem , Imagem Óptica/métodos , Animais , Linhagem Celular Tumoral , Ferroptose , Fluorescência , Camundongos , Sondas Moleculares/química , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/radioterapia , Técnicas Fotoacústicas , Espectroscopia de Luz Próxima ao Infravermelho
2.
ACS Appl Mater Interfaces ; 13(30): 36106-36116, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34313120

RESUMO

Metal-organic frameworks (MOFs) are significant useful molecular materials as a result of their high surface area and flexible catalytic activities by tuning the metal centers and ligands. MOFs have attracted great attention as efficient nanozymes recently; however, it is still difficult to understand polymetallic MOFs for enzymatic catalysis because of their complicated structure and interactions. Herein, bimetallic NiFe2 MOF octahedra were well prepared and exhibited enhanced peroxidase-like activities. The synergistic effect of Fe and Ni atoms was systematically investigated by electrochemistry, X-ray photoelectron spectrometry, (XPS) and in situ Raman techniques. The electrons tend to transfer from Ni2+ to Fe3+ in NiFe2 MOFs, and the resulting Fe2+ is ready to decompose H2O2 and generate ·OH by a Fenton-like reaction. After integration with glucose oxidase (GOx), which can downgrade the pH value and generate H2O2 by oxidation of glucose, a self-activated cascade reagent is therefore established for efficiently inducing cell death. The changes of cell morphology, DNA, and protein are also successfully recorded during the cell death process by Raman spectroscopy and fluorescence imaging.


Assuntos
Antineoplásicos/farmacologia , Estruturas Metalorgânicas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzidinas/química , Catálise , Glucose/química , Glucose Oxidase/química , Células HeLa , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Radical Hidroxila/metabolismo , Ferro/química , Cinética , Estruturas Metalorgânicas/síntese química , Estruturas Metalorgânicas/química , Níquel/química , Oxirredução
3.
ACS Appl Mater Interfaces ; 13(29): 33915-33925, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34279905

RESUMO

Macrophage accumulation is central to the pathogenesis of atherosclerotic plaques. Reducing macrophages in plaques is an appealing approach to attenuate the development of atherosclerosis. Chemodynamic therapy, specifically inhibiting hydrogen peroxide (H2O2)-rich cells in slightly acidic microenvironment, has emerged as a new method in tumor treatment. Herein, we manufactured ultrasmall dopamine-modified hyaluronic acid (HD)-stabilized Fe(III)-tannic acid nanoparticles (HFTNPs). HFTNPs can specifically accumulate in inflammatory macrophages in atherosclerotic plaques, provide brighter magnetic resonance images, promote reactive oxygen species (ROS) generation, and induce the death of inflammatory macrophages without damaging normal cells and tissues. In conclusion, HFTNPs have a tremendous potential as safe and effective diagnostic and therapeutic reagents for atherosclerosis.


Assuntos
Meios de Contraste/uso terapêutico , Compostos Férricos/uso terapêutico , Nanopartículas/uso terapêutico , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/tratamento farmacológico , Taninos/uso terapêutico , Animais , Catálise , Meios de Contraste/química , Meios de Contraste/toxicidade , Dopamina/análogos & derivados , Dopamina/toxicidade , Compostos Férricos/química , Compostos Férricos/toxicidade , Ácido Hialurônico/química , Ácido Hialurônico/toxicidade , Radical Hidroxila/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Nanopartículas/toxicidade , Células RAW 264.7 , Taninos/química , Taninos/toxicidade
4.
Theranostics ; 11(15): 7439-7449, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34158859

RESUMO

X-ray excited persistent luminescence (XEPL) imaging has attracted increasing attention in biomedical imaging due to elimination of autofluorescence, high signal-to-noise ratio and repeatable activation with high penetration. However, optical imaging still suffers from limited for high spatial resolution. Methods: Herein, we report Mn3+-rich manganese oxide (MnOx)-coated chromium-doped zinc gallogermanate (ZGGO) nanoparticles (Mn-ZGGOs). Enhanced XEPL and magnetic resonance (MR) imaging were investigated by the decomposition of MnOx shell in the environment of tumors. We also evaluated the tumor cell-killing mechanism by detection of reactive oxygen (ROS), lipid peroxidation and mitochondrial membrane potential changes in vitro. Furthermore, the in vivo biodistribution, imaging and therapy were studied by U87MG tumor-bearing mice. Results: In the tumor region, the MnOx shell is quickly decomposed to produce Mn3+ and oxygen (O2) to directly generate singlet oxygen (1O2). The resulting Mn2+ transforms endogenous H2O2 into highly toxic hydroxyl radical (·OH) via a Fenton-like reaction. The Mn2+ ions and ZGGOs also exhibit excellent T1-weighted magnetic resonance (MR) imaging and ultrasensitive XEPL imaging in tumors. Conclusion: Both the responsive dual-mode imaging and simultaneous self-supplied O2 for the production of 1O2 and oxygen-independent ·OH in tumors allow for more accurate diagnosis of deep tumors and more efficient inhibition of tumor growth without external activation energy.


