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1.
Medicine (Baltimore) ; 99(38): e22241, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957369

RESUMO

BACKGROUND: Quercetin, a major flavonol, wildly exists in plantage, which has been reported to have an anti-apoptosis and anti-inflammation effects on vascular endothelial cells, but its underlying molecular mechanisms remain unclear. OBJECTIVE: The aim of this study was to investigate the mechanisms of how quercetin inhibits tumor necrosis factor alpha (TNF-α) induced human umbilical vein endothelial cells (HUVECs) apoptosis and inflammation. METHODS AND RESULTS: HUVECs were preconditioned with quercetin for 18 hours, and subsequently treated with TNF-α for 6 hours to induce apoptosis. The expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin, ß-actin mRNA was then detected by RT-PCR. Flow cytometry was used to estimate the apoptosis rates, and the expression of activator protein 1 (AP-1) and nuclear factor kappa B (NF-κB) was measured by Western blot. TNF-α induced elevated apoptosis rates and upregulation of VCAM-1, ICAM-1, and E-selectin were meaningfully reduced in HUVECs by pretreatment with quercetin. In addition, quercetin also inhibited the activation of AP-1and NF-κB. CONCLUSION: Results indicate that quercetin could suppress TNF-α induced apoptosis and inflammation by blocking NF-κB and AP-1 signaling pathway in HUVECs, which might be one of the underlying mechanisms in treatment of coronary heart disease.


Assuntos
Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Inflamação/prevenção & controle , NF-kappa B/metabolismo , Quercetina/farmacologia , Fator de Transcrição AP-1/metabolismo , Regulação para Baixo , Selectina E/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Molécula 1 de Adesão Intercelular/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/farmacologia , Molécula 1 de Adesão de Célula Vascular/metabolismo
2.
Eur Rev Med Pharmacol Sci ; 24(16): 8585-8591, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32894566

RESUMO

Some surface proteins of the newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can bind to the hemoglobin molecule of an erythrocyte, which leads to the destruction of the structure of the heme and the release of harmful iron ions to the bloodstream. The degradation of hemoglobin results in the impairment of oxygen-carrying capacity of the blood, and the accumulation of free iron enhances the production of reactive oxygen species. Both events can lead to the development of oxidative stress. In this case, oxidative damage to the lungs leads then to the injuries of all other tissues and organs. The use of uridine, which preserves the structure of pulmonary alveoli and the air-blood barrier of the lungs in the course of experimental severe hypoxia, and dihydroquercetin, an effective free radical scavenger, is promising for the treatment of COVID-19. These drugs can also be used for the recovery of the body after the severe disease.


Assuntos
Infecções por Coronavirus/patologia , Estresse Oxidativo , Pneumonia Viral/patologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Eritrócitos/citologia , Eritrócitos/metabolismo , Eritrócitos/virologia , Depuradores de Radicais Livres/farmacologia , Depuradores de Radicais Livres/uso terapêutico , Hemoglobinas/metabolismo , Humanos , Estresse Oxidativo/efeitos dos fármacos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/fisiologia , Quercetina/análogos & derivados , Quercetina/farmacologia , Quercetina/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Uridina/farmacologia , Uridina/uso terapêutico
3.
Life Sci ; 259: 118293, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32822714

