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1.
Life Sci ; 236: 116939, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593705

RESUMO

Taxifolin (TAX) reportedly exerts protective and therapeutic effects in liver. Herein, the effects of TAX against acetaminophen (APAP)-induced hepatotoxicity were investigated. Pharmacodynamics, pharmacology and metabolomics analyses of TAX were assessed on C57 mice and L-02 cells. TAX was administered for 7 days, and APAP was given on the last day to establish an acute liver injury model. ALT and AST levels were determined, and liver ROS, MDA, GST, GSH and GPX1 were analysed. The expression and protein abundance of GPX1, GPS-Pi, GCLC and GCLM were assessed by PCR and western blotting, and metabolic changes in cells and serum were investigated by UPLC-Q-Orbitrap-MS. Serum ALT and AST, and liver ROS, MDA, GST, GSH and GPX1 levels confirmed the protective effects of TAX. Besides, we found Only treating with TAX decreased the expression of CYP2E1 in mice liver tissue. TAX reversed the APAP-induced decrease in cell viability in L-02 cells, and reduced cellular ROS levels. Furthermore, TAX reversed the APAP-induced decrease in antioxidant enzymes at both mRNA and protein levels. Metabolomics analysis identified metabolites mainly related to glutathione metabolism (36 in vivo and 23 in vitro). The concentration of glutathione, oxidized glutathione, carnitine, succinic acid, pyroglutamic acid, citrulline, taurine, palmitoleic acid, phytoshingosine-1-P and sphingosine-1-P were close to normal levels after treating with TAX. These results indicate that TAX prevents APAP-induced liver injury by inhibiting APAP metabolic activation mediated by CYP450 enzymes, modulating glutathione metabolism, and expression of related antioxidative signals. These properties could be harnessed to prevent or treat hepatotoxicity.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Glutationa/metabolismo , Metaboloma , Substâncias Protetoras/farmacologia , Quercetina/análogos & derivados , Analgésicos não Entorpecentes/toxicidade , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Quercetina/farmacologia , Espécies Reativas de Oxigênio/metabolismo
2.
Life Sci ; 236: 116933, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31614146

RESUMO

AIMS: Hepatocellular carcinoma (HCC) pathogenesis involves the interplay of multiple signalling pathways. Notch and Hedgehog (Hh) are two major developmental pathways that act in concert to regulate adult cell repair. CK2α -serine-threonine kinase-down-regulation enhanced apoptotic activity and was proven beneficial for HCC patients. Quercetin is a bioactive flavonoid and has been shown to protect against HCC through its antioxidant activity. This study was carried out to elucidate the antineoplastic effect of quercetin through regulating both Notch and Hh pathways, apoptosis, cell proliferation and CK2α activity. MAIN METHODS: Hepatocellular carcinoma was induced in male Sprague Dawley rats by thioacetamide. Quercetin was administered in both protective and curative doses. Parameters of liver function and oxidative stress were assessed. CK2α, Notch and Hh pathways were evaluated using RT-PCR and ELISA. Apoptosis was investigated by detecting caspase-3, caspase-8 and p53. Proliferative and cell cycle markers as cyclin D1 and Ki-67 were detected immunohistochemically. KEY FINDINGS: Quercetin inhibited CK2α and downregulated mRNA and protein expression of Notch1 and Gli2. Quercetin also suppressed caspase-3 expression but not caspase-8. Quercetin elevated p53 expression whereas proliferative and cell cycle markers cyclin D1 and Ki-67 were downregulated. Markers of hepatic cellular integrity such as AST, ALT, ALP, GGT, albumin and bilirubin were significantly ameliorated. This was confirmed by histological examination. Quercetin also alleviated oxidative stress as shown by SOD, GSH, MDA and NO levels. SIGNIFICANCE: We can conclude that in addition to its antioxidant power, quercetin blocked Notch, Hedgehog, regulated the apoptotic and proliferative pathways and inhibited CK2α in HCC.