Assuntos
Radical Hidroxila/metabolismo , Substâncias Luminescentes , Compostos de Manganês , Nanopartículas , Neoplasias Experimentais , Imagem Óptica , Óxidos , Oxigênio Singlete/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Substâncias Luminescentes/química , Substâncias Luminescentes/farmacocinética , Substâncias Luminescentes/farmacologia , Compostos de Manganês/química , Compostos de Manganês/farmacocinética , Compostos de Manganês/farmacologia , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Óxidos/química , Óxidos/farmacocinética , Óxidos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
ACS Appl Mater Interfaces ; 13(24): 27856-27867, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34110146

RESUMO

Combining photodynamic therapy (PDT), chemodynamic therapy (CDT), and ferroptosis is a valuable means for an enhanced anticancer effect. However, traditional combination of PDT/CDT/ferroptosis faces several hurdles, including excess glutathione (GSH) neutralization and preparation complexity. In this work, a versatile multifunctional nanoparticle (HCNP) self-assembled from two porphyrin molecules, chlorin e6 and hemin, is developed. The as-constructed HCNPs exhibit a peroxidase-mimic catalytic activity, which can lead to the in situ generation of endogenous O2, thereby enhancing the efficacy of PDT. Furthermore, the generation of hydroxyl radicals (•OH) in the tumor environment in reaction to the high level of H2O2 and the simultaneous disruption of intracellular GSH endow the HCNPs with the capacity of enhanced CDT, resulting in a more effective therapeutic outcome in combination with PDT. More importantly, GSH depletion further leads to the inactivation of GSH peroxide 4 and induced ferroptosis. Both in vitro and in vivo results showed that the combination of PDT/CDT/ferroptosis realizes highest antitumor efficacy significantly under laser irradiation. Therefore, by integrating the superiorities of O2 and •OH generation capacity, GSH-depletion effect, and bioimaging into a single nanosystem, the HCNPs are a promising single therapeutic agent for tumor PDT/CDT/ferroptosis combination therapy.


Assuntos
Antineoplásicos/uso terapêutico , Hemina/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Catálise , Linhagem Celular Tumoral , Feminino , Ferroptose/efeitos dos fármacos , Glutationa/metabolismo , Hemina/química , Hemina/efeitos da radiação , Células Endoteliais da Veia Umbilical Humana , Humanos , Radical Hidroxila/metabolismo , Luz , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/efeitos da radiação , Oxigênio/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Porfirinas/química , Porfirinas/efeitos da radiação
6.
ACS Appl Mater Interfaces ; 13(26): 30274-30283, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34170100

RESUMO

In this work, an iron self-boosting polymer nanoenzyme was prepared by using pyrrole-3-carboxylic acid as a monomer and iron as an oxidizing agent via a simple and one-step method [hereafter referred to as FePPy nanoparticles (NPs)]. In fact, researchers previously paid negligible attention on the iron element during the polymerization reaction of polypyrrole, thus the intrinsically catalytic functions and enzymatic activities of the high iron content (wt %: 21.11%) are ignored and not fully explored. As expected, results demonstrate that the as-synthesized FePPy NPs can decompose H2O2 to generate hydroxyl radicals (•OH) which exhibit enzyme characteristics, further inducing a nonapoptotic ferroptosis pathway. Moreover, the nanoenzyme shows impressive photothermal properties which can accelerate the Fenton reactions to enhance ferroptosis. The combined photothermal and ferroptosis therapy of FePPy NPs was found to have high efficacy. With the properties of easy synthesis, high efficacy, and good biocompatibility, the FePPy NPs are considered as potential agents for cancer treatments.


Assuntos
Antineoplásicos/uso terapêutico , Ferroptose/efeitos dos fármacos , Nanoestruturas/uso terapêutico , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Ácidos Carboxílicos/química , Ácidos Carboxílicos/efeitos da radiação , Ácidos Carboxílicos/uso terapêutico , Catálise , Feminino , Células HeLa , Humanos , Peróxido de Hidrogênio/química , Radical Hidroxila/metabolismo , Ferro/química , Ferro/efeitos da radiação , Luz , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanoestruturas/química , Nanoestruturas/efeitos da radiação , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Terapia Fototérmica , Polímeros/química , Polímeros/efeitos da radiação , Polímeros/uso terapêutico , Pirróis/química , Pirróis/efeitos da radiação , Pirróis/uso terapêutico , Temperatura
7.
Nat Commun ; 12(1): 3393, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099712

RESUMO

The iron gall ink-triggered chemical corrosion of hand-written documents is a big threat to Western cultural heritages, which was demonstrated to result from the iron gall (GA-Fe) chelate-promoted reactive oxygen species generation. Such a phenomenon has inspired us to apply the pro-oxidative mechanism of GA-Fe to anticancer therapy. In this work, we construct a composite cancer nanomedicine by loading gallate into a Fe-engineered mesoporous silica nanocarrier, which can degrade in acidic tumor to release the doped Fe3+ and the loaded gallate, forming GA-Fe nanocomplex in situ. The nanocomplex with a highly reductive ligand field can promote oxygen reduction reactions generating hydrogen peroxide. Moreover, the resultant two-electron oxidation form of GA-Fe is an excellent Fenton-like agent that can catalyze hydrogen peroxide decomposition into hydroxyl radical, finally triggering severe oxidative damage to tumors. Such a therapeutic approach by intratumoral synthesis of GA-Fe nano-metalchelate may be instructive to future anticancer researches.


Assuntos
Antineoplásicos/administração & dosagem , Ácido Gálico/administração & dosagem , Ferro/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Catálise , Complexos de Coordenação/administração & dosagem , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Portadores de Fármacos/química , Feminino , Ácido Gálico/química , Ácido Gálico/metabolismo , Células HeLa , Células Endoteliais da Veia Umbilical Humana , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Concentração de Íons de Hidrogênio , Radical Hidroxila/química , Radical Hidroxila/metabolismo , Injeções Intravenosas , Ferro/química , Ferro/metabolismo , Ligantes , Nanopartículas Metálicas/química , Camundongos , Neoplasias/patologia , Oxirredução , Oxigênio/metabolismo , Dióxido de Silício/química , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Mar Drugs ; 19(5)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066101

RESUMO

Gracilariopsis lemaneiformis polysaccharides (GLP) were degraded using pectinase, glucoamylase, cellulase, xylanase, and ß-dextranase into low-molecular-weight polysaccharides, namely, GPP, GGP, GCP, GXP, and GDP, respectively, and their antioxidant capacities were investigated. The degraded GLP showed higher antioxidant activities than natural GLP, and GDP exhibited the highest antioxidant activity. After the optimization of degradation conditions through single-factor and orthogonal optimization experiments, four polysaccharide fractions (GDP1, GDP2, GDP3, and GDP4) with high antioxidant abilities (hydroxyl radical scavenging activity, DPPH radical scavenging activity, reduction capacity, and total antioxidant capacity) were obtained. Their cytoprotective activities against H2O2-induced oxidative damage in human fetal lung fibroblast 1 (HFL1) cells were examined. Results suggested that GDP pretreatment can significantly improve cell viability, reduce reactive oxygen species and malonaldehyde levels, improve antioxidant enzyme activity and mitochondria membrane potential, and alleviate oxidative damage in HFL1 cells. Thus, the enzyme degradation of GLP with ß-dextranase can significantly improve its antioxidant activity, and GDP might be a suitable source of natural antioxidants.