RESUMO

AIMS: Liver fibrosis is an inflammatory and fibrogenic process that occurs following chronic liver damage. TGFß1 is the key inducer of fibrosis. MiR-21 and miR-122 are two miRNAs that their expression changes during fibrosis. In the present study, we investigate the effects of curcumin, quercetin, and atorvastatin on the expression levels of miR-21 and miR-122 and evaluated their correlation with TGFß1 expression in bile duct ligation (BDL)-induced fibrotic rats. MATERIALS AND METHODS: Thirty two adult male Wistar rats were divided into 8 groups (n = 8 for each): Sham, Sham + curcumin (100 mg/kg/day), Sham + quercetin (30 mg/kg/day), Sham + atorvastatin (15 mg/kg/day), BDL, BDL + curcumin, BDL + quercetin, BDL + atorvastatin and treated for four weeks via oral gavage. The expression of miR-21, miR-122, and TGFß1 was evaluated via RT-qPCR. KEY FINDINGS: The expression levels of TGFß1 and miR-21 were significantly increased in the BDL group compared to the Sham group (P < 0.05), but the expression of miR-122 was significantly decreased in the BDL group compared to the Sham group (P < 0.05). Curcumin, quercetin, and atorvastatin treatment lead to down-regulation of miR-21 and TGFß1 and up-regulation of miR-122 in the BDL groups. There was no significant difference between these drugs in altering gene expression and all had the same effects. Moreover, a direct significant correlation was observed between mir-21 and TGFß1 and an inverse significant correlation between mir-122 and TGFß1 expression. SIGNIFICANCE: In summary, targeting these molecular pathways may partially prevent the progression of liver fibrosis.


Assuntos
Atorvastatina/farmacologia , Curcumina/farmacologia , Cirrose Hepática/metabolismo , MicroRNAs/metabolismo , Quercetina/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real
4.
PLoS One ; 15(8): e0237752, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817626

RESUMO

Pseudomonas aeruginosa remains a leading cause of nosocomial and serious life-threatening infections, and contributes to increased mortality in immunocompromised individuals. P. aeruginosa infection triggers host immune response and often provokes potent inflammatory mediators, which do not necessarily eradicate the causative pathogen. On the other hand, it causes severe airway damage and eventually decreased lung function. Such unfavorable outcomes of inflammatory injury have necessitated the development of novel effective agents that can combat with P. aeruginosa-mediated inflammation. Herein, we investigated the potential of quercetin in regulating P. aeruginosa-induced inflammation, with particular emphasized on the interleukin-1ß (IL-1ß). Our results showed that quercetin exerted the potent inhibitory activity against the production of IL-1ß in macrophages infected by live P. aeruginosa PAO1, without exhibiting cytotoxicity. According to our settings, such the potent inhibitory activity of quercetin was clearly demonstrated through its ability to efficiently inhibit IL-1ß during P. aeruginosa infection, pre- or even post-infection. In addition, quercetin strongly suppressed MAPK signaling pathway by inhibiting phosphorylation of the p38 MAPK and JNK2, and molecular docking study supported well with this observation. Moreover, quercetin reduced the NLRP3 expression and inhibited the P. aeruginosa-mediated cleavage of caspase-1 as well as mature IL-1ß. These results thus indicated that quercetin inhibition of P. aeruginosa-induced IL-1ß production is mediated by suppressing the initial priming step and by inhibiting the NLRP3 inflammasome activation. Taken together, our findings demonstrated the promising regulatory activity of quercetin against IL-1ß production in P. aeruginosa-infected macrophages, and indicated that quercetin has the potential to be effective as a novel therapeutic agent for treatment of P. aeruginosa-induced inflammation.


Assuntos
Interleucina-1beta/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Infecções por Pseudomonas/tratamento farmacológico , Quercetina/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/genética , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Infecções por Pseudomonas/genética , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/patogenicidade , Transdução de Sinais/efeitos dos fármacos
5.
Chem Biol Interact ; 330: 109230, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32828744