Assuntos
Antioxidantes/farmacologia , Carcinoma Hepatocelular/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Quercetina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Receptores Notch/antagonistas & inibidores , Receptores Notch/metabolismo
3.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(4): 533-539, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31642231

RESUMO

OBJECTIVE: To investigate the protective effect of (2R, 3R)-dihydroquercetin 7-O-ß-D-glucopyranose (C1) extracted from Coreopsis tinctoria Nutt. in a mouse model of alcoholic acute pancreatitis (FAEE-AP) induced byfatty acid ethyl ester (FAEE). METHODS: The 30 healthy SPF mice were randomly divided into control group, model group, low dose group, middle dose group and high dose group, 6 in each group. Alcoholic pancreatitis was induced by ethanol and palmitoleic acid administration (1.75 g/kg ethanol, 200 mg/kg palmitoleic acid, 2 times peritoneal injections). The three treatment groups were given C1 (0 h, 4 h, 8 h) at the dose of 12.5, 25 and 50 mg/kg, respectively. After 24 h of molding, the serum amylase, lipase and IL-6 levels were detected. The trypsin level in pancreatic tissue and myeloperoxidase (MPO) level in pancreatic and lung tissue were detected. Hematoxylin-eosin (HE) staining was used to observe the pathological changes of pancreatic tissue and immunohistochemical (IHC) staining was used to detect the expression of nuclear factor-erythroid 2 related factor 2 (Nrf2) in pancreatic tissue. RESULTS: The pancreatic histopathological scores, serum amylase and lipase activity, trypsin level in pancreatic tissue, serum IL-6 level, MPO level of pancreas and lung were significantly higher in the model group than in the control group (P < 0.01). Compared with the model group, the pancreatic histopathologies of the low dose group was significantly improved (P < 0.05), as well as the serum amylase and lipase activity, trypsin level of pancreas, serum IL-6 level, the pancreas andthe lung's MPO level decreased significantly (P < 0.05), and up-regulate that expression of Nrf2 in pancreatic tissue. CONCLUSION: 12.5 mg/kg of (2R, 3R) -dihydroquercetin 7-O-ß-D-glucopyranose (C1) improved the expression of Nrf2, reduced the expression of inflammatory factor IL-6, and protected acute pancreatitis caused by FAEE.


Assuntos
Coreopsis/química , Glicosídeos/farmacologia , Pancreatite Alcoólica/tratamento farmacológico , Quercetina/farmacologia , Doença Aguda , Animais , Modelos Animais de Doenças , Interleucina-6/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Pâncreas , Quercetina/análogos & derivados , Distribuição Aleatória
4.
Zhongguo Zhong Yao Za Zhi ; 44(17): 3786-3791, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31602954

RESUMO

It is reported that energy metabolism is the core feature of tumor cells. This study is aimed to investigate the regulatory effect of two flavonoids( glabridin and quercetin) on energy supply and glycolysis of breast cancer cells,and provide reference for developing some anticancer herbal drugs with the function of regulating tumor energy metabolism. Based on the characteristics of each pathway during energy metabolism,in the present study,the triple negative breast cancer tumor cells( MDA-MB-231) were selected to investigate the effects of glabridin and quercetin on the energy metabolism of breast cancer cells and discuss the possible mechanisms from the following five potential targets: glucose uptake,protein expression of glucose transporter 1( GLUT1),adenosine triphosphate( ATP) level,lactate dehydrogenase( LDH) activity,and lactic acid( LD) concentration. The results showed that both quercetin and glabridin could decrease the glucose uptake capacity of breast cancer cells by down-regulating the protein expression of GLUT1. Quercetin had no significant effect on LDH activity and LD concentration; it did not affect the glycolysis process,but increased the intracellular ATP level. Glabridin decreased the activity of LDH and reduced LD concentration,thereby inhibiting the glycolysis metabolism of breast cancer cells. Therefore,both quercetin and glabridin can regulate the energy metabolism of breast cancer cells and can be used as potential anticancer agents or anti-cancer adjuvants.


Assuntos
Neoplasias da Mama/metabolismo , Metabolismo Energético , Isoflavonas/farmacologia , Fenóis/farmacologia , Quercetina/farmacologia , Linhagem Celular Tumoral , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Humanos
5.
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
6.
Cell Biochem Funct ; 37(7): 474-485, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31365139

RESUMO

The effect of quercetin was assessed in rats induced with complete Freund adjuvant (CFA). Arthritis scores, paw oedema, latency, activities of myeloperoxidase (MPO), ectonucleoside triphosphate diphosphohydrolase (E-NTPDase), and ectoadenosine deaminase (E-ADA) in lymphocytes were determined. Furthermore, nucleotide and nucleoside levels as well as the secretion of pro- and anti-inflammatory cytokines were evaluated. Animals were treated with saline and quercetin in doses of 5, 25, and 50 mg/kg for 45 days. The result revealed that quercetin (50 mg/kg) reduced arthritis score and paw oedema, and increased the latency in the thermal hyperalgesia test. Histopathological analysis showed that all the doses of quercetin reduced infiltration of inflammatory cells. MPO activity was increased in the arthritis group; however, quercetin reduced this activity. E-NTPDase activity was increased in lymphocytes of arthritis rats, and treatment with quercetin reversed this increase. However, E-ADA activity was reduced in the arthritis group, and treatment with quercetin modulated the activity of this enzyme in arthritis rat groups. Serum adenosine levels were increased in arthritis, and the levels were lowered with quercetin treatment. Quercetin treatment in arthritis groups decreased the elevated levels of cytokines in the arthritis control group. Thus, quercetin demonstrated an anti-inflammatory effect, and this flavonoid may be a promising natural compound for the treatment of arthritis. SIGNIFICANCE OF THE STUDY: Quercetin may represent a potential therapeutic compound in the treatment of rheumatoid arthritis. Findings from this study indicate that quercetin suppresses swelling and attenuates the underlying inflammatory responses. This is the first report where quercetin was shown to modulate the immune response to arthritis via attenuation of the purinergic system (E-NTPDase and E-ADA activities) and the levels of IFN-gamma and IL-4. Thus, this work is relevant to basic research and may be translated into clinical practice.


Assuntos
AMP Desaminase/antagonistas & inibidores , Adenosina Trifosfatases/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Reumatoide/tratamento farmacológico , Citocinas/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Quercetina/farmacologia , AMP Desaminase/metabolismo , Adenosina Trifosfatases/metabolismo , Animais , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/metabolismo , Citocinas/metabolismo , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Feminino , Adjuvante de Freund , Ratos , Ratos Wistar
7.
Int J Nanomedicine ; 14: 5449-5475, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409998

RESUMO

Purpose: We created and evaluated an enhanced topical delivery system featuring a combination of highly skin-permeable growth factors (GFs), quercetin (QCN), and oxygen; these synergistically accelerated re-epithelialization and granulation tissue formation of/in diabetic wounds by increasing the levels of GFs and antioxidants, and the oxygen partial pressure, at the wound site. Methods: To enhance the therapeutic effects of exogenous administration of GFs for the treatment of diabetic wounds, we prepared highly skin-permeable GF complexes comprised of epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), platelet-derived growth factor-A (PDGF-A), and basic fibroblast growth factor (bFGF), genetically attached, via the N-termini, to a low-molecular-weight protamine (LMWP) to form LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, and LMWP-bFGF, respectively. Furthermore, quercetin (QCN)- and oxygen-carrying 1-bromoperfluorooctane (PFOB)-loaded nanoemulsions (QCN-NE and OXY-PFOB-NE) were developed to improve the topical delivery of QCN and oxygen, respectively. After confirming the enhanced penetration of LMWP-GFs, QCN-NE, and oxygen delivered from OXY-PFOB-NE across human epidermis, we evaluated the effects of combining LMWP-GFs, QCN-NE, and OXY-PFOB-NE on proliferation of keratinocytes and fibroblasts, and the chronic wound closure rate of a diabetic mouse model. Results: The optimal ratios of LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, LMWP-bFGF, QCN-NE, and OXY-PFOB-NE were 1, 1, 0.02, 0.02, 0.2, and 60, respectively. Moreover, a Carbopol hydrogel containing LMWP-GFs, QCN-NE, and OXY-PFOB-NE (LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL) significantly improved scratch-wound recovery of keratinocytes and fibroblasts in vitro compared to that afforded by hydrogels containing each component alone. LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL significantly accelerated wound-healing in a diabetic mouse model, decreasing wound size by 54 and 35% compared to the vehicle and LMWP-GFs, respectively. Conclusion: LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL synergistically accelerated the healing of chronic wounds, exerting both rapid and prolonged effects.


Assuntos
Diabetes Mellitus/patologia , Hidrogéis/química , Fator de Crescimento Insulin-Like I/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Oxigênio/metabolismo , Quercetina/farmacologia , Absorção Cutânea , Cicatrização/efeitos dos fármacos , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Colágeno/biossíntese , Modelos Animais de Doenças , Emulsões/química , Fator de Crescimento Epidérmico/farmacologia , Epiderme/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Peso Molecular , Nanopartículas/química , Nanopartículas/ultraestrutura , Octanos/química , Fator de Crescimento Derivado de Plaquetas/farmacologia , Protaminas/química , Absorção Cutânea/efeitos dos fármacos
8.
Transplant Proc ; 51(6): 2051-2059, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399183

RESUMO

PURPOSE: Hepatic ischemia-reperfusion (IR) injury is a serious complication of many clinical conditions, which may lead to liver or multiple organ failure. Hyperoside, a flavonoid compound, has been reported to protect against myocardial and cerebral injury induced by IR. This study aimed to investigate the protective effects of hyperoside on hepatic IR injury in rats. METHODS: Using the 70% hepatic IR injury model, we divided 32 male Wistar rats into 4 groups (n = 8): sham-operated, IR+saline (saline/p.o.), IR+vehicle (carboxy methyl cellulose/p.o.), and IR+hyperoside (50 mg/kg/d/p.o.). At 24 hours after reperfusion, blood and liver tissue were collected. The effects of hyperoside on hepatic IR injury were assessed through tests of serum transaminase, hepatic histopathology, and measurement of markers of oxidative stress and apoptosis. RESULTS: Pretreatment with hyperoside protected the liver from IR injury by a reduction in serum aspartate aminotransferase/alanine aminotransferase levels and a decrease in the severity of histologic changes. Hyperoside treatment also decreased the activity of malondialdehyde, increased the activities of superoxide dismutase and glutathione peroxidase, up-regulated the expression of heme oxygenase 1 and NAD(P)H:quinone oxidoreductase 1, and reduced the apoptotic index after IR injury. A decrease in the expression of caspase-3 and an increase in the ratio of B cell lymphoma 2 to B cell lymphoma 2-associated X also were observed. CONCLUSION: Hyperoside has a protective effect on hepatic IR injury in rats, which may be due to its antioxidant and antiapoptotic properties.


Assuntos
Apoptose/efeitos dos fármacos , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Quercetina/análogos & derivados , Traumatismo por Reperfusão/patologia , Animais , Antioxidantes/farmacologia , Fígado/patologia , Masculino , Quercetina/farmacologia , Ratos , Ratos Wistar
9.
Ecotoxicol Environ Saf ; 183: 109582, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31442803

RESUMO

Di-2-ethylhexyl phthalate (DEHP), widely used as a plasticizer, is a ubiquitous artificial pollutant. DEHP can induce biological toxicity in various organs, with an especially high potential for toxicity to the cardiovascular system. Taxifolin (TAX) is used in the treatment of cardiovascular diseases due to its antioxidative capacities. However, it is not clear whether TAX can alleviate apoptosis induced by DEHP exposure through the cytochrome P450 (CYP) pathway in cardiomyocytes. To understand the role of TAX in attenuating cardiomyocyte toxicity induced by DEHP, primary cardiomyocytes were divided into 4 groups (control group, DEHP group, TAX group and DEHP + TAX group). The results showed that in the cardiomyocytes, DEHP initiated apoptosis by increasing the expression of caspase-3, caspase-9, cyt c, and Bax at both the mRNA and protein levels and by decreasing the Bcl-2 levels compared with that of the control group. In addition, the activities of catalase (CAT), superoxide dismutase (SOD), and total antioxidative capacity (T-AOC) were clearly decreased (P < 0.05), while in the DEHP group, the malondialdehyde (MDA) and hydrogen peroxide (H2O2) levels were observably increased (P < 0.05), compared with those in control group. Furthermore, compared with the control group, the DEHP group demonstrated a clear partial decrease in the expression of the mRNA levels of CYP1B1 and CYP2C18 (P < 0.05), and DEHP/TAX cotreatment partially prevented apoptosis and oxidative stress damage (P < 0.05). These results showed that exposure to DEHP induced apoptosis in chicken cardiomyocytes, while TAX could antagonize the toxicity of DEHP on cardiomyocytes by attenuating oxidative stress responses and modulating CYPs.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Dietilexilftalato/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Plastificantes/toxicidade , Quercetina/análogos & derivados , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Células Cultivadas , Galinhas , Homeostase , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Quercetina/farmacologia
10.
Chem Pharm Bull (Tokyo) ; 67(9): 985-991, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31270295

RESUMO

Chemically stable ester derivatives of taxifolin have become a focus of interest for their role in the satisfactory effects on human health. Accordingly, the aim of this study was to evaluate the physical and chemical stability of different formulations containing 0.02% taxifolin tetra-octanoate, which was proved to possess higher inhibitory effect on tyrosinase activity compared with taxifolin in a cell-free system. In the studies of physical stability, a Brookfield viscometer was used to determine rheological behavior of formulations containing taxifolin tetra-octanoate, and a portable pH meter was used to determine pH change. Moreover, chemical stability was determined by HPLC with UV detection. Formulations were evaluated for 12 weeks stored at 25 and 40°C. Results showed that storage time had no significant influence on viscosity of the formulations containing taxifolin tetra-octanoate, and pH value was relatively stable, which was within the limits of normal skin pH range. In the chemical stability studies, taxifolin tetra-octanoate in the essence formulation was most unstable at 40°C with about 81% degradation in 12 weeks of storage, however, the percentage of remaining taxifolin tetra-octanoate in cream formulation stored for 12 weeks at 25°C was the highest, about 93%. The results in this study may contribute to the development of more stable formulations containing taxifolin tetra-octanoate.


Assuntos
Caprilatos/farmacologia , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Quercetina/análogos & derivados , Caprilatos/síntese química , Caprilatos/química , Cromatografia Líquida de Alta Pressão , Composição de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Concentração de Íons de Hidrogênio , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Quercetina/síntese química , Quercetina/química , Quercetina/farmacologia , Relação Estrutura-Atividade , Viscosidade
11.
Life Sci ; 232: 116617, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260685

RESUMO

AIM: To investigate the effects and underlying mechanisms of taxifolin on proliferation, migration and invasion of highly aggressive breast cancer in vitro and in vivo. MAIN METHODS: The antineoplastic activity of taxifolin was evaluated in MDA-MB-231 and 4 T1 cells by crystal violet assay and colony formation assay. The effects of taxifolin on migration and invasion were determined by wound healing assay and Transwell assay, respectively. mRNA and protein expression of genes were assayed respectively with qRT-PCR and western blot, and the protein expression and location was also detected by immunofluorescence and immunohistochemistry. ß-catenin overexpression was performed with adenovirus infection. The effects of taxifolin on growth and metastasis of breast cancer in vivo were investigated in BALB/c mice bearing 4T1 xenografts. KEY FINDINGS: We found that taxifolin had the potential to inhibit proliferation, migration and invasion of highly aggressive breast cancer cells in a dose-dependent manner. In addition, taxifolin promoted the MET process, the reversed process of EMT, as evaluated by EMT markers and EMT-transcriptional factors in breast cancer cell lines. Meanwhile, the protein and mRNA expressions of ß-catenin were dose-dependently downregulated by taxifolin, and overexpression of ß-catenin by adenoviruses abrogated these beneficial effects of taxifolin above-mentioned. Furthermore, within a 4T1 xenograft mouse model, taxifolin markedly inhibited the growth of primary tumors and reduced lung metastasis of breast cancer. SIGNIFICANCE: Our findings provide a theoretical foundation for the possibility of taxifolin used as a promising agent in the clinical treatment of highly aggressive breast cancer patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quercetina/análogos & derivados , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Quercetina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismo
12.
Phytochemistry ; 166: 112066, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325613