Assuntos
Antioxidantes/metabolismo , Antioxidantes/farmacologia , Polissacarídeos/metabolismo , Polissacarídeos/farmacologia , Rodófitas/química , Antioxidantes/análise , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Glicosídeo Hidrolases/metabolismo , Humanos , Peróxido de Hidrogênio/toxicidade , Hidrólise , Radical Hidroxila/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Peso Molecular , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/análise , Espécies Reativas de Oxigênio/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier
9.
Fish Physiol Biochem ; 47(4): 1073-1085, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34021418

RESUMO

In this study, substance P, an antioxidant peptide of tachykinin, was identified using bioinformatics tools from the earlier established muscle transcriptome of a freshwater murrel Channa striatus and the peptide was named RM12. The antioxidant properties of RM12 were screened using various colorimetric assays. The toxicity of RM12 was experimented using fish erythrocytes, and it is observed that the maximum concentration (320 µM) of RM12 was found to have 15 or 20% of hemolytic activity; however, it was not significant with other tested concentrations (10, 20, 40, 80, and 160 µM). Further, the in vivo antioxidant properties of RM12 were experimented on zebrafish embryo, the intracellular ROS level was estimated by 5 mM H2O2 stress in the zebrafish embryo, and inhibition of apoptosis was evaluated. The antioxidant enzymes were extracted from the H2O2-stressed zebrafish embryo, and the intracellular ROS was eliminated due to RM12. Collectively, the experiment showed that the substance P from the freshwater murrel C. striatus possessed potent antioxidant properties; thus, it can further be focused to develop it as antioxidant molecule in aquaculture organisms.


Assuntos
Antioxidantes/farmacologia , Eritrócitos/efeitos dos fármacos , Peixes/metabolismo , Substância P/farmacologia , Animais , Compostos de Bifenilo/metabolismo , Catalase/metabolismo , Embrião não Mamífero/metabolismo , Eritrócitos/metabolismo , Feminino , Peixes/embriologia , Água Doce , Hemólise/efeitos dos fármacos , Radical Hidroxila/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Picratos/metabolismo , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo
10.
J Biol Chem ; 297(1): 100826, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34044019

RESUMO

Binding of antibodies to their receptors is a core component of the innate immune system. Understanding the precise interactions between antibodies and their Fc receptors has led to the engineering of novel mAb biotherapeutics with tailored biological activities. One of the most significant findings is that afucosylated monoclonal antibodies demonstrate increased affinity toward the receptor FcγRIIIa, with a commensurate increase in antibody-dependent cellular cytotoxicity. Crystal structure analysis has led to the hypothesis that afucosylation in the Fc region results in reduced steric hindrance between antibody-receptor intermolecular glycan interactions, enhancing receptor affinity; however, solution-phase data have yet to corroborate this hypothesis. In addition, recent work has shown that the fragment antigen-binding (Fab) region may directly interact with Fc receptors; however, the biological consequences of these interactions remain unclear. By probing differences in solvent accessibility between native and afucosylated immunoglobulin G1 (IgG1) using hydroxyl radical footprinting-MS, we provide the first solution-phase evidence that an IgG1 bearing an afucosylated Fc region appears to require fewer conformational changes for FcγRIIIa binding. In addition, we performed extensive molecular dynamics (MD) simulations to understand the molecular mechanism behind the effects of afucosylation. The combination of these techniques provides molecular insight into the steric hindrance from the core Fc fucose in IgG1 and corroborates previously proposed Fab-receptor interactions. Furthermore, MD-guided rational mutagenesis enabled us to demonstrate that Fab-receptor interactions directly contribute to the modulation of antibody-dependent cellular cytotoxicity activity. This work demonstrates that in addition to Fc-polypeptide and glycan-mediated interactions, the Fab provides a third component that influences IgG-Fc receptor biology.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos/imunologia , Receptores Fc/metabolismo , Animais , Células CHO , Cricetulus , Análise Mutacional de DNA , Fucose/metabolismo , Glicosilação , Radical Hidroxila/metabolismo , Fragmentos Fab das Imunoglobulinas/metabolismo , Imunoglobulina G/química , Imunoglobulina G/metabolismo , Simulação de Dinâmica Molecular , Mutação/genética , Ligação Proteica , Conformação Proteica , Receptores Fc/química
11.
Biomed Pharmacother ; 140: 111680, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34020247

RESUMO

The great diversity of marine habitats and organisms renders them a high-value source to find/develop novel drugs and formulations. Therefore, herein, sardine (Sardina pilchardus) roe was used as a lipidic source to produce liposomes. This fish product presents high nutritional value, being its lipidic content associated with important health benefits. Consequently, it can be advantageously used to produce therapeutically active delivery devices. Roe lipids were extracted using the Matyash method. After lipid film hydration and extrusion, sardine roe-derived large unilamellar liposomes (LUVs), designated as fishroesomes, presented a size of ≈330 nm and a significant negative surface charge (≈-27 mV). Radical scavenging assays demonstrated that fishroesomes efficiently neutralized peroxyl, hydroxyl and nitric oxide radicals. Moreover, fishroesomes significantly reduced the expression of pro-inflammatory cytokines and chemokines by LPS-stimulated macrophages at non-toxic concentrations for L929 and THP-1 cells. Consequently, the developed liposomes exhibit unique properties as bioactive drug carriers for inflammatory diseases treatment.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Portadores de Fármacos/química , Lipossomos/química , Animais , Linhagem Celular , Quimiocinas/metabolismo , Citocinas/metabolismo , Humanos , Radical Hidroxila/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Células THP-1
12.
Chem Biol Interact ; 344: 109501, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33974898

RESUMO

The pandemic of SARS-CoV-2 stimulates significant efforts and approaches to understand its global spread. Although the recent introduction of the vaccine is a crucial prophylactic step, the effective treatment for SARS-CoV-2 is still undiscovered. An in-depth analysis of symptoms and clinical parameters, as well as molecular changes, is necessary to comprehend COVID-19 and propose a remedy for affected people to fight that disease. The analysis of available clinical data and SARS-CoV-2 infection markers underlined the main pathogenic process in COVID-19 is cytokine storm and inflammation. That led us to suggest that the most important pathogenic feature of SARS-CoV-2 leading to COVID-19 is oxidative stress and cellular damage stimulated by iron, a source of Fenton reaction and its product hydroxyl radical (•OH), the most reactive ROS with t1/2-10-9s. Therefore we suggest some scavenging agents are a reasonable choice for overcoming its toxic effect and can be regarded as a treatment for the disease on the molecular level.


Assuntos
COVID-19/metabolismo , COVID-19/prevenção & controle , Estresse Oxidativo/fisiologia , Pandemias/prevenção & controle , Síndrome da Liberação de Citocina/metabolismo , Citocinas/metabolismo , Humanos , Radical Hidroxila/metabolismo , Inflamação/metabolismo , Ferro/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo
13.
Angew Chem Int Ed Engl ; 60(32): 17570-17578, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34041833

RESUMO

The clinical application of chemodynamic therapy is impeded by the insufficient intracellular H2 O2 level in tumor tissues. Herein, we developed a supramolecular nanoparticle via a simple one-step supramolecular polymerization-induced self-assembly process using platinum (IV) complex-modified ß-cyclodextrin-ferrocene conjugates as supramolecular monomers. The supramolecular nanoparticles could dissociate rapidly upon exposure to endogenous H2 O2 in the tumor and release hydroxyl radicals as well as platinum (IV) prodrugs in situ, which is reduced into cisplatin to significantly promote the generation of H2 O2 in the tumor tissue. Thus, the supramolecular nanomedicine overcomes the limitation of conventional chemodynamic therapy via the self-augmented cascade radical generation and drug release. In addition, dissociated supramolecular nanoparticles could be readily excreted from the body via renal clearance to effectively avoid systemic toxicity and ensure long term biocompatibility of the nanomedicine. This work may provide new insights on the design and development of novel supramolecular nanoassemblies for cascade chemo/chemodynamic therapy.


Assuntos
Antineoplásicos/uso terapêutico , Portadores de Fármacos/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Polímeros/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Complexos de Coordenação/uso terapêutico , Complexos de Coordenação/toxicidade , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Feminino , Compostos Ferrosos/síntese química , Compostos Ferrosos/metabolismo , Compostos Ferrosos/uso terapêutico , Compostos Ferrosos/toxicidade , Peróxido de Hidrogênio/metabolismo , Radical Hidroxila/metabolismo , Metalocenos/síntese química , Metalocenos/metabolismo , Metalocenos/uso terapêutico , Metalocenos/toxicidade , Camundongos Endogâmicos BALB C , Nanomedicina/métodos , Nanopartículas/química , Nanopartículas/metabolismo , Nanopartículas/toxicidade , Platina/química , Polimerização , Polímeros/síntese química , Polímeros/metabolismo , Polímeros/toxicidade , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Pró-Fármacos/uso terapêutico , Pró-Fármacos/toxicidade , beta-Ciclodextrinas/síntese química , beta-Ciclodextrinas/metabolismo , beta-Ciclodextrinas/uso terapêutico , beta-Ciclodextrinas/toxicidade
14.
Biomolecules ; 11(3)2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809550

RESUMO

3,3'-diindolylmethane (DIM) belongs to a family of indole glucosinolate compounds that have been shown to improve Brassica napus growth through the modulation of reactive oxygen species when applied exogenously. The B. napus cultivar AV Garnet was previously identified as a vanadium-sensitive cultivar. Therefore, in this study we investigated whether exogenous DIM could improve the vanadium tolerance of AV Garnet. We performed the following experiments: seed germination assessment, dry weight assessment, cell viability assay, chlorophyll content assay, malondialdehyde (MDA) assay, conjugated diene (CD) content assay, hydrogen peroxide (H2O2) content assay, superoxide (O2-) content determination, methylglyoxal (MG) content determination, hydroxyl radical (·OH) concentration determination, ascorbate peroxidase (APX) activity assay, superoxide dismutase (SOD) activity assay, glyoxalase I (Gly I) activity assay, glutathione S-transferase (GST) activity assay and inductively coupled plasma optical emission spectroscopy (ICP-OES) analysis for vanadium content determination. Under vanadium stress, exogenous DIM increased the seed germination percentage, shoot dry weight, cell viability and chlorophyll content. Exogenous DIM also led to a decrease in MDA, CD, H2O2, O2-, MG and ·OH, under vanadium stress in the shoots. Furthermore, DIM application led to an increase in the enzymatic activities of APX, SOD, Gly I and GST under vanadium stress. Interestingly, under vanadium stress, DIM treatment did not alter vanadium content in B. napus shoots. Our results indicate that exogenous application of DIM can improve B. napus seedling shoot growth and biomass under vanadium stress by priming the antioxidant enzymes via reactive oxygen species (ROS) signaling.


Assuntos
Adaptação Fisiológica/efeitos dos fármacos , Antioxidantes/metabolismo , Brassica napus/enzimologia , Brassica napus/fisiologia , Indóis/farmacologia , Brotos de Planta/fisiologia , Plântula/fisiologia , Vanádio/toxicidade , Brassica napus/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Clorofila/metabolismo , Germinação/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Radical Hidroxila/metabolismo , Malondialdeído , Brotos de Planta/efeitos dos fármacos , Brotos de Planta/crescimento & desenvolvimento , Aldeído Pirúvico/metabolismo , Plântula/efeitos dos fármacos , Superóxidos/metabolismo
15.
Angew Chem Int Ed Engl ; 60(26): 14324-14328, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-33822451

RESUMO

Despite the great efforts of using DNAzyme for gene therapy, its clinical success is limited by the lack of simple delivery systems and limited anticancer efficacy. Here, we develop a simple approach for the synthesis of hybrid nanostructures that exclusively consist of DNAzyme and Cu2+ with ultra-high loading capacity. The Cu-DNAzyme nanohybrids allow to effectively co-deliver DNAzyme and Cu2+ into cancer cells for combinational catalytic therapy. The released Cu2+ can be reduced to Cu+ by glutathione and then catalyze endogenous H2 O2 to form cytotoxic hydroxyl radicals for chemodynamic therapy (CDT), while the 10-23 DNAzyme enables the catalytic cleavage of VEGFR2 mRNA and activates gene silencing for gene therapy. We demonstrate that the system can efficiently accumulate in the tumor and exhibit amplified cascade antitumor effects with negligible systemic toxicity. Our work paves an extremely simple way to integrate DNAzyme with CDT for the dual-catalytic tumor treatment.


Assuntos
Antineoplásicos/uso terapêutico , Cobre/metabolismo , DNA Catalítico/metabolismo , Radical Hidroxila/uso terapêutico , Nanoestruturas/química , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Antineoplásicos/química , Antineoplásicos/metabolismo , Cobre/química , DNA Catalítico/química , Humanos , Radical Hidroxila/química , Radical Hidroxila/metabolismo , Neoplasias/metabolismo
16.
J Pharmacol Sci ; 146(1): 29-32, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33858652

RESUMO

Hydroxyl radical (•OH) production in the rat striatum during carbon monoxide (CO) poisoning, which inhibits complex IV, was enhanced synergistically by malonate, a mitochondrial complex II inhibitor, but not N-methyl-4-phenylpyridinium or NaCN, complex I and IV inhibitors, respectively. No such enhancement appeared in the case of NaCN combined with malonate. Intrastriatal dopamine, which is involved in •OH production by malonate, did not synergistically enhance CO-induced •OH production. Diphenyleneiodonium, a nonselective NADPH oxidase inhibitor, partly suppressed the potentiation of CO-induced •OH production by malonate. Impairment of mitochondrial functions might potentiate oxidative stress and intensify CO toxicity in the brain.


Assuntos
Intoxicação por Monóxido de Carbono/metabolismo , Corpo Estriado/metabolismo , Radical Hidroxila/metabolismo , Animais , Complexo IV da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Masculino , Malonatos/farmacologia , Mitocôndrias/metabolismo , NADPH Oxidases/antagonistas & inibidores , Oniocompostos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley
17.
Bioorg Med Chem Lett ; 40: 127922, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33705910

RESUMO

A ferrocene-substituted thiobarbituric acid (FT) has been synthesized to explore its photophysical properties and photodynamic and photoantimicrobial chemotherapy activities. FT has an intense metal-to-ligand charge transfer (MLCT) band at ca. 575 nm. The ferrocene moiety of FT undergoes photooxidation to form a ferrocenium species which in turn produces hydroxyl radical in an aqueous environment, which was confirmed via the bleaching reaction of p-nitrosodimethylaniline (RNO). FT exhibits efficient PDT activity against MCF-7 cancer cells with an IC50 value of 5.6 µM upon irradiation with 595 nm for 30 min with a Thorlabs M595L3 LED (240 mW cm-2). Photodynamic inactivation of Staphylococcus aureus and Escherichia coli by FT shows significant activity with log reduction values of 6.62 and 6.16 respectively, under illumination for 60 min at 595 nm. These results demonstrate that ferrocene-substituted thiobarbituric acids merit further study for developing novel bioorganometallic PDT agents.


Assuntos
Antibacterianos/farmacologia , Compostos Ferrosos/farmacologia , Metalocenos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Tiobarbitúricos/farmacologia , Antibacterianos/química , Antibacterianos/efeitos da radiação , Escherichia coli/efeitos dos fármacos , Compostos Ferrosos/química , Compostos Ferrosos/efeitos da radiação , História Medieval , Humanos , Radical Hidroxila/metabolismo , Luz , Células MCF-7 , Metalocenos/química , Metalocenos/efeitos da radiação , Testes de Sensibilidade Microbiana , Oxirredução/efeitos da radiação , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Staphylococcus aureus/efeitos dos fármacos , Tiobarbitúricos/química , Tiobarbitúricos/efeitos da radiação
18.
Life Sci ; 275: 119361, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33774022

RESUMO

AIMS: Indole-3-carbinol (I3C) is a natural compound derived from brassica vegetables, displaying antibacterial activity. The study aims to elucidate the antibacterial mode of action(s) induced by indole-3-carbionol in Escherichia coli and enhance the understandings on the respective contribution of each reactive oxygen species (ROS), superoxide anion (O2-), hydrogen peroxide (H2O2), hydroxyl radical (OH-) during the process. MAIN METHODS: The antibacterial activity of I3C was assessed through kinetic assay. The generation of ROS was measured by flow cytometer using H2DCFDA dye, while further analysis of respective contribution was done through application of each scavenger: tiron, thiourea and sodium pyruvate. DNA fragmentation and chromatin condensation were observed by TUNEL and DAPI staining agent. Finally, Annexin V/PI, FITC-VAD-FMK and DiBAC4(3) was applied for detection of apoptosis-like death. KEY FINDINGS: I3C exhibited antibacterial activity in E. coli through accumulation of ROS and DNA damage, eventually leading to apoptosis-like death. Contribution of each ROS displayed respective manner, OH- exerting the most potent influence whereas O2- showed least impact. SIGNIFICANCE: Our study is the first to link I3C to the bacterial apoptosis-like death and displays the potential of this agent as a candidate for potential drugs that could help regulating the E. coli, an opportunistic human pathogen. Moreover, the study focused on investigating the individual contribution of each ROS during the process, trying to enhance the understanding regarding ROS and cellular processes followed by oxidative stress in bacteria.


Assuntos
Antibacterianos/farmacologia , Apoptose/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Indóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Cromatina/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Escherichia coli/metabolismo , Peróxido de Hidrogênio/metabolismo , Radical Hidroxila/metabolismo , Oxigênio Singlete/metabolismo
19.
J Photochem Photobiol B ; 216: 112112, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33524930

RESUMO

For the first time, using sturgeon sperm as a model system, sensitive to optical radiation, the comparative studies of biological effect of continuous wave, quasi-continuous wave, nano- and picosecond laser radiation under conditions with equal average irradiance (3 mW/cm2) and wavelength (532 nm) have been carried out. Analyzing the parameters of spermatozoa motion it has been shown that, depending on the energy dose and mode of laser operation, the radiation may have both stimulatory and inhibitory effect on the velocity of motion and spermatozoa motility duration as well as on sustaining of functional characteristics of cold-stored sperm. The possibility of increasing the fertilization rate due to use of the sperm preliminary treated with laser radiation is demonstrated. For the first time, the possibility of enhancement of biological effect going from continuous wave to quasi-continuous wave laser radiation at equal irradiance and wavelength has experimentally been proven. It is shown that the difference in biological effect of continuous wave, quasi-continuous wave, nano- and picosecond laser radiation is due to amplitude (peak) values of intensity. Using fluorescence analysis and luminol-dependent chemiluminescence assay, evidence for the participation of endogenous flavins and metal-free porphyrins in sensitized ROS formation (singlet oxygen, hydrogen peroxide, and hydroxyl radicals) in sturgeon sperm was obtained. Mechanisms of photochemical and photothermal reactions explaining the difference in efficacy of action of laser radiation in above modes are discussed.


Assuntos
Fertilização/efeitos da radiação , Fármacos Fotossensibilizantes/química , Espermatozoides/efeitos da radiação , Animais , Cordados , Relação Dose-Resposta à Radiação , Flavinas/química , Flavinas/metabolismo , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Radical Hidroxila/química , Radical Hidroxila/metabolismo , Lasers , Medições Luminescentes , Masculino , Processos Fotoquímicos , Porfirinas/química , Porfirinas/metabolismo , Espécies Reativas de Oxigênio/química , Espécies Reativas de Oxigênio/metabolismo , Motilidade Espermática/efeitos da radiação , Nanomedicina Teranóstica
20.
Theranostics ; 11(1): 64-78, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391461

RESUMO

Background: Conventional therapeutic strategies for advanced hepatocellular carcinoma (HCC) remains a great challenge, therefore the alternative therapeutic modality for specific and efficient HCC suppression is urgently needed. Methods: In this work, HCC-derived extracellular vesicles (EVs) were applied as surface nanocarrier for sequential nanocatalysts GOD-ESIONs@EVs (GE@EVs) of tumor-specific and cascade nanocatalytic therapy against HCC. By enhancing the intracellular endocytosis through arginine-glycine-aspartic acid (RGD)-targeting effect and membrane fusion, sequential nanocatalysts led to more efficient treatment in the HCC tumor region in a shorter period of time. Results: Through glucose consumption as catalyzed by the loaded glucose oxidase (GOD) to overproduce hydrogen peroxide (H2O2), highly toxic hydroxyl radicals were generated by Fenton-like reaction as catalyzed by ESIONs, which was achieved under the mildly acidic tumor microenvironment, enabling the stimuli of the apoptosis and necrosis of HCC cells. This strategy demonstrated the high active-targeting capability of GE@EVs into HCC, achieving highly efficient tumor suppression both in vitro and in vivo. In addition, the as-synthesized nanoreactor could act as a desirable nanoscale contrast agent for magnetic resonance imaging, which exhibited desirable imaging capability during the sequential nanocatalytic treatment. Conclusion: This application of surface-engineering EVs not only proves the high-performance catalytic therapeutic modality of GE@EVs for HCC, but also broadens the versatile bio-applications of EVs.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Vesículas Extracelulares/metabolismo , Glucose Oxidase/administração & dosagem , Peróxido de Hidrogênio/metabolismo , Radical Hidroxila/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas Magnéticas de Óxido de Ferro/administração & dosagem , Animais , Catálise , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos , Vesículas Extracelulares/ultraestrutura , Feminino , Humanos , Imageamento por Ressonância Magnética , Camundongos , Camundongos Nus , Transplante de Neoplasias , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/efeitos dos fármacos
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