RESUMO

Although physiological levels of iron are essential for numerous biological processes, excess iron causes critical tissue injury. Under iron overload conditions, non-chelated iron generates reactive oxygen species that mediate iron-induced tissue injury with subsequent induction of apoptosis, necrosis, and inflammatory responses. Because liver is a central player in iron metabolism and storage, it is vulnerable to iron-induced tissue injury. Taxifolin is naturally occurring compound that has shown potent antioxidant and potential iron chelation competency. The aim of the current study was to investigate the potential protective effects of taxifolin against iron-induced hepatocellular injury and to elucidate the underlining mechanisms using rats as a mammalian model. The results of the current work indicated that taxifolin inhibited iron-induced apoptosis and enhanced hepatocellular survival as demonstrated by decreased activity of caspase-3 and activation of the pro-survival signaling PI3K/AKT, respectively. Western blotting analysis revealed that taxifolin enhanced liver regeneration as indicated by increased PCNA protein abundance. Taxifolin mitigated the iron-induced histopathological aberration and reduced serum activity of liver enzymes (ALT and AST), highlighting enhanced liver cell integrity. Mechanistically, taxifolin modulated the redox-sensitive MAPK signaling (p38/c-Fos) and improved redox status of the liver tissues as indicated by decreased lipid peroxidation and protein oxidation along with enhanced total antioxidant capacity. Interestingly, it decreased liver iron content and down-regulated the pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß. Collectively, these data highlight, for the first time, the ameliorating effects of taxifolin against iron overload-induced hepatocellular injury that is potentially mediated through anti-inflammatory, antioxidant, and potential iron chelation activities.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Sobrecarga de Ferro/complicações , Regeneração Hepática/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quercetina/análogos & derivados , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Ferro/metabolismo , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quercetina/farmacologia , Quercetina/uso terapêutico , Ratos
6.
Nat Commun ; 11(1): 4289, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855397

RESUMO

Older organs represent an untapped potential to close the gap between demand and supply in organ transplantation but are associated with age-specific responses to injury and increased immunogenicity, thereby aggravating transplant outcomes. Here we show that cell-free mitochondrial DNA (cf-mt-DNA) released by senescent cells accumulates with aging and augments immunogenicity. Ischemia reperfusion injury induces a systemic increase of cf-mt-DNA that promotes dendritic cell-mediated, age-specific inflammatory responses. Comparable events are observed clinically, with the levels of cf-mt-DNA elevated in older deceased organ donors, and with the isolated cf-mt-DNA capable of activating human dendritic cells. In experimental models, treatment of old donor animals with senolytics clear senescent cells and diminish cf-mt-DNA release, thereby dampening age-specific immune responses and prolonging the survival of old cardiac allografts comparable to young donor organs. Collectively, we identify accumulating cf-mt-DNA as a key factor in inflamm-aging and present senolytics as a potential approach to improve transplant outcomes and availability.


Assuntos
DNA Mitocondrial/efeitos adversos , Dasatinibe/farmacologia , Inflamação/prevenção & controle , Transplante de Órgãos/métodos , Quercetina/farmacologia , Adulto , Envelhecimento/fisiologia , Animais , Diferenciação Celular , Ácidos Nucleicos Livres , Senescência Celular/efeitos dos fármacos , Senescência Celular/fisiologia , Citocinas/metabolismo , DNA Mitocondrial/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/fisiologia , Transplante de Coração/efeitos adversos , Transplante de Coração/métodos , Humanos , Inflamação/etiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Pessoa de Meia-Idade , Transplante de Órgãos/efeitos adversos , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia , Doadores de Tecidos
7.
Int J Nanomedicine ; 15: 5181-5202, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801685

RESUMO

Background: Combating infectious diseases caused by influenza virus is a major challenge due to its resistance to available drugs and vaccines, side effects, and cost of treatment. Nanomedicines are being developed to allow targeted delivery of drugs to attack specific cells or viruses. Materials and Methods: In this study, mesoporous silica nanoparticles (MSNs) functionalized with amino groups and loaded with natural prodrugs of shikimic acid (SH), quercetin (QR) or both were explored as a novel antiviral nanoformulations targeting the highly pathogenic avian influenza H5N1 virus. Also, the immunomodulatory effects were investigated in vitro tests and anti-inflammatory activity was determined in vivo using the acute carrageenan-induced paw edema rat model. Results: Prodrugs alone or the MSNs displayed weaker antiviral effects as evidenced by virus titers and plaque formation compared to nanoformulations. The MSNs-NH2-SH and MSNs-NH2-SH-QR2 nanoformulations displayed a strong virucidal by inactivating the H5N1 virus. They induced also strong immunomodulatory effects: they inhibited cytokines (TNF-α, IL-1ß) and nitric oxide production by approximately 50% for MSNs-NH2-SH-QR2 (containing both SH and QR). Remarkable anti-inflammatory effects were observed during in vivo tests in an acute carrageenan-induced rat model. Conclusion: Our preliminary findings show the potential of nanotechnology for the application of natural prodrug substances to produce a novel safe, effective, and affordable antiviral drug.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antivirais/farmacologia , Virus da Influenza A Subtipo H5N1/efeitos dos fármacos , Nanopartículas/química , Pró-Fármacos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/imunologia , Antivirais/imunologia , Citocinas/metabolismo , Cães , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Edema/tratamento farmacológico , Edema/metabolismo , Fatores Imunológicos/imunologia , Fatores Imunológicos/farmacologia , Células Madin Darby de Rim Canino , Masculino , Camundongos , Quercetina/imunologia , Quercetina/farmacologia , Ratos , Ácido Chiquímico/imunologia , Ácido Chiquímico/farmacologia , Dióxido de Silício/química
8.
Anticancer Res ; 40(8): 4695-4700, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727794