RESUMO

Taxifolin (3,5,7,3,4-pentahydroxy flavanone or dihydroquercetin) is a flavonoid commonly found in onion, milk thistle, French maritime pine bark and Douglas fir bark. It is also used in various commercial preparations like Legalon™, Pycnogenol®, and Venoruton®. This review focuses on taxifolin's biological activities and related molecular mechanisms. Published literatures were gathered from the scientific databases like PubMed, SciFinder, ScienceDirect, Wiley Online Library, Google Scholar, and Web of Science up to January 2019. Taxifolin showed promising pharmacological activities in the management of inflammation, tumors, microbial infections, oxidative stress, cardiovascular, and liver disorders. The anti-cancer activity was more prominent than other activities evaluated using different in vitro and in vivo models. Further research on the pharmacokinetics, in-depth molecular mechanisms, and safety profile using well-designed randomized clinical studies are suggested to develop a drug for human use.


Assuntos
Saúde , Quercetina/análogos & derivados , Animais , Humanos , Quercetina/farmacologia
13.
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
14.
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
15.
J Appl Microbiol ; 127(4): 1038-1047, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31319012

RESUMO

AIMS: Global spread of carbapenem-resistant Pseudomonas aeruginosa (CRPsA) and Acinetobacter baumannii (CRAB) is an emerging clinical problem. Since, quercetin is a well-known antibacterial agent; it would be relevant to demonstrate synergy between quercetin and meropenem and elucidate molecular basis of effective bactericidal activity of quercetin-meropenem against CRPsA and CRAB. METHODS AND RESULTS: Hence, minimum inhibitory concentration (MIC), checkerboard, time-kill and Baclight assays were performed to determine the antibacterial and synergistic activity of quercetin with meropenem against CRPsA and CRAB. To corroborate synergism, fractional inhibitory concentration index, combination index calculation and isobologram analysis were performed on selected isolates. Finally, to elucidate molecular basis of effective bactericidal activity of quercetin-meropenem against CRPsA and CRAB, effect of meropenem, quercetin and their combinations on cellular morphology and levels of blaNDM , mexB and adeB expressions were evaluated on selected isolates by scanning electron microscope and qRT-PCR. Quercetin exhibited synergy with meropenem. It inhibited blaNDM and AdeB expression. Half-MIC combination of quercetin-meropenem exerted bactericidal activity by disrupting cell wall/membrane integrity and altering cellular morphology. CONCLUSION: Quercetin could potentiate meropenem activity against CRPsA and CRAB. SIGNIFICANCE AND IMPACT OF THE STUDY: This study had demonstrated bactericidal and synergistic activity of quercetin with meropenem against CRPsA and CRAB.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Meropeném/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Quercetina/farmacologia , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Carbapenêmicos/farmacologia , Farmacorresistência Bacteriana/genética , Sinergismo Farmacológico , Testes de Sensibilidade Microbiana
16.
Chem Commun (Camb) ; 55(61): 8919-8922, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31270526

RESUMO

Cancer development is often associated with lipid metabolic reprogramming, including aberrant lipid accumulation. We create novel paradigms endowed with dual functions of anticancer activity and inhibition of lipid accumulation by conjugating the natural product quercetin and synthetic alkylphospholipid drugs, and harnessing the biomedical effects of both. These conjugates offer fresh perspectives in the search for anticancer candidates.


Assuntos
Fármacos Antiobesidade/farmacologia , Antineoplásicos/farmacologia , Éteres Fosfolipídicos/farmacologia , Fosforilcolina/análogos & derivados , Quercetina/análogos & derivados , Quercetina/farmacologia , Fármacos Antiobesidade/síntese química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Gotículas Lipídicas/metabolismo , Receptores X do Fígado/metabolismo , PPAR gama/metabolismo , Éteres Fosfolipídicos/síntese química , Fosforilcolina/síntese química , Fosforilcolina/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Quercetina/síntese química , Transdução de Sinais/efeitos dos fármacos
17.
Bioengineered ; 10(1): 292-305, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31284815

RESUMO

In the present study, Probit, Cauchy Fractional and three types of Log methods, i.e., Logit, Log-log, and Complementary log-log were employed to model the feeding deterrence of the lesser grain borer, Rhyzopertha dominica (F) (Coleoptera: Bostrichidae), when fed latex protein, crude flavonoid fraction, 3-O-rutinosides of quercetin, kaempferol and isorhamnetin, isolated from Calotropis procera (Ait.) (Gentianales: Asclepiadaceae). A nutritional study with treated flour discs at sub-lethal concentrations indicated that the tested natural products negatively affected the feeding behavior of the lesser grain borer, causing high feeding deterrent indices. Our results assure that Probit, Logit and Clog-log model the feeding deterrent indices with high goodness of fit. The models aim to support the management of the test insect when fed grains treated with sub-lethal doses of the tested phytochemicals in order to develop a viable, precise and long-term strategy to minimize the excessive reliance on the chemical pesticides currently in use.


Assuntos
Produtos Biológicos/farmacologia , Calotropis/química , Besouros/efeitos dos fármacos , Quempferóis/farmacologia , Modelos Estatísticos , Quercetina/análogos & derivados , Quercetina/farmacologia , Animais , Besouros/fisiologia , Grão Comestível/parasitologia , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Glicosídeos/farmacologia , Larva/efeitos dos fármacos , Larva/fisiologia , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Triticum/parasitologia
18.
Bratisl Lek Listy ; 120(6): 449-455, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223026

RESUMO

OBJECTIVE: The effects of quercetin and selenium on oxidative stress in endometrial adenocarcinoma cells are unclear. In this study, the effects of quercetin and selenium on oxidative stress caused by both hydrogen peroxide and UV radiation in endometrial adenocarcinoma cells were examined. METHODS: The viability of endometrial adenocarcinoma cells cultured in vitro and treated with different concentrations of quercetin and sodium selenite was measured using the MTT assay. Malondialdehyde (MDA) levels were investigated, and expression levels of BAD and p53 genes were analysed using real­time quantitative polymerase chain reaction. Acridine orange/ethidium bromide staining technique was applied to detect apoptosis. Mass attenuation coefficient of each quercetin and sodium selenite combinations was evaluated using Monte Carlo simulation. RESULTS: The combination of quercetin and sodium selenite enhanced cell viability, and reduced MDA levels. The expression levels of BAD and p53 genes decreased by combined treatment with quercetin and selenium while showing synergistic effects in terms of gene expression. Fluorescent microscopic examination showed a decrease in apoptotic cells in endometrial adenocarcinoma cells treated with the combination of quercetin and selenium. CONCLUSIONS: For the first time, selenium and quercetin have synergistic cytoprotective and radioprotective effects on oxidative stress caused by hydrogen peroxide in endometrial adenocarcinoma cells for the first time (Tab. 1, Fig. 7, Ref. 39).


Assuntos
Adenocarcinoma , Neoplasias do Endométrio , Estresse Oxidativo , Quercetina , Selênio , Adenocarcinoma/patologia , Apoptose , Neoplasias do Endométrio/patologia , Feminino , Humanos , Peróxido de Hidrogênio , Malondialdeído , Estresse Oxidativo/efeitos dos fármacos , Quercetina/farmacologia , Selênio/farmacologia
19.
Int J Nanomedicine ; 14: 4045-4057, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213814

RESUMO

Background: Quercetin (QUE) shows a potential antileukemic activity, but possesses poor solubility and low bioavailability. Purpose: This article explored the bile salt transport pathway for oral deliver of QUE using cholate-modified polymer-lipid hybrid nanoparticles (cPLNs) aiming to enhance its antileukemic effect. Methods: QUE-loaded cPLNs (QUE-cPLNs) were developed through a nanoprecipitation technique and characterized by particle size, entrapment efficiency (EE), microscopic morphology and in vitro drug release. In vitro cellular uptake and cytotoxicity of QUE-cPLNs were examined on Caco-2 and P388 cells; in vivo pharmacokinetics and antileukemic effect were evaluated using Sprague Dawley rats and leukemic model mice, respectively. Results: The prepared QUE-cPLNs possessed a particle size of 110 nm around with an EE of 96.22%. QUE-cPLNs resulted in significantly enhanced bioavailability of QUE, up to 375.12% relative to the formulation of suspensions. In addition, QUE-cPLNs exhibited excellent cellular uptake and internalization capability compared to cholate-free QUE-PLNs. The in vitro cytotoxic and in vivo antileukemic effects of QUE-cPLNs were also signally superior to free QUE and QUE-PLNs. Conclusion: These findings indicate that cPLNs are a promising nanocarrier able to improve the oral bioavailability and therapeutic index of QUE.


Assuntos
Antineoplásicos/farmacologia , Colatos/química , Lipídeos/química , Nanopartículas/química , Polímeros/química , Quercetina/administração & dosagem , Administração Oral , Animais , Área Sob a Curva , Células CACO-2 , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Endocitose/efeitos dos fármacos , Humanos , Leucemia/patologia , Camundongos , Nanopartículas/ultraestrutura , Tamanho da Partícula , Quercetina/farmacocinética , Quercetina/farmacologia , Ratos Sprague-Dawley
20.
Phytother Res ; 33(7): 1770-1783, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31155811

RESUMO

N-acetyl-p-benzoquinoneimine (NAPQI) is toxic metabolite of paracetamol formed primarily by cytochrome P4502E1 (CYP2E1) metabolic pathway when administered at therapeutic doses or overdose. The influence of quercetin (flavonoid) on the bioactivation of paracetamol to NAPQI was investigated using rat liver microsomes and rats in vivo. Paracetamol (80 mg/kg) was administered orally without or with silymarin (100 mg/kg), a known inhibitor of CYP2E1, CYP3A4 and quercetin (10 and 20 mg/kg) to rats for 15 consecutive days. Area under the plasma concentration-time curve (AUC0-∞ ) and the peakplasma concentration (Cmax ) of paracetamol were dose-dependently increased with quercetin (10 and 20 mg/kg) compared to paracetamol control group (p < 0.001). On the other hand, the AUC0-∞ and Cmax of NAPQI were decreased significantly with quercetin. The same results were observed with silymarin also. The elevated liver and kidney functional enzymes/compounds were significantly reduced by quercetin and silymarin compared to paracetamol control group. The formation of NAPQI was reduced in the incubation samples in presence of quercetin in experiment using isolated rat hepatocytes. The presentstudy results revealed that quercetin might be inhibited the CYP2E1-mediated metabolism of paracetamol; thereby decreased the formation of NAPQI and protected the liver and kidney.


Assuntos
Acetaminofen/farmacocinética , Benzoquinonas/metabolismo , Hepatócitos/efeitos dos fármacos , Iminas/metabolismo , Quercetina/farmacologia , Acetaminofen/sangue , Animais , Células Cultivadas , Citocromo P-450 CYP2E1/metabolismo , Inibidores do Citocromo P-450 CYP2E1/farmacologia , Hepatócitos/metabolismo , Rim/metabolismo , Fígado/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Ratos Wistar , Silimarina/farmacologia
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