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1.
PLoS One ; 15(6): e0234435, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574221

RESUMO

This study was designed to investigate the antioxidant properties of the extracts and subfractions of various polarities from Clerodendrum cyrtophyllum Turcz leaves and the related phenolic compound profiles. The ethyl acetate fraction (EAF) showed the most potent radical-scavenging activity for DPPH radicals, ABTS radicals, and superoxide anion (O2·-) radicals as well as the highest reducing power of the fractions tested; the n-butyl alcohol fraction (BAF) was the most effective in scavenging hydroxyl radical (OH·), and the dichloromethane fraction (DMF) exhibited the highest ferrous ion chelating activity. Twelve phenolic components were identified from the EAF of C. cyrtophyllum. Additionally, acteoside (1) was found to be a major component (0.803 g, 0.54%) and show DPPH and ABTS radical scavenging activities with IC50 values of 79.65±3.4 and 23.00±1.5 µg/ml, indicating it is principally responsible for the significant total antioxidant effect of C. cyrtophyllum. Our work offers a theoretical basis for further utilization of C. cyrtophyllum as a potential source of natural, green antioxidants derived from plants.


Assuntos
Antioxidantes/farmacologia , Clerodendrum/química , Glucosídeos/farmacologia , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Antioxidantes/análise , Antioxidantes/isolamento & purificação , Glucosídeos/análise , Glucosídeos/isolamento & purificação , Radical Hidroxila/metabolismo , Fenóis/análise , Fenóis/isolamento & purificação , Extratos Vegetais/análise , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Superóxidos/metabolismo
2.
PLoS One ; 15(4): e0227582, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32302306

RESUMO

Molecular hydrogen is thought to have an inhibitory effect on oxidative stress, thereby attenuating the onset and progression of various diseases including cardiovascular disease; however, few reports have assessed the preventive effect of constitutive inhalation of hydrogen gas on of vascular remodeling. Here, we investigated the effect of constitutive inhalation of hydrogen gas on vascular neointima formation using a cuff-induced vascular injury mouse model. After constitutive inhalation of compressed hydrogen gas (O2 21%, N2 77.7%, hydrogen 1.3%) or compressed air only (O2 21%, N2 79%) by C57BL/6 mice for 2 weeks from 8 weeks of age in a closed chamber, inflammatory cuff injury was induced by polyethylene cuff placement around the femoral artery under anesthesia, and hydrogen gas administration was continued until sampling of the femoral artery. Neointima formation, accompanied by an increase in cell proliferation, was significantly attenuated in the hydrogen group compared with the control group. NADPH oxidase NOX1 downregulation in response to cuff injury was shown in the hydrogen group, but the expression levels of NADPH oxidase subunits, p40phox and p47phox, did not differ significantly between the hydrogen and control groups. Although the increase in superoxide anion production did not significantly differ between the hydrogen and control groups, DNA damage was decreased as a result of reduction of reactive oxygen species such as hydroxyl radical (⋅OH) and peroxynitrite (ONOO-) in the hydrogen group. These results demonstrate that constitutive inhalation of hydrogen gas attenuates vascular remodeling partly via reduction of oxidative stress, suggesting that constitutive inhalation of hydrogen gas at a safe concentration in the living environment could be an effective strategy for prevention of vascular diseases such as atherosclerosis.


Assuntos
Hidrogênio/administração & dosagem , Isquemia Miocárdica/prevenção & controle , Neointima/prevenção & controle , Remodelação Vascular/efeitos dos fármacos , Lesões do Sistema Vascular/complicações , Administração por Inalação , Animais , Dano ao DNA/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Gases/administração & dosagem , Gases/química , Humanos , Radical Hidroxila/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Isquemia Miocárdica/patologia , NADPH Oxidase 1/metabolismo , Neointima/etiologia , Neointima/patologia , Nitrogênio/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/administração & dosagem , Ácido Peroxinitroso/metabolismo
3.
Adv Mater ; 32(12): e1907152, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32053261

RESUMO

Nanocatalytic medicine has been developed recently to trigger intratumoral generation of highly toxic reactive oxygen species (ROS) for cancer therapy, which, unfortunately, suffers from compromised therapeutic efficacy due to a self-protective mechanism, autophagy, of cancer cells to mitigate oxidative damage. In this work, during the efforts of ROS generation by nanocatalytic medicine, a pharmacological autophagy inhibition strategy is implemented for augmenting ROS-induced oxidative damage for synergetic cancer therapy. An iron-containing metal-organic framework [MOF(Fe)] nanocatalyst as a peroxidase mimic is used to catalyze the generation of highly oxidizing •OH radicals specifically within cancer cells, while chloroquine is applied to deacidify lysosomes and inhibit autophagy, cutting off the self-protection pathway under severe oxidative stress. Cancer cells fail to extract their components to detoxicate and strengthen themselves, finally succumbing to the ROS-induced oxidative damage during nanocatalytic therapy. Both in vitro and in vivo results demonstrate the synergy between nanocatalytic therapy and autophagy inhibition, suggesting that such a combined strategy is applicable to amplify tumor-specific oxidative damage and may be informative to future design of therapeutic regimen.


Assuntos
Autofagia/efeitos dos fármacos , Cloroquina/farmacologia , Estruturas Metalorgânicas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Catálise , Linhagem Celular Tumoral , Cloroquina/química , Cloroquina/uso terapêutico , Sinergismo Farmacológico , Feminino , Humanos , Peróxido de Hidrogênio/química , Radical Hidroxila/química , Radical Hidroxila/metabolismo , Radical Hidroxila/farmacologia , Ferro/química , Estimativa de Kaplan-Meier , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/uso terapêutico , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Neoplasias/patologia , Estresse Oxidativo , Transplante Heterólogo
4.
Sci Rep ; 10(1): 2602, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054947

RESUMO

Oxidative stress has been suggested to play a role in brain damage during carbon monoxide (CO) poisoning. Severe poisoning induced by CO at 3000 ppm, but not 1000 ppm, enhances hydroxyl radical (˙OH) production in the rat striatum, which might be mediated by NADPH oxidase (NOX) activation associated with Ras-related C3 botulinum toxin substrate (Rac) via cAMP signaling pathway activation. CO-induced ˙OH production was suppressed by antagonists of angiotensin II (AngII) type 1 receptor (AT1R) and type 2 receptor (AT2R) but not an antagonist of the Mas receptor. Suppression by an AT1R antagonist was unrelated to peroxisome proliferator-activated receptor γ. Angiotensin-converting enzyme inhibitors also suppressed CO-induced ˙OH production. Intrastriatal AngII at high concentrations enhanced ˙OH production. However, the enhancement of ˙OH production was resistant to inhibitors selective for NOX and Rac and to AT1R and AT2R antagonists. This indicates a different mechanism for ˙OH production induced by AngII than for that induced by CO poisoning. AT1R and AT2R antagonists had no significant effects on CO-induced cAMP production or ˙OH production induced by forskolin, which stimulates cAMP production. These findings suggest that the renin-angiotensin system might be involved in CO-induced ˙OH production in a manner independent of cAMP signaling pathways.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Bloqueadores do Receptor Tipo 2 de Angiotensina II/uso terapêutico , Intoxicação por Monóxido de Carbono/tratamento farmacológico , Corpo Estriado/efeitos dos fármacos , Radical Hidroxila/antagonistas & inibidores , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Intoxicação por Monóxido de Carbono/metabolismo , Corpo Estriado/metabolismo , Radical Hidroxila/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo
5.
Sci Rep ; 10(1): 1588, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005913

RESUMO

Rhythms in the pseudo-steady state (PSS) levels of reactive species (RS), particularly superoxide and hydroxyl radicals, exist in cancer cells. The RS rhythm characteristics, particularly frequency and amplitude, are entrained (reset) by the anticancer compounds/drugs. In this work, we show for the first time that the phase of the RS rhythm at which the drug is added is significantly important in determining the cytotoxicity of anticancer compounds/drugs such as menadione and curcumin, in two different cancer cell lines. Curcumin, the more effective of the two drugs (IC50 = 15 µM, SiHa; 6 µM, HCT116) induced reset of superoxide and hydroxyl rhythms from 15.4 h to 9 h, and 25 h to 11 h respectively, as well as caused increases in these radical levels. However, menadione (IC50 = 20 µM, SiHa; 17 µM, HCT116) affected only the superoxide levels. Drug treatment at different time points/phase of the RS rhythm resulted in a maximum of 27% increase in cytotoxicity, which is significant. Further, we report for the first time, an unexpected absence of a correlation between the intracellular PSS RS and antioxidant levels; thus, the practice of using antioxidant enzyme levels as surrogate markers of intracellular oxidative stress levels may need a re-consideration. Therefore, the RS rhythm could be a fundamental/generic target to manipulate for improved cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Curcumina/uso terapêutico , Neoplasias/tratamento farmacológico , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Vitamina K 3/uso terapêutico , Antioxidantes/metabolismo , Linhagem Celular Tumoral , Células HCT116 , Humanos , Radical Hidroxila/metabolismo , Neoplasias/metabolismo , Superóxidos/metabolismo
6.
Inorg Chem ; 59(6): 3919-3933, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32096986