RESUMO

BACKGROUND/AIM: We investigated the anti-proliferative effect of quercetin on liver cancer cell lines. MATERIALS AND METHODS: Thirteen liver cancer cell lines were cultured followed by treatment with varying concentrations of quercetin (0-100 µM) or quercetin and 5-FU, and the cell viability was analysed by the MTT assay. Flow cytometry was also used to examine cell cycle progression after treatment with quercetin. RESULTS: The addition of quercetin resulted in a dose- and time-dependent suppression of cell proliferation. In some cell lines, treatment with quercetin and 5-FU caused an additional or synergistic effect. Most cell lines displayed cell cycle arrest at different phases of the cell cycle. CONCLUSION: Quercetin inhibits the proliferation of liver cancer cells via induction of apoptosis and cell cycle arrest.


Assuntos
Neoplasias Hepáticas/tratamento farmacológico , Quercetina/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/patologia
9.
Life Sci ; 257: 118116, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32702447

RESUMO

Emerging evidence implicates accelerated renal tubular epithelial cell (RTEC) senescence in renal fibrosis progression. Mitophagy protects against kidney injury. However, the mechanistic interplay between cell senescence and mitophagy in RTECs is not clearly defined. The purpose of this study was to evaluate the inhibition of RTEC senescence and renal fibrosis by quercetin and explore the underlying mechanisms. We found that quercetin attenuated RTEC senescence induced by angiotensin II (AngII) in vitro and unilateral ureteral obstruction in vivo. Moreover, we demonstrated that mitochondrial abnormalities such as elevated reactive oxygen species, decreased membrane potential, and fragmentation and accumulation of mitochondrial mass, occurred in AngII-treated RTECs. Quercetin treatment reversed these effects. Furthermore, quercetin enhanced mitophagy in AngII-treated RTECs, which was markedly reduced by treatment with mitophagy-specific inhibitors. Sirtuin-1 (SIRT1) was involved in quercetin-mediated PTEN-induced kinase 1 (PINK1)/Parkin-associated mitophagy activation. Pharmacological antagonism of SIRT1 in AngII-treated RTECs blocked the effects of quercetin on mitophagy and cellular senescence. Finally, quercetin alleviated kidney fibrosis by reducing RTEC senescence via mitophagy. Collectively, the antifibrotic effect of quercetin involved inhibition of RTEC senescence, possibly through activation of SIRT1/PINK1/Parkin-mediated mitophagy. These findings suggest that pharmacological elimination of senescent cells and stimulation of mitophagy represent effective therapeutic strategies to prevent kidney fibrosis.


Assuntos
Antioxidantes/farmacologia , Senescência Celular/efeitos dos fármacos , Túbulos Renais Proximais/efeitos dos fármacos , Rim/patologia , Mitofagia/efeitos dos fármacos , Proteínas Quinases/metabolismo , Quercetina/farmacologia , Sirtuína 1/metabolismo , Animais , Antioxidantes/uso terapêutico , Linhagem Celular , Epitélio/efeitos dos fármacos , Fibrose , Citometria de Fluxo , Rim/efeitos dos fármacos , Túbulos Renais Proximais/patologia , Quercetina/uso terapêutico , Ratos
10.
Life Sci ; 257: 118062, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32652138

RESUMO

AIMS: In this study, for the first time, the effect of quercetin (Q) on the characteristic properties, antimicrobial activity, and cell viability of polycaprolactone (PCL)/graphene oxide (GO) electrospun scaffold was investigated. MAIN METHODS: Quercetin loaded graphene oxide nanoparticles have been incorporated into the poly-caprolactone solution, and their mixture has been electrospun to be applied as a nanofibrous scaffold for wound dressing and tissue engineering applications. The properties of scaffolds, like their morphology, tensile strength, hydrophilicity, and in vitro biological performance, are investigated. KEY FINDINGS: The SEM micrographs reveal the uniform bead-free nanofibers with smooth structures have been successfully fabricated via the electrospinning procedure. The overall average of cell viability of NIH/3 T3 fibroblast cells on scaffolds is 95% that means the scaffolds have no toxicity, and FESEM shows cells attach and proliferate on scaffolds. Moreover, among all the fabricated scaffolds, the maximum release of quercetin belongs to PCL/GO/Q 0.5 with about 70% after 15 days, and this scaffold reduces bacterial growth by about 50% after 12 h shows the excellent effect of GO/Q on the antibacterial activity of PCL nanofibers. SIGNIFICANCE: The results confirm that more than 1% of GO has some cytotoxicity, which limits its concentration; therefore, a second antibacterial agent is essential to improve the antibacterial activity of PCL/GO scaffold, and quercetin shows that it is an excellent candidate for this purpose.


Assuntos
Grafite/farmacologia , Poliésteres/química , Quercetina/farmacologia , Tecidos Suporte , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Bandagens , Sobrevivência Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Grafite/administração & dosagem , Grafite/toxicidade , Camundongos , Células NIH 3T3 , Nanofibras , Quercetina/administração & dosagem , Engenharia Tecidual
11.
Chem Biol Interact ; 330: 109198, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32692981

RESUMO

Quercetin 3-O-beta-d-glucopyranoside (isoquercetin) is one of the most frequent metabolites of the Passiflora ligularis Juss. The purpose of this study was to investigate the effect of the aqueous extract and ethanol fraction from P. ligularis Juss leaves on glycaemia and the mechanism of action of isoquercetin on glucose uptake. In the glucose tolerance test, the aqueous extract and ethanol fraction from P. ligularis Juss (125 mg/kg to 500 mg/kg o. g.) reduced glycaemia and increased the hepatic and muscular glycogen content. Phytochemical analysis evidenced the dominant presence of isoquercetin in the extract and fraction from leaves of P. ligularis Juss. Isoquercetin mediates the stimulatory effect on glucose uptake independent of insulin receptor activation but, involve PI3K, MAPK, MEK/ERK pathways and de novo protein synthesis to GLUT-4 translocation. Overall findings revealed that isoquercetin and aqueous extract and ethanol fraction of P. ligularis Juss leaves might be a promising functional food or medicine for the treatment or prevention of diabetes.


Assuntos
Glucose/farmacocinética , Músculo Esquelético/metabolismo , Passiflora/química , Quercetina/análogos & derivados , Animais , Transporte Biológico , Diabetes Mellitus/prevenção & controle , Transportador de Glucose Tipo 4/metabolismo , Compostos Fitoquímicos/análise , Extratos Vegetais/química , Folhas de Planta/química , Quercetina/isolamento & purificação , Quercetina/farmacologia , Ratos
12.
Life Sci ; 258: 118106, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32682916

RESUMO

AIMS: Endothelial dysfunction is a hallmark of hypertension. Herein, we assessed the effect of quercetin, a common dietary antioxidant, on endothelial function of spontaneously hypertensive rats (SHRs), and investigated the underlying molecular mechanisms. MAIN METHODS: The Wistar-Kyoto (WKY) and SHR rats were administered vehicle (1% w/v methyl cellulose) or quercetin (10 mg/kg body weight) by oral gavage once a day for 6 weeks. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured with a tail-cuff system. Functional of rat mesenteric arterioles was assessed by the temperature-controlled myograph. A dose-response curve was generated by the cumulative addition of acetylcholine (ACh) or sodium nitroprusside (SNP). NO production in the culture medium was assessed by measuring the concentration of nitrite, a stable metabolite of NO, using a modified Griess reagent. KEY FINDINGS: Quercetin improved endothelial function and decreased blood pressure in SHRs. Endothelial autophagy, an important cellular homeostatic process, was increased in the early phase of treatment, and decreased in the late phase of treatment. Quercetin promoted autophagy in cultured endothelial cells under both normal and oxidative stress conditions. Pharmacological inhibition of autophagy aggravated endothelial dysfunction in quercetin-treated endothelial cells under oxidative stress, and attenuated the antihypertensive and endothelial protective effects of quercetin in SHRs. SIGNIFICANCE: Quercetin protects endothelial function in hypertensive rats through promotion of autophagy. Thus, autophagy could serve as a potential therapeutic target for hypertension.


Assuntos
Autofagia/efeitos dos fármacos , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Hipertensão/fisiopatologia , Quercetina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
13.
Int. j. morphol ; 38(3): 585-591, June 2020. graf
Artigo em Inglês | LILACS | ID: biblio-1098291

RESUMO

Acetaminophen (also called paracetamol, or APAP) induced nephrotoxicity is reported after accidental or intentional ingestion of an overdose of the drug. Renal tubular ultrastructural alterations induced by APAP overdose associated with the induction of biomarkers of kidney injury have not been investigated before. Also, we investigated whether the combined polyphenolic anti-inflammatory and antioxidants agents, resveratrol (RES) and quercetin (QUR) can protect against APAP-induced acute kidney injury. The model group of rats received a single dose of APAP (2 g/kg), whereas the protective group of rats was pre-treated for 7 days with combined doses of RES (30 mg/kg) and QUR (50 mg/kg) before being given a single dose of APAP. All rats were then sacrificed one day post APAP ingestion. Harvested kidney tissues were prepared for transmission electron microscopy (TEM) staining and blood samples were assayed for urea, creatinine, and biomarkers of inflammation and oxidative stress. TEM images and blood chemistry analysis showed that APAP overdose induced kidney damage as demonstrated by substantial alterations to the proximal convoluted tubule ultrastructure, and a significant (p<0.05) increase in urea, creatinine, tumor necrosis factor-alpha (TNF-a), and malondialdehyde (MDA) blood levels, which were protected by RES+QUR. These findings indicate that APAP induces alterations to the renal tubular ultrastructure, which is inhibited by resveratrol plus quercetin, which also decreases blood levels of kidney injury biomarkers.


El objetivo de este trabajo fue estudiar la nefrotoxicidad inducida por acetaminofeno (también llamado paracetamol o APAP) después de la ingestión accidental o intencional de una sobredosis de la droga. Las alteraciones ultraestructurales tubulares renales inducidas por sobredosis de APAP asociadas con la inducción de biomarcadores de daño renal no se han investigado. Además, estudiamos si los agentes combinados antiinflamatorios y antioxidantes polifenólicos, el resveratrol (RES) y la quercetina (QUR) pueden proteger contra la lesión renal aguda inducida por APAP. El grupo modelo de ratas recibió una dosis única de APAP (2 g / kg), mientras que el grupo protector de ratas se trató previamente durante 7 días con dosis combinadas de RES (30 mg / kg) y QUR (50 mg / kg) antes de recibir una dosis única de APAP. Todas las ratas se sacrificaron un día después de la ingestión de APAP. Los tejidos renales fueron preparados para el análisis a través de la microscopía electrónica de transmisión (MET). En las muestras de sangre se determinaron la urea, creatinina y los biomarcadores de inflamación y estrés oxidativo. Las imágenes MET y el análisis químico de la sangre mostