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1.
Int J Nanomedicine ; 14: 6481-6495, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496698

RESUMO

Background: Despite the numerous pharmacological activities of quercetin, its biomedical application has been hampered, because of poor water solubility and low oral bioavailability. In the present study, we fabricated a novel form of quercetin-conjugated Fe3O4-ß-cyclodextrin (ßCD) nanoparticles (NPs), and the effect of these prepared NPs was evaluated in a chronic model of epilepsy. Methods: Quercetin-loaded NPs were prepared using an iron oxide core coated with ßCD and pluronic F68 polymer. The chronic model of epilepsy was developed by intraperitoneal injection of pentylenetetrazole (PTZ) at dose of 36.5 mg/kg every second day. Quercetin or its nanoformulation at doses of 25 or 50 mg/kg were administered intraperitoneally 10 days before PTZ injections and their applications continued 1 hour before each PTZ injection. Immunostaining was performed to evaluate the neuronal density and astrocyte activation of hippocampi. Results: Our data showed successful fabrication of quercetin onto Fe3O4-ßCD NPs. In comparison to free quercetin, quercetin NPs markedly reduced seizure behavior, neuronal loss, and astrocyte activation in a PTZ-induced kindling model. Conclusion: Overall, quercetin-Fe3O4-ßCD NPs might be regarded as an ideal therapeutic approach in epilepsy disorder.


Assuntos
Epilepsia/tratamento farmacológico , Nanopartículas de Magnetita/química , Quercetina/uso terapêutico , beta-Ciclodextrinas/química , Animais , Astrócitos/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/patologia , Excitação Neurológica , Nanopartículas de Magnetita/administração & dosagem , Nanopartículas de Magnetita/ultraestrutura , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Pentilenotetrazol/administração & dosagem , Quercetina/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier
2.
Chem Biol Interact ; 310: 108734, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276661

RESUMO

This work aimed to evaluate the mechanisms involved in the apoptosis induction of isorhamnetin-3-O-glucosyl-pentoside (IGP) in metastatic human colon cancer cells (HT-29). To achieve this, we assessed phosphatidylserine (PS) exposure, cell membrane disruption, chromatin condensation, cell cycle alterations, mitochondrial damage, ROS production, and caspase-dependence on cell death. Our results showed that IGP induced cell death on HT-29 cells through PS exposure (48%) and membrane permeabilization (30%) as well as nuclear condensation (54%) compared with control cells. Moreover, IGP treatment induced cell cycle arrest in G2/M phase. Bax/Bcl-2 ratio increased and the loss of mitochondrial membrane potential (63%) was observed in IGP-treated cells. Finally, as apoptosis is a caspase-dependent cell death mechanism, we used a pancaspase-inhibitor (Q-VD-OPh) to demonstrate that the cell death induced by IGP was caspase-dependent. Overall these results indicated that IGP induced apoptosis through caspase-dependent mitochondrial damage in HT-29 colon cancer cells.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Glicosídeos/farmacologia , Mitocôndrias/efeitos dos fármacos , Opuntia/química , Quercetina/análogos & derivados , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Neoplasias do Colo/patologia , Flavonóis , Glicosídeos/isolamento & purificação , Glicosídeos/uso terapêutico , Células HT29 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/patologia , Extratos Vegetais/farmacologia , Quercetina/isolamento & purificação , Quercetina/farmacologia , Quercetina/uso terapêutico
3.
Chem Biol Interact ; 310: 108759, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31326407

RESUMO

Sustained exogenous stimuli induce oxidative stress in granulosa cells and cause cell apoptosis, thereby resulting in follicular atresia. Hyperoside is a natural flavonoid that possesses anti-oxidant activity. The present study aimed to evaluate the effect of hyperoside on hydrogen peroxide (H2O2)-induced oxidative stress and apoptosis in granulosa cells. Cell viability was measured using MTT assay. The malondialdehyde (MDA) level and activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) were detected to reflect the oxidative stress. Flow cytometry was performed to measure the apoptotic rate. Western blot was carried out to determine the expression of Bcl-2, Bax, Sonic hedgehog (SHH), Gli1, and smoothened (SMO). The mRNA levels of SHH, Gli1, and SMO were analyzed using qRT-PCR. We found that hyperoside improved cell viability in H2O2-stimulated granulosa cells. The increased MDA level and decreased activities of SOD, GSH-Px, and CAT caused by H2O2 stimulation were reversed by hyperoside treatment. The apoptotic rate of H2O2-stimulated granulosa cells was reduced after treatment with hyperoside. Hyperoside treatment caused a decrease in Bax expression and an increase in Bcl-2 expression in H2O2-stimulated granulosa cells. The mRNA and protein levels of SHH, Gli1, and SMO in H2O2-stimulated granulosa cells were elevated by hyperoside treatment. Suppression of SHH pathway by cyclopamine attenuated the protective effects of hyperoside on H2O2-induced injury. In short, hyperoside protected granulosa cells from H2O2-induced cell apoptosis and oxidative stress via activation of the SHH signaling pathway.


Assuntos
Células da Granulosa/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Peróxido de Hidrogênio/efeitos adversos , Ovário/citologia , Quercetina/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Feminino , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras , Quercetina/farmacologia , Quercetina/uso terapêutico , Ratos , Transdução de Sinais
4.
J Photochem Photobiol B ; 196: 111508, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31152936

RESUMO

Cardiovascular malady (CVM) isn't just the essential driver of death in created western nations, yet additionally, its sickness load is expanding in China. Oxidative pressure initiated free radicals assume a basic job in cell forms involved in atherosclerosis and numerous other heart illnesses. Quercetin (QC) is cancer prevention agents medicate which is demonstrated that successfully secures against CVMs. Encapsulations of medications in polymeric materials are generally utilized in creating continued and controllable medication discharge, or to keep away from the debasement of non-discharged medications. In this present work, a novel arrangement of polymeric superparamagnetic nano-silica (SiN)@poly(lactic-co-glycolic acid) (PLGA) (SiN@PLGA) stacked with QC was created by means of lyophilization method so as to improve poor watery solvency and steadiness of the medication with the point of preventing atherosclerosis. The aftereffects of SEM investigation and the checking, TEM affirmed the manufacture of the circular nanocomposite, smooth surface, and thin size dispersion. The discharge profile of QC from the particles was explored by deciding the medication sum discharged at explicit interims for by iridescence. The data got from this investigation encourages the structure and manufacture of nanocomposite as conceivable conveyance frameworks for epitome, assurance and controlled arrival of the flavonoid QC which is expecting to secure against CVMs.


Assuntos
Nanocompostos/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Quercetina/química , Dióxido de Silício/química , Animais , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Nanocompostos/toxicidade , Quercetina/metabolismo , Quercetina/uso terapêutico
5.
Acta Cir Bras ; 34(4): e201900404, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31066786

RESUMO

PURPOSE: To examine the effect of taxifolin on I/R induced gastric injury in rats using biochemical and histopatholohical methods. METHODS: Eighteen albino Wistar male rats equally grouped as; gastric I/R (I/R), 50 mg/kg taxifolin + gastric I/R (TAX+ I/R) and sham operation applied (SHAM). Ischemia induced for 1 hour, and reperfusion induced for 3 hours. RESULTS: Oxidant parameters like, Malondialdehyde (MDA) and Hydroxyguanine (8-OHdG) were higher, whereas total glutathione (tGSH) was lower in the I/R group according to SHAM group, histopathological findings such as marked destruction, edema, and proliferated dilated congested blood vessels were observed severely in the I/R group, whereas there was not any pathological finding except mild dilated congested blood vessels in the TAX+ I/R group. CONCLUSION: The taxifolin can be clinically beneficial in the treatment of gastric injury due to I/R procedure.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Mucosa Gástrica/lesões , Quercetina/análogos & derivados , Traumatismo por Reperfusão/prevenção & controle , Animais , Artéria Celíaca/cirurgia , Modelos Animais de Doenças , Ligadura , Masculino , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Quercetina/uso terapêutico , Ratos , Ratos Wistar
6.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052203

RESUMO

Amyloid-ß (Aß) has been closely implicated in the pathogenesis of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD), the major causes of dementia. Thus, Aß could be a target for the treatment of these diseases, for which, currently, there are no established effective treatments. Taxifolin is a bioactive catechol-type flavonoid present in various plants, such as herbs, and it exhibits pleiotropic effects including anti-oxidant and anti-glycation activities. Recently, we have demonstrated that taxifolin inhibits Aß fibril formation in vitro and have further shown that it improves cerebral blood flow, facilitating Aß clearance in the brain and suppressing cognitive decline in a mouse model of CAA. These findings suggest the novel therapeutic potentials of taxifolin for CAA. Furthermore, recent extensive studies have reported several novel aspects of taxifolin supporting its potential as a therapeutic drug for AD and metabolic diseases with a high risk for dementia as well as for CAA. In this review, we have summarized the recent advances in taxifolin research based on in vitro, in vivo, and in silico approaches. Furthermore, we have discussed future research directions on the potential of taxifolin for use in novel therapeutic strategies for CAA, AD, and metabolic diseases with an increased risk for dementia.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Angiopatia Amiloide Cerebral/tratamento farmacológico , Quercetina/análogos & derivados , Animais , Humanos , Fármacos Neuroprotetores/uso terapêutico , Quercetina/uso terapêutico
7.
Int J Nanomedicine ; 14: 2879-2902, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118613

RESUMO

Purpose: Lung cancer has a high incidence rate worldwide with a 5-year survival rate of 18%, and is the leading cause of cancer-related deaths. The aim of this study is to augment therapeutic efficacy of quercetin (QR) for lung cancer therapy by targeting transferrin receptors, which are overexpressed and confined to tumor cells. Methods: In this study, T7 surface-functionalized liposomes loaded with QR (T7-QR-lip) having different T7 peptide densities (0.5%, 1% and 2%) were prepared by the film hydration method. T7 surface-functionalized liposomes were characterized and evaluated in terms of in vitro cytotoxicity and cellular uptake, 3D tumor spheroid penetration and inhibition capabilities, in vivo biodistribution and therapeutic efficacy in mice with orthotopic lung-tumor implantation by fluorescent and bioluminescent imaging via pulmonary administration. Results: In vitro, 2% T7-QR-lip exhibited significantly augmented cytotoxicity (~3-fold), higher apoptosis induction and S-phase cell-cycle arrest. A prominent peak right-shift and enhanced mean fluorescence intensity was observed in A549 cells treated with T7 Coumarin-6 liposomes (T7-Cou6-lip), confirming the target specificity of T7 targeted liposomes; while, after treatment with T7-QR-lip and non-targeted QR-lip, no significant difference was observed in cellular uptake and in vitro cytotoxicity studies in MRC-5 (normal lung fibroblast) cells. T7-Cou6-lip showed higher fluorescence intensity in A549 cells and a significantly deeper penetration depth of 120 µm in the core of the tumor spheroids and T7-QR-lip produced significantly higher tumor-spheroid growth inhibition. The in vivo biodistribution study via pulmonary delivery of T7 1,1'-dioctadecyltetramethyl-indotricarbocyanine iodide liposomes demonstrated liposome accumulation in the lungs and sustained-release behavior up to 96 h. Further, T7-QR-lip significantly enhanced the anticancer activity of QR and lifespan of mice (p<0.01, compared with saline) in orthotopic lung tumor-bearing mice via pulmonary administration. Conclusion: T7 surface-functionalized liposomes provide a potential drug delivery system for a range of anticancer drugs to enhance their therapeutic efficacy by localized (pulmonary) administration and targeted delivery.


Assuntos
Sistemas de Liberação de Medicamentos , Neoplasias Pulmonares/tratamento farmacológico , Pulmão/patologia , Peptídeos/administração & dosagem , Peptídeos/uso terapêutico , Quercetina/uso terapêutico , Receptores da Transferrina/metabolismo , Células A549 , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Cumarínicos/química , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Humanos , Lipossomos , Pulmão/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Tamanho da Partícula , Peptídeos/farmacologia , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Quercetina/farmacologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Distribuição Tecidual/efeitos dos fármacos
8.
Mediators Inflamm ; 2019: 3740867, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30992689

RESUMO

The effect of taxifolin on cisplatin-induced oxidative pulmonary damage was investigated biochemically and histopathologically in male albino Wistar rats. There were four groups, with six animals in each group: 50 mg/kg of taxifolin plus 2.5 mg/kg of cisplatin (TC) group, 2.5 mg/kg of cisplatin only (CIS) group, 50 mg/kg of taxifolin only (TG) group, and a healthy control group (HG). In terms of the experimental procedure, the animals in the TC and TG groups were first treated via oral gavage. The CIS and HG groups received distilled water as solvent, respectively. One hour later, the TC and CIS groups received cisplatin at a dose of 2.5 mg/kg (injected intraperitoneally). Taxifolin, cisplatin, and the distilled water were administered at the indicated dose and volume, using the same method daily for 14 d. At the end of this period, the animals were killed with a high dosage of thiopental anaesthesia (50 mg/kg). Blood and lung tissue samples were taken for biochemical (malondialdehyde (MDA), myeloperoxidase (MPO), total glutathione (tGSH), and 8-hydroxy-2 deoxyguanosine (8-OHdG)) analyses and histopathological examinations. The biochemical and histopathological results in the TC and HG groups were then compared with those in the CIS group. Cisplatin increased the levels of MDA, myeloperoxidase, and 8-OHdG, a marker of oxidative DNA damage, and reduced the amount of tGSH in the lung tissue. Moreover, severe alveolar damage, including oedema and extensive alveolar septal fibrosis, in addition to infiltration of polymorphic nuclear leucocytes and haemorrhagic foci, was observed in the CIS group. These histopathological findings demonstrate that taxifolin provides protection against pulmonary oxidative stress by preventing increases in oxidant parameters and decreases in antioxidants.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Cisplatino/efeitos adversos , Quercetina/análogos & derivados , Lesão Pulmonar Aguda/metabolismo , Animais , Antioxidantes/metabolismo , Dano ao DNA/efeitos dos fármacos , Glutationa/metabolismo , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Quercetina/uso terapêutico , Ratos , Ratos Wistar
9.
Medicina (Kaunas) ; 55(4)2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31013662

RESUMO

: Background and objectives: Previous studies have shown anti-tumor activity of quercetin (QT). However, the low bioavailability of QT has restricted its use. This study aimed to assess the toxic effect of QT encapsulated in solid lipid nanoparticles (QT-SLNs) on the growth of MCF-7 human breast cancer cells. Materials and Methods: MCF-7 and MCF-10A (non-tumorigenic cell line) cell lines treated with 25 µmol/mL of QT or QT-SLNs for 48 h. Cell viability, colony formation, oxidative stress, and apoptosis were evaluated to determine the toxic effects of the QT-SLNs. Results: The QT-SLNs with appropriate characteristics (particle size of 85.5 nm, a zeta potential of -22.5 and encapsulation efficiency of 97.6%) were prepared. The QT-SLNs showed sustained QT release until 48 h. Cytotoxicity assessments indicated that QT-SLNs inhibited MCF-7 cells growth with a low IC50 (50% inhibitory concentration) value, compared to the free QT. QT-SLNs induced a significant decrease in the viability and proliferation of MCF-7 cells, compared to the free QT. QT-SLN significantly increased reactive oxygen species (ROS) level and MDA contents and significantly decreased antioxidant enzyme activity in the MCF-7 cells. Following QT-SLNs treatment, the expression of the Bcl-2 protein significantly decreased, whereas Bx expression showed a significant increase in comparison with free QT-treated cells. Furthermore, The QT-SLNs significantly increased apoptotic and necrotic indexes in MCF-7 cells. Viability, proliferation, oxidative stress and apoptosis of MCF-10A cells were not affected by QT or QT-SLNs. Conclusion: According to the results of this study, SLN significantly enhanced the toxic effect of QT against human breast cancer cells.


Assuntos
Antioxidantes/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Nanocápsulas , Nanomedicina/métodos , Quercetina/uso terapêutico , Apoptose/efeitos dos fármacos , Catalase/análise , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Malondialdeído/análise , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Espécies Reativas de Oxigênio/análise , Superóxido Dismutase/análise , Resultado do Tratamento
10.
Pharmazie ; 74(4): 193-200, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30940301

RESUMO

Background: Chronic Venous Disorders or Diseases (CVD) of the lower extremities are a common finding affecting almost 90 % of an adult population. CVD includes varicose veins with a prevalence of approx. 25 %, overlapping with Chronic Venous Insufficiency (CVI) with a prevalence of approx. 17% in the adult population. CVI is characterized by venous pathology and objective signs like edema, skin changes or venous leg ulcers. Objective: To review and evaluate non-clinical and clinical data on a standardised herbal product containing flavonoids (AS195; Antistax®) and to put them into a perspective with the pathophysiology of CVD. Methods: Literature available on non-clinical pharmacology and clinical studies with AS195 in CVI of the lower extremities was reviewed and described. Conclusion: Antistax® is a well-described herbal product with standardised starting materials and manufacturing process. Its active ingredients accumulate in the venous intima, preserve the endothelial barrier function, and inhibit the inflammatory and prothrombotic cascade behind the progression of CVD. Its efficacy was analysed in adequately planned and executed clinical trials in patients with mild to moderately severe CVD (CEAP C1s to C4). AS195 showed a statistically significant and clinically relevant efficacy over placebo: in objective endpoints like volumetry of lower leg edema, but also in outcomes directly relevant for patients like tension and heaviness of the legs, tingling, and pain. Supportive studies confirmed and validated these results also for the broader population treated in daily practice. AS195 was well tolerated in studies and in everyday therapy. There are no known interactions with other medications. In the later stages, it can be used in combination with compression, complementing the beneficial haemodynamic effects of compression at a cellular level. AS195 is an addition to compression and closes a therapeutic gap especially in patients, who cannot use compression stockings, but still require CVD therapy.


Assuntos
Extratos Vegetais/uso terapêutico , Varizes/tratamento farmacológico , Insuficiência Venosa/tratamento farmacológico , Adulto , Doença Crônica , Progressão da Doença , Humanos , Quercetina/análogos & derivados , Quercetina/uso terapêutico , Índice de Gravidade de Doença , Varizes/fisiopatologia , Insuficiência Venosa/fisiopatologia
11.
Mater Sci Eng C Mater Biol Appl ; 100: 129-140, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30948047

RESUMO

Naturally occurring bioactive compounds are gaining much importance as anti-tumor agents in recent times due to their high therapeutic potential and less systemic toxicity. However, different preclinical and clinical studies have noted significant shortcomings, such as nonspecific tumor targeting and low bioavailability which limit their usage in therapeutics. Therefore, a safe and compatible nanoparticle mediated controlled drug delivery system is in high demand to enable effective transport of the drug candidates in the tumor tissue. Herein, we have synthesized phenylboronic acid (PBA) conjugated Zinc oxide nanoparticles (PBA-ZnO), loaded with quercetin (a bioflavonoid widely found in plants), with zeta potential around -10.2 mV and diameter below 40 nm. Presence of PBA moieties over the nanoparticle surface facilitates targeted delivery of quercetin to the sialic acid over-expressed cancer cells. Moreover, Quercetin loaded PBA-ZnO nanoparticles (denoted as PBA-ZnO-Q) showed pH responsive drug release behavior. Results suggested that PBA-ZnO-Q induced apoptotic cell death in human breast cancer cells (MCF-7) via enhanced oxidative stress and mitochondrial damage. In line with the in vitro results, PBA-ZnO-Q was found to be effective in reducing tumor growth in EAC tumor bearing mice. Most interestingly, PBA-ZnO-Q is found to reduce tumor associated toxicity in liver, kidney and spleen. The cytotoxic potential of the nanohybrid is attributed to the combinatorial cytotoxic effects of quercetin and ZnO in the cancer cells. Overall, the presented data highlighted the chemotherapeutic potential of the novel nanohybrid, PBA-ZnO-Q which can be considered for clinical cancer treatment.


Assuntos
Portadores de Fármacos/química , Nanopartículas Metálicas/química , Quercetina/química , Óxido de Zinco/química , Animais , Apoptose/efeitos dos fármacos , Ácidos Borônicos/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Quercetina/farmacologia , Quercetina/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Transplante Heterólogo
12.
Chem Biol Interact ; 303: 62-69, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-30817903

RESUMO

Lifestyle and genetic factors contribute to the initiation of oxidative stress and inflammation in diabetes mellitus (DM). Oxidative stress and lipid peroxidation worked in an orchestrated manner and reported to be strongly associated with the formation of the hyperlipidemic condition in DM patients. Isoquercetin, a bioactive constituent isolated from guava leaves has attracted considerable attention because of its antidiabetic activity. The antidiabetic activity of guava leaves may be due to the presence of isoquercetin at a significant level. However, how isoquercetin regulates different pathways in DM is insufficiently studied. We have selected versatile regulators of oxidative stress and inflammatory pathways to fully analyze if isoquercetin effectively modulated the genes of these pathways. At the end of our experimental duration, rats were dissected and analyzed for the oxidative stress, lipid peroxidation, inflammatory and lipid markers. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is believed to be the key regulator of expression of various antioxidant enzyme genes and it is directly or indirectly related to nuclear factor Kappa- B (NF-kB) and AMP-activated protein kinase (AMPK) pathways. Therefore, we tend to study the effects of STZ on Nrf2, NF-kB and AMPK pathway and how the isoquercetin treatment performs at a molecular level to overcome the burden of DM. The results of our study provided convincing evidence of significant pharmacological properties of isoquercetin in context of its ability to inhibit the oxidative stress elicited by the STZ through generation of the free radicals and regulation of the expression of Nrf2 pathway-associated proteins and genes and it also reduced the burden of hyperlipidemia and inflammation. By taking the above results into consideration isoquercetin can be studied further to elucidate its antidiabetic effects at various levels.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Quercetina/análogos & derivados , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Animais , Citocinas/genética , Diabetes Mellitus Experimental/induzido quimicamente , Hiperlipidemias/tratamento farmacológico , Inflamação/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/genética , Quercetina/farmacologia , Quercetina/uso terapêutico , Ratos , Estreptozocina
13.
Life Sci ; 224: 109-119, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30914316

RESUMO

Quercetin belongs to the flavonoids family, which is present in most of the plants including fruits, vegetables, green tea and even in red wine having antioxidant activities. It is available as a food supplement in the market and has physiological health effects. Quercetin has anti-inflammatory, anticancer and anti-prostate activities along with its beneficial effects on high cholesterol, kidney transplantation, asthma, diabetes, viral infections, pulmonary, schizophrenia and cardiovascular diseases. Quercetin possesses scavenging potential of hydroxyl radical (OH-), hydrogen peroxide (H2O2), and superoxide anion (O2-). These reactive oxygen species (ROS) hampers lipid, protein, amino acids and deoxyribonucleic acid (DNA) processing leading to epigenetic alterations. Quercetin has the ability to combat these harmful effects. ROS plays a vital role in the progression of Alzheimer's disease (AD), and we propose that quercetin would be the best choice to overcome cellular and molecular signals in regulating normal physiological functions. However, data are not well documented regarding exact cellular mechanisms of quercetin. The neuroprotective effects of quercetin are mainly due to potential up- and/or down-regulation of cytokines via nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Paraoxonase-2, c-Jun N-terminal kinase (JNK), Protein kinase C, Mitogen-activated protein kinase (MAPK) signalling cascades, and PI3K/Akt pathways. Therefore, the aim of the present review was to elaborate on the cellular and molecular mechanisms of the quercetin involved in the protection against AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Quercetina/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Humanos
14.
Int J Dev Neurosci ; 74: 18-26, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30822517

RESUMO

The decline in neurogenesis is a very critical problem in Alzheimer disease. Different biological activities have been reported for medicinal application of quercetin. Herein, we investigated the neurogenesis potential of quercetin in a rat model of Alzheimer's disease induced by amyloid-beta injection. Rats were randomly divided into Control, Alzheimer + Saline and Alzheimer + Quercetin groups. Following the administration of Amyloid-beta, rats in the Alzheimer + Quercetin group received 40 mg/kg/day quercetin orally for one month. Our data demonstrated amyloid-ß injection could impair learning and memory processing in rats indicated by passive avoidance test evaluation. We noted that one-month quercetin treatment alleviated the detrimental effects of amyloid-ß on spatial learning and memory parameters using Morris water maze analysis. Quercetin was found to increase the number of proliferating neural stem/progenitor cells. Notably, quercetin increased the number of DCX-expressing cells, indicating the active dynamic growth of neural progenitor cells in the dentate gyrus of the hippocampus. We further observed that the quercetin improved the number of BrdU/NeuN positive cells contributed to enhanced adult neurogenesis. Based on our results, quercetin had the potential to promote the expression of BDNF, NGF, CREB, and EGR-1 genes involved in regulating neurogenesis. These data suggest that quercetin can play a valuable role in alleviating Alzheimer's disease symptoms by enhancing adult neurogenesis mechanism.


Assuntos
Antioxidantes/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Giro Denteado/patologia , Transtornos de Aprendizagem/tratamento farmacológico , Células-Tronco Neurais/fisiologia , Neurogênese/efeitos dos fármacos , Quercetina/uso terapêutico , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/toxicidade , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Giro Denteado/efeitos dos fármacos , Modelos Animais de Doenças , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Transtornos de Aprendizagem/etiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Neuropeptídeos/metabolismo , Fragmentos de Peptídeos/toxicidade , Ratos , Ratos Wistar
15.
Phytother Res ; 33(5): 1330-1340, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30848564

RESUMO

This systematic review and meta-analysis of randomized controlled trials was performed to determine the effect of quercetin supplementation on glycemic control among patients with metabolic syndrome and related disorders. Databases including PubMed, MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials were searched until August 30, 2018. Nine studies with 10 effect sizes out of 357 selected reports were identified eligible to be included in current meta-analysis. The pooled findings indicated that quercetin supplementation did not affect fasting plasma glucose (FPG), homeostasis model of assessment-estimated insulin resistance, and hemoglobin A1c levels. In subgroup analysis, quercetin supplementation significantly reduced FPG in studies with a duration of ≥8 weeks (weighted mean difference [WMD]: -0.94; 95% confidence interval [CI; -1.81, -0.07]) and used quercetin in dosages of ≥500 mg/day (WMD: -1.08; 95% CI [-2.08, -0.07]). In addition, subgroup analysis revealed a significant reduction in insulin concentrations following supplementation with quercetin in studies that enrolled individuals aged <45 years (WMD: -1.36; 95% CI [-1.76, -0.97]) and that used quercetin in dosages of ≥500 mg/day (WMD: -1.57; 95% CI [-1.98, -1.16]). In summary, subgroup analysis based on duration of ≥8 weeks and used quercetin in dosages of ≥500 mg/day significantly reduced FPG levels.


Assuntos
Glicemia/efeitos dos fármacos , Suplementos Nutricionais/análise , Síndrome Metabólica/tratamento farmacológico , Quercetina/uso terapêutico , Humanos , Síndrome Metabólica/patologia , Pessoa de Meia-Idade , Quercetina/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
Artigo em Inglês | MEDLINE | ID: mdl-30727927

RESUMO

BACKGROUND: Production of tumor necrosis factor (TNF)-α by inflammatory cells in lesions is the hallmark of the pathogenesis of rheumatoid arthritis (RA). Regulation of inflammatory responses in knee joints of patients with RA is critical for improving severe symptoms. Flavonoids have inhibitory effects on the acute and chronic inflammatory responses caused by TNF-α. The flavonoid quercetin (QUER) is one of the most prominent dietary antioxidants. OBJECTIVE: The present study investigated the preventive and therapeutic effects of QUER on inflammatory responses in collagen-induced arthritis (CIA) in mice. METHODS: Mice with CIA, a mouse model for RA, were treated with QUER orally three times a week either from the second immunization with collagen (day 21) or day 28 when symptoms of CIA had developed midway. RESULTS: In both cases, inflammation-related clinical scores of knee joints were significantly reduced by treatment with QUER. Histological analyses showed that the representative characteristics of RA, such as damage to interchondral joints, infiltration of inflammatory cells, and pannus formation, were significantly reduced by QUER treatment. Oral administration of QUER significantly decreases lipopolysaccharide (LPS)-induced TNF-α production in a dose-dependent manner. Expression of TNF- α mRNA in knee joints was decreased in QUER-treated mice, compared with those of CIA controls. CONCLUSION: These results suggest that oral administration of QUER might effectively improve symptoms of RA.


Assuntos
Antioxidantes/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Quercetina/uso terapêutico , Animais , Antioxidantes/farmacologia , Artrite Experimental/patologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Quercetina/farmacologia
17.
EBioMedicine ; 40: 554-563, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30616998

RESUMO

BACKGROUND: Cellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice. METHODS: A two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks) was conducted in participants with IPF (n = 14) to evaluate feasibility of implementing a senolytic intervention. The primary endpoints were retention rates and completion rates for planned clinical assessments. Secondary endpoints were safety and change in functional and reported health measures. Associations with the senescence-associated secretory phenotype (SASP) were explored. FINDINGS: Fourteen patients with stable IPF were recruited. The retention rate was 100% with no DQ discontinuation; planned clinical assessments were complete in 13/14 participants. One serious adverse event was reported. Non-serious events were primarily mild-moderate, with respiratory symptoms (n = 16 total events), skin irritation/bruising (n = 14), and gastrointestinal discomfort (n = 12) being most frequent. Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinically-meaningfully improved (p < .05). Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulat.ing SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and pro-inflammatory cytokines (23/48 markers r ≥ 0.50). INTERPRETATION: Our first-in-humans open-label pilot supports study feasibility and provides initial evidence that senolytics may alleviate physical dysfunction in IPF, warranting evaluation of DQ in larger randomized controlled trials for senescence-related diseases. ClinicalTrials.gov identifier: NCT02874989 (posted 2016-2018).


Assuntos
Senescência Celular/efeitos dos fármacos , Dasatinibe/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Quercetina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Senescência Celular/genética , Dasatinibe/administração & dosagem , Dasatinibe/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Medidas de Resultados Relatados pelo Paciente , Projetos Piloto , Qualidade de Vida , Quercetina/administração & dosagem , Quercetina/efeitos adversos , Testes de Função Respiratória , Resultado do Tratamento
18.
J Med Food ; 22(2): 152-161, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30596535

RESUMO

We investigated the immune-regulatory function of quercetin, in interleukin (IL)-17-produced osteoclastogenesis in rheumatoid arthritis (RA). RA fibroblasts-like synoviocytes (RA-FLS) were stimulated with IL-17, and the mRNA expression and secretion of receptor activator of nuclear factor kappa-B ligand (RANKL) were detected by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. CD14+ monocytes (osteoclast precursors) were stimulated with IL-17, RANKL, with/without quercetin, and tartrate-resistant acid phosphatase activity was evaluated to assess osteoclast differentiation. Osteoclast differentiation was investigated after coculturing IL-17-stimulated RA-FLS and Th17 cells with monocytes. CD4+ T cells were cocultured with quercetin under Th17-inducing conditions, and their differentiation to Th17 cells and Treg cells was determined by flow cytometry analysis. We found that IL-17 stimulated RA-FLS to produce RANKL and quercetin decreased the IL-17-induced RANKL protein levels. Quercetin decreased the IL-17-produced activation of mammalian target of rapamycin, extracellular signal-regulated kinase and inhibitor of kappa B-alpha. When monocytes were stimulated with IL-17, macrophage colony-stimulating factor or RANKL, mature osteoclasts were formed, and quercetin decreased this osteoclastogenesis. When monocytes were cultured with IL-17-prestimulated RA-FLS or Th17 cells, osteoclasts were produced, and quercetin decreased this osteoclast differentiation. In Th17-differentiation conditions, quercetin suppressed Th17 cell and the production of IL-17, but quercetin did not affect Treg cells. Quercetin inhibits IL-17-stimulated RANKL production in RA-FLS and IL-17-stimulated osteoclast formation. Quercetin reduces Th17 differentiation. Quercetin could be an additional therapeutic option for bone destructive processes in RA.


Assuntos
Artrite Reumatoide , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/farmacologia , Quercetina/farmacologia , Fosfatase Ácida/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Diferenciação Celular , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Interleucina-17/efeitos adversos , Interleucina-17/metabolismo , Monócitos , Extratos Vegetais/uso terapêutico , Quercetina/uso terapêutico , Ligante RANK/metabolismo , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fosfatase Ácida Resistente a Tartarato/metabolismo , Células Th17
19.
Nutrients ; 11(1)2019 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-30669587

RESUMO

The aim of the present investigation was to test the hypothesis that quercetin (Q) may prevent the strength loss and neuromuscular impairment associated with eccentric exercise-induced muscle damage (EEIMD). Twelve young men (26.1 ± 3.1 years) ingested either Q (1000 mg/day) or placebo (PLA) for 14 days using a randomized, double-blind, crossover study design. Participants completed a comprehensive neuromuscular (NM) evaluation before, during and after an eccentric protocol able to induce a severe muscle damage (10 sets of 10 maximal lengthening contractions). The NM evaluation comprised maximal voluntary isometric contraction (MVIC) and force⁻velocity relationship assessments with simultaneous recording of electromyographic signals (EMG) from the elbow flexor muscles. Soreness, resting arm angle, arm circumference, plasma creatine kinase (CK) and lactate dehydrogenase (LDH) were also assessed. Q supplementation significantly increased the isometric strength recorded during MVIC compared to baseline (+4.7%, p < 0.05). Moreover, the torque and muscle fiber conduction velocity (MFCV) decay recorded during the eccentric exercise was significant lower in Q compared to PLA. Immediately after the EEIMD, isometric strength, the force⁻velocity relationship and MFCV were significantly lower when participants were given PLA rather than Q. Fourteen days of Q supplementation seems able to attenuate the severity of muscle weakness caused by eccentric-induced myofibrillar disruption and sarcolemmal action potential propagation impairment.


Assuntos
Suplementos Nutricionais , Exercício/fisiologia , Contração Isométrica/efeitos dos fármacos , Força Muscular/efeitos dos fármacos , Debilidade Muscular/prevenção & controle , Músculo Esquelético/efeitos dos fármacos , Quercetina/uso terapêutico , Adulto , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Braço , Creatina Quinase/sangue , Estudos Cross-Over , Método Duplo-Cego , Articulação do Cotovelo , Eletromiografia/métodos , Humanos , L-Lactato Desidrogenase/sangue , Masculino , Fibras Musculares Esqueléticas/efeitos dos fármacos , Força Muscular/fisiologia , Debilidade Muscular/etiologia , Debilidade Muscular/fisiopatologia , Músculo Esquelético/citologia , Músculo Esquelético/fisiopatologia , Mialgia , Miofibrilas/efeitos dos fármacos , Quercetina/farmacologia , Treinamento de Resistência , Adulto Jovem
20.
Nutrients ; 11(2)2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30678282

RESUMO

Due to poor water solubility and high susceptibility to chemical degradation, the applications of quercetin have been limited. This study investigated the effects of pH on the formation of quercetin-loaded nanoemulsion (NQ) and compared the hypocholesterolemic activity between quercetin and NQ to utilize the quercetin as functional food ingredient. NQ particle size exhibited a range of 207⁻289 nm with polydispersity index range (<0.47). The encapsulation efficiency increased stepwise from 56 to 92% as the pH increased from 4.0 to 9.0. Good stability of NQ was achieved in the pH range of 6.5⁻9.0 during 3-month storage at 21 and 37 °C. NQ displayed higher efficacy in reducing serum and hepatic cholesterol levels and increasing the release of bile acid into feces in rats fed high-cholesterol diet, compared to quercetin alone. NQ upregulated hepatic gene expression involved in bile acid synthesis and cholesterol efflux, such as cholesterol 7 alpha-hydroxylase (CYP7A1), liver X receptor alpha (LXRα), ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette sub-family G member 1 (ABCG1). These results suggest at least partial involvement of hepatic bile acid synthesis and fecal cholesterol excretion in nanoemulsion quercetin-mediated beneficial effect on lipid abnormalities.


Assuntos
Colesterol na Dieta/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Nanoestruturas , Quercetina/uso terapêutico , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Emulsões/química , Masculino , Quercetina/química , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
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