RESUMO

We report the synthesis and photochemical and biological characterization of Ru(II) complexes containing π-expansive ligands derived from dimethylbenzo[i]dipyrido[3,2-a:2',3'-c]phenazine (Me2dppn) adorned with flanking aryl substituents. Late-stage Suzuki couplings produced Me2dppn ligands substituted at the 10 and 15 positions with phenyl (5), 2,4-dimethylphenyl (6), and 2,4-dimethoxyphenyl (7) groups. Complexes of the general formula [Ru(tpy)(L)(py)](PF6)2 (8-10), where L = 4-7, were characterized and shown to have dual photochemotherapeutic (PCT) and photodynamic therapy (PDT) behavior. Quantum yields for photodissociation of monodentate pyridines from 8-10 were about 3 times higher than that of parent complex [Ru(tpy)(Me2dppn)(py)](PF6)2 (1), whereas quantum yields for singlet oxygen (1O2) production were ∼10% lower than that of 1. Transient absorption spectroscopy indicates that 8-10 possess long excited state lifetimes (τ = 46-50 µs), consistent with efficient 1O2 production through population and subsequent decay of ligand-centered 3ππ* excited states. Complexes 8-10 displayed greater lipophilicity relative to 1 and association to DNA but do not intercalate between the duplex base pairs. Complexes 1 and 8-10 showed photoactivated toxicity in breast and prostate cancer cell lines with phototherapeutic indexes, PIs, as high as >56, where the majority of cell death was achieved 4 h after treatment with Ru(II) complexes and light. Flow cytometric data and rescue experiments were consistent with necrotic cell death mediated by the production of reactive oxygen species, especially 1O2. Collectively, this study confirms that DNA intercalation by Ru(II) complexes with π-expansive ligands is not required to achieve photoactivated cell death.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/efeitos da radiação , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Complexos de Coordenação/efeitos da radiação , DNA/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Radical Hidroxila/metabolismo , Ligantes , Luz , Necrose/induzido quimicamente , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/efeitos da radiação , Rutênio/química , Oxigênio Singlete/metabolismo
7.
Molecules ; 25(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31906260

RESUMO

Yam yellow pigments (YP) are natural pigments formed during the storage of freshly cut yam (Dioscorea opposita) under certain conditions. The interaction of YP with calf thymus DNA (ctDNA) and its protective effect against DNA oxidative damage were investigated using multiple spectroscopic techniques, competitive binding experiments, viscosity measurements, and gel electrophoresis. Results showed that YP participated in intercalative binding with ctDNA. YP exhibited a protective effect against hydroxyl-induced DNA damage, which was attributed to the high hydroxyl radical scavenging activity of YP. Our findings improve our understanding of the mechanism of interaction between YP and ctDNA, and provide a theoretical basis for the application of YP in the food and drug industry.


Assuntos
Dioscorea/química , Depuradores de Radicais Livres/química , Radical Hidroxila/química , Pigmentos Biológicos/química , Ligação Competitiva , DNA/química , DNA/metabolismo , Dano ao DNA , Dioscorea/metabolismo , Radical Hidroxila/metabolismo , Cinética , Pigmentos Biológicos/isolamento & purificação , Pigmentos Biológicos/metabolismo , Espectrometria de Fluorescência
8.
ACS Appl Mater Interfaces ; 12(5): 5624-5632, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31918542

RESUMO

The aggregation of hydrophobic photosensitizers limits the therapeutic effect of photodynamic therapy (PDT). Improving the hydrophilicity of photosensitizers can reduce their aggregation for enhancing PDT. Herein, a nanosystem (TPFcNP) is developed by a hydrophobic photosensitizer 5,10,15,20-tetrakis(4-methacryloyloxyphenyl)porphyrin (TMPP) containing multiple carbon-carbon double bonds and a ferrocene-containing amphiphilic block copolymer (PEG-b-PMAEFc), which catalyzes hydrogen peroxide (H2O2) to produce hydroxyl radicals (•OH) in a tumor microenvironment by the Fenton reaction. The •OH could catalyze the addition reaction between the carbon-carbon double bonds of TMPP and overexpressed water-soluble glutathione (GSH) in tumor cells, which greatly improves the hydrophilicity of photosensitizers and reduces their aggregation. Experiments in vitro and in vivo have proved that this strategy significantly enhances the therapeutic efficacy of PDT. Catalyzing intracellular reactions in situ by making use of the tumor microenvironment will open up a new opportunity to solve the aggregation of materials in the tumor for cancer treatment.


Assuntos
Peróxido de Hidrogênio/química , Radical Hidroxila/química , Fármacos Fotossensibilizantes/química , Animais , Catálise , Linhagem Celular Tumoral , Feminino , Compostos Ferrosos/química , Glutationa/química , Glutationa/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Radical Hidroxila/metabolismo , Metalocenos/química , Camundongos , Camundongos Endogâmicos BALB C , Nanoestruturas/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Polímeros/química , Porfirinas/química , Transplante Heterólogo
9.
Adv Mater ; 32(8): e1905994, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31930751

RESUMO

The intrinsic deficiencies of nanoparticle-initiated catalysis for biomedical applications promote the fast development of alternative versatile theranostic modalities. The catalytic performance and selectivity are the critical issues that are challenging to be augmented and optimized in biological conditions. Single-atom catalysts (SACs) featuring atomically dispersed single metal atoms have emerged as one of the most explored catalysts in biomedicine recently due to their preeminent catalytic activity and superior selectivity distinct from their nanosized counterparts. Herein, an overview of the pivotal significance of SACs and some underlying critical issues that need to be addressed is provided, with a specific focus on their versatile biomedical applications. Their fabrication strategies, surface engineering, and structural characterizations are discussed briefly. In particular, the catalytic performance of SACs in triggering some representative catalytic reactions for providing the fundamentals of biomedical use is discussed. A sequence of representative paradigms is summarized on the successful construction of SACs for varied biomedical applications (e.g., cancer treatment, wound disinfection, biosensing, and oxidative-stress cytoprotection) with an emphasis on uncovering the intrinsic catalytic mechanisms and understanding the underlying structure-performance relationships. Finally, opportunities and challenges faced in the future development of SACs-triggered catalysis for biomedical use are discussed and outlooked.


Assuntos
Nanopartículas/química , Animais , Apoptose/efeitos dos fármacos , Técnicas Biossensoriais , Catálise , Humanos , Peróxido de Hidrogênio/análise , Peróxido de Hidrogênio/química , Radical Hidroxila/química , Radical Hidroxila/metabolismo , Radical Hidroxila/farmacologia , Metais/química , Neoplasias/patologia , Neoplasias/terapia
10.
Food Chem Toxicol ; 135: 110888, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31629789

RESUMO

Glyphosate is used for cereal, vegetable and fruit crops for reducing or inhibiting the growth of weeds as well as a desiccant for various grain crops. That is why, glyphosate has been shown to be accumulated in humans and animals through ingestion of food of both plant and animal origin. The study aimed to assessed the effect of glyphosate, its metabolites: aminomethylphosphonic acid (AMPA), methylphosphonic acid and its impurities: PMIDA, N-methylglyphosate, hydroxymethylphosphonic acid and bis(phosphonomethyl)amine on apoptosis induction in human peripheral blood mononuclear cells (PBMCs). PBMCs were exposed to the compounds studied at the concentrations ranging from 0.01 to 5 mM for 4 h. We have observed an increase in reactive oxygen species (including hydroxyl radical) and cytosolic calcium ions levels as well as reduction of transmembrane mitochondrial potential (ΔΨm) in PBMCs exposed to the compounds examined. All substances studied changed PBMCs membrane permeability, activated caspase-8, -9, -3 and caused chromatin condensation, which showed that they were capable of inducing apoptosis both via extrinsic and particularly intrinsic pathway. Generally the study demonstrated that there were no differences between apoptotic changes induced by glyphosate, its metabolites or impurities, and observed changes were provoked by high concentrations of investigated compounds.


Assuntos
Apoptose/efeitos dos fármacos , Glicina/análogos & derivados , Herbicidas/toxicidade , Monócitos/efeitos dos fármacos , Cálcio/sangue , Caspases/metabolismo , Cromatina/metabolismo , Ativação Enzimática , Glicina/metabolismo , Glicina/toxicidade , Herbicidas/metabolismo , Humanos , Radical Hidroxila/metabolismo , Técnicas In Vitro , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Monócitos/metabolismo , Espécies Reativas de Oxigênio/metabolismo
11.
J Stroke Cerebrovasc Dis ; 29(3): 104531, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31882337

RESUMO

BACKGROUND: The purpose of this study was to investigate the effects of edaravone on nitric oxide (NO) production, hydroxyl radical (OH-) metabolism, and neuronal nitric oxide synthase (nNOS) expression during cerebral ischemia and reperfusion. METHODS: Edaravone (3 mg/kg) was administered intravenously to 14 C57BL/6 mice just before reperfusion. Eleven additional mice received saline (controls). NO production and OH- metabolism were continuously monitored using bilateral striatal in vivo microdialysis. OH- formation was monitored using the salicylate trapping method. Forebrain ischemia was produced in all mice by bilateral occlusion of the common carotid artery for 10 minutes. Levels of NO metabolites, nitrite (NO2-) and nitrate (NO3-), were determined using the Griess reaction. Brain sections were immunostained with an anti-nNOS antibody and the fractional area density of nNOS-immunoreactive pixels to total pixels determined. RESULTS: Blood pressure and regional cerebral blood flow were not significantly different between the edaravone and control groups. The levels of NO2- did not differ significantly between the 2 groups. The level of NO3- was significantly higher in the edaravone group compared with the control group after reperfusion. 2,3-dihydroxybenzoic acid levels were lower in the edaravone group compared with those in the control group after reperfusion. Immunohistochemistry showed nNOS expression in the edaravone group to be significantly lower than that in the control group 96 hours after reperfusion. CONCLUSIONS: These in vivo data indicate that edaravone may have a neuroprotective effect by reducing levels of OH- metabolites, increasing NO production and decreasing nNOS expression in brain cells.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Edaravone/farmacologia , Depuradores de Radicais Livres/farmacologia , Radical Hidroxila/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Animais , Encéfalo/enzimologia , Encéfalo/patologia , Isquemia Encefálica/enzimologia , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Neurônios/enzimologia , Neurônios/patologia , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Fatores de Tempo
12.
Molecules ; 24(23)2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31783535

RESUMO

The beneficial effects of polyphenols, predominantly in the context of oxidative stress-related diseases such as cancer, cardiovascular diseases and neurological conditions including Alzheimer's and Parkinson's diseases, have been documented by a number of papers and reviews. The antioxidant/prooxidant properties of phenolic compounds are related mainly to the number and positions of hydroxyl groups and to their redox metal (Cu, Fe) chelating capacity. In this work we studied structurally distinct phenolic molecules such as myricetin, morin, 3',4'-dihydroxy-flavone, taxifolin and 4-hydroxycoumarin, either alone or as interacting with Cu2+ ions. EPR and UV-Vis spectroscopy confirmed that the effective binding of cupric ions to phenolic compounds requires the presence of the 3-OH and 4-CO groups on the flavonoid C ring and unsaturated C2-C3 bond of the C-ring, which permits through-conjugation with the B-ring. An ABTS assay revealed that radical scavenging activities of phenolic compounds are related to their number of hydroxyl groups, planarity of the molecular skeleton, extent of delocalization and they decrease in the order: myricetin > morin > 3',4'-dihydroxyflavone ~ 4-hydroxy coumarin > taxifolin. Absorption titrations indicate that copper ions can modulate the DNA binding affinity of flavonoids via the formation of their Cu-chelates. Gel electrophoresis measurements indicated that the protective effect of the phenolic compounds decreases in the order: 3',4'-dihydroxyflavone > 4-OH coumarin > morin > taxifolin ~ myricetin. This can be explained by the fact that myricetin, taxifolin and morin form stable Cu(II) complexes capable of causing DNA damage via interaction with DNA and ROS formation via the Fenton reaction. Application of ROS scavengers revealed the formation of singlet oxygen, superoxide and hydroxyl radicals and their concerted synergistic effect on the DNA. The overall results suggest that the most pronounced DNA damage has been observed for flavonoids containing higher number of hydroxyl groups (including 3-OH group of the C ring), such as myricetin (six hydroxyl groups), morin and taxifolin (five hydroxyl groups) in the presence of Cu(II) ions. The proposed mechanism of action by which Cu(II) complexes of myricetin, morin and taxifolin interact with DNA predispose these substances to act as potential anticancer agents. The anticancer activity of phenolic compounds can be explained by their moderate prooxidant properties, which can boost ROS formation and kill cancer cells. Alternatively, slight prooxidant properties may activate antioxidant systems, including antioxidant enzymes and low molecular antioxidants such as glutathione and thus act as preventive anticancer agents.


Assuntos
Antioxidantes/química , Cobre/química , Dano ao DNA/efeitos dos fármacos , Flavonoides/química , Flavonoides/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Quelantes/farmacologia , Cobre/metabolismo , Cumarínicos/química , Cumarínicos/farmacologia , Espectroscopia de Ressonância de Spin Eletrônica , Humanos , Radical Hidroxila/química , Radical Hidroxila/metabolismo , Íons/química , Íons/metabolismo , Espectroscopia Fotoeletrônica , Polifenóis/química , Polifenóis/farmacologia , Quercetina/análogos & derivados , Quercetina/química , Quercetina/farmacologia , Espécies Reativas de Oxigênio/metabolismo
13.
Pak J Pharm Sci ; 32(5): 1949-1956, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31813857

RESUMO

The caryopses (seeds) of Echinochloa colona Link of family Poaceae are traditionally used for the treatment of jaundice. The methanolic extract of caryopses of Echinochloa colona (ECME) was evaluated for its hepatoprotective activity in paracetamol (3g/kg per oral) and ethanol (5g/kg per oral) intoxicated rats while its antihepatotoxic activity against D-galactosamine (400mg/kg body weight intra peritoneal). The activity of the extract was assessed on the basis of improvement in the altered level of various serum biochemical parameters and in the changes occurred in the histology of liver of the rats. The extract was also investigated for its antioxidant potential by employing different in vitro methods. The extract exhibited ferrous ion reducing power, 1,1 Diphenyl-1-picryl hydrazyl (DPPH), superoxide, nitric oxide and hydroxyl radical scavenging activities. The significant (p<0.001) hepatoprotective and antioxidant activities exhibited by the extract ECME, in different in vivo models and in vitro studies respectively may be attributed to the flavonoids and phenolic compounds present in the extract.


Assuntos
Echinochloa/química , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Sementes/química , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Compostos de Bifenilo/farmacologia , Flavonoides/farmacologia , Galactosamina/farmacologia , Radical Hidroxila/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Metanol/química , Óxido Nítrico/metabolismo , Fenóis/farmacologia , Picratos/farmacologia , Extratos Vegetais/química , Folhas de Planta/química , Substâncias Protetoras/química , Ratos , Superóxidos/metabolismo
14.
Molecules ; 24(23)2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31779066

RESUMO

Herein, we report the synthesis, characterisation, X-ray crystallography, and oxidative DNA binding interactions of the copper artificial metallo-nuclease [Cu(DPQ)2(NO3)](NO3), where DPQ = dipyrido[3,2-f:2',3'-h]quinoxaline. The cation [Cu(DPQ)2]2+ (Cu-DPQ), is a high-affinity binder of duplex DNA and presents an intercalative profile in topoisomerase unwinding and viscosity experiments. Artificial metallo-nuclease activity occurs in the absence of exogenous reductant but is greatly enhanced by the presence of the reductant Na-L-ascorbate. Mechanistically, oxidative DNA damage occurs in the minor groove, is mediated aerobically by the Cu(I) complex and is dependent on both superoxide and hydroxyl radical generation. To corroborate cleavage at the minor groove, DNA oxidation of a cytosine-guanine (5'-CCGG-3')-rich oligomer was examined in tandem with a 5-methylcytosine (5'-C5mCGG-3') derivative where 5mC served to sterically block the major groove and direct damage to the minor groove. Overall, both the DNA binding affinity and cleavage mechanism of Cu-DPQ depart from Sigman's reagent [Cu(1,10-phenanthroline)2]2+; however, both complexes are potent oxidants of the minor groove.


Assuntos
Cobre/farmacologia , Clivagem do DNA/efeitos dos fármacos , DNA/metabolismo , Desoxirribonucleases/metabolismo , Compostos Organometálicos/farmacologia , Quinoxalinas/farmacologia , Superóxidos/metabolismo , Cristalografia por Raios X/métodos , Citosina/metabolismo , Dano ao DNA/efeitos dos fármacos , Guanina/metabolismo , Radical Hidroxila/metabolismo , Substâncias Intercalantes/farmacologia , Oxirredução/efeitos dos fármacos
15.
Mar Drugs ; 17(11)2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31739542

RESUMO

Antioxidant peptides have elicited interest for the versatility of their use in the food and pharmaceutical industry. In the current study, antioxidant peptides were prepared by microwave-assisted alkaline protease hydrolysis of collagen from sea cucumber (Acaudina molpadioides). The results showed that microwave irradiation significantly improved the degree of hydrolysis of collagen and the hydroxyl radical (OH⋅) scavenging activity of hydrolysate. The content and OH⋅ scavenging activity of collagen peptides with molecular weight ≤ 1 kDa (CPS) in the hydrolysate obtained at 250 W increased significantly compared with the non-microwave-assisted control. CPS could scavenge OH⋅ and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical in a dose-dependent manner. The scavenging activity of OH⋅ and DPPH radical was 93.1% and 41.2%, respectively, at CPS concentration of 1 mg/mL. CPS could significantly promote RAW264.7 cell proliferation and reduce the Reactive Oxygen Species (ROS) level of H2O2-induced damage in RAW264.7 cells in a dose-dependent manner. Furthermore, all CPS-treated groups exhibited an increase in superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and a decrease in malondialdehyde (MDA) level compared with the control. These results showed that CPS could effectively protect RAW264.7 cells from H2O2-induced damage, implying the potential utilization of CPS as a natural antioxidant for food and pharmaceutical applications.


Assuntos
Antioxidantes/farmacologia , Colágeno/metabolismo , Peróxido de Hidrogênio/farmacologia , Peptídeos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Compostos de Bifenilo/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Hidrólise , Radical Hidroxila/metabolismo , Malondialdeído/metabolismo , Camundongos , Micro-Ondas , Estresse Oxidativo/efeitos dos fármacos , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
16.
J Am Soc Mass Spectrom ; 30(12): 2795-2804, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31720974

RESUMO

Mass spectrometry (MS)-based protein footprinting, a valuable structural tool in mapping protein-ligand interaction, has been extensively applied to protein-protein complexes, showing success in mapping large interfaces. Here, we utilized an integrated footprinting strategy incorporating both hydrogen-deuterium exchange (HDX) and hydroxyl radical footprinting (i.e., fast photochemical oxidation of proteins (FPOP)) for molecular-level characterization of the interaction of human bromodomain-containing protein 4 (BRD4) with a hydrophobic benzodiazepine inhibitor. HDX does not provide strong evidence for the location of the binding interface, possibly because the shielding of solvent by the small molecule is not large. Instead, HDX suggests that BRD4 appears to be stabilized by showing a modest decrease in dynamics caused by binding. In contrast, FPOP points to a critical binding region in the hydrophobic cavity, also identified by crystallography, and, therefore, exhibits higher sensitivity than HDX in mapping the interaction of BRD4 with compound 1. In the absence or under low concentrations of the radical scavenger, FPOP modifications on Met residues show significant differences that reflect the minor change in protein conformation. This problem can be avoided by using a sufficient amount of proper scavenger, as suggested by the FPOP kinetics directed by a dosimeter of the hydroxyl radical.


Assuntos
Benzodiazepinas/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Espectrometria de Massas em Tandem/métodos , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Benzodiazepinas/química , Proteínas de Ciclo Celular/química , Medição da Troca de Deutério/métodos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Radical Hidroxila/análise , Radical Hidroxila/metabolismo , Modelos Moleculares , Conformação Proteica/efeitos dos fármacos , Fatores de Transcrição/química
17.
Int J Med Mushrooms ; 21(7): 657-669, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679300

RESUMO

The yield and efficacy of bioactive compounds from Cordyceps militaris fruiting bodies and its fermented grains usually vary with the strain used. In this study, we compared the antiproliferative, apoptotic, and antioxidative properties of ethanolic extracts of fruiting bodies and solid-stated fermented rice (FRE) from two wild-type strains of C. militaris applied to human breast cancer cell lines. We observed that FRE of the Zhangzhou strain (FRE-Z) produced a high level of cordycepin and exhibited comprehensive in vitro antioxidant activity against the oxidation of 2,2-diphenyl-1-picrylhydrazyl, superoxide, and hydroxyl radicals and low-density lipoprotein. Only FRE-Z exhibited dose-dependent inhibition of cell proliferation in MCF-7 (0.7 mg/mL) and MDA-MB-231 cells (1 mg/mL) after culturing for 24 h. The antiproliferative effects of FRE-Z were associated with an early stage of apoptosis induction at 4 h of treatment with 0.5 mg/mL FRE-Z in MCF-7 cells. The antiproliferative effect was determined to occur through p53 activation but not through the release of mitochondrial apoptosis-inducing factor or caspase-9 activation for an initial culture period of 16 h. In addition to a transient increase in cellular antioxidant enzyme, Cu/Zn superoxide dismutase was identified in MCF-7 cells after 2 h of treatment with FRE-Z. Therefore, FRE-Z, which exhibits various dose- and exposure time-dependent activities, has potential application in breast cancer chemoprevention.


Assuntos
Proliferação de Células/efeitos dos fármacos , Misturas Complexas/farmacologia , Cordyceps/química , Carpóforos/química , Micélio/química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Misturas Complexas/química , Etanol , Feminino , Fermentação , Humanos , Radical Hidroxila/metabolismo , Células MCF-7 , Oryza , Superóxido Dismutase/metabolismo
18.
Mar Drugs ; 17(10)2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31623339

RESUMO

For full use of fish by-products, scale gelatin (TG) and antioxidant peptides (APs) of skipjack tuna (Katsuwonus pelamis) were prepared, and their properties were characterized using an amino acid analyzer, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Fourier transform infrared spectroscopy (FTIR), electrospray ionization mass spectrometers (ESI-MS), and radical scavenging assays. The results indicate that TG with a yield of 3.46 ± 0.27% contained Gly (327.9 ± 5.2 residues/1000 residues) as the major amino acid and its imino acid content was 196.1 residues/1000 residues. The structure of TG was more unstable than that of type I collagen from scales of skipjack tuna (TC) and TG was more suitable for preparation of hydrolysate by protease than mammalian gelatins. Therefore, TG was separately hydrolyzed under five proteases (pepsin, papain, trypsin, neutrase, and alcalase) and ten APs (TGP1-TGP10) were isolated from the alcalase-hydrolysate. Among them, TGP5, TGP7, and TGP9 with high antioxidant activity were identified as His-Gly-Pro-Hyp-Gly-Glu (TGP5), Asp-Gly-Pro-Lys-Gly-His (TGP7) and Met-Leu-Gly-Pro-Phe-Gly-Pro-Ser (TGP9), respectively. Furthermore, TGP5, TGP7, and TGP9 exhibited a high radical scavenging capability on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical (EC50 values of 1.34, 0.54, and 0.67 mg/mL, respectively), hydroxyl radical (EC50 values of 1.03, 0.41, and 0.74 mg/mL, respectively), and superoxide anion radical (EC50 values of 1.19, 0.71, and 1.59 mg/mL, respectively). These results suggest that three APs (TGP5, TGP7, and TGP9), especially TGP7, have a strong antioxidant activity and could act as potential antioxidant ingredients applied in functional products.


Assuntos
Antioxidantes/farmacologia , Gelatina/farmacologia , Peptídeos/farmacologia , Atum/metabolismo , Aminoácidos/metabolismo , Animais , Colágeno Tipo I/metabolismo , Depuradores de Radicais Livres/farmacologia , Hidrólise/efeitos dos fármacos , Radical Hidroxila/metabolismo , Superóxidos/metabolismo
19.
Chem Commun (Camb) ; 55(86): 12956-12959, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31602444

RESUMO

A bimetallic complex, containing Mn(ii) and Cu(ii) moieties, was synthesized for chemodynamic therapy (CDT) of cancer. The complex was capable of generating a hydroxyl radical (˙OH) via a Fenton-like reaction involving a Mn complex, and simultaneously depleting glutathione via a Cu complex induced oxidative reaction, thereby enhancing the efficiency of CDT.


Assuntos
Complexos de Coordenação/química , Cobre/química , Glutationa/metabolismo , Manganês/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Glutationa/química , Humanos , Radical Hidroxila/metabolismo , Azul de Metileno/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fotoquimioterapia
20.
PLoS One ; 14(10): e0223198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31584975

RESUMO

A novel polysaccharide STSP-I was isolated and purified from Sargassum thunbergii. Its structure and bioactivity were studied using gas chromatography (GC), fourier transform infrared spectroscopy (FTIR), periodate oxidation-smith degradation, partial acid hydrolysis, methylation-GC-MS, nuclear magnetic resonance (NMR), transmission electron microscopy (TEM), radicals scavenging assays and anti-inflammatory assays. STSP-I was consisted of fucose and galactose with a molar ratio of 1.2:1, and its mass was 373 kDa. The main structural components of STSP-I were →4)-α-D-Galp-(1→ and →3)-ß-L-Fucp-(1→, STSP-I was a non-branched polysaccharide, and TEM further revealed the existence of entangled chains and linear forms. Compared with Vitamin C (Vc), STSP-I showed a higher scavenging effect of superoxide radical (EC50 = 0.22 mg/mL) and an equivalent scavenging effect of hydroxyl radical (EC50 = 0.88 mg/mL). STSP-I also exhibited good inhibitory effects of TNF-α, IL-6 and COX-2 mRNA expressions in LPS-stimulated RAW 264.7 mouse macrophage cells, and the inhibitory effects were more than 91% at the concentrations of 75 and 150 µg/ml. The results indicate that the polysaccharide STSP-I from S. thunbergii with the linear structure may serve as potential antioxidant and anti-inflammatory agents.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Polissacarídeos/farmacologia , Sargassum/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Ácido Ascórbico/farmacologia , Radical Hidroxila/metabolismo , Mediadores da Inflamação/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Microscopia Eletrônica de Transmissão , Estrutura Molecular , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Células RAW 264.7 , Espectroscopia de Infravermelho com Transformada de Fourier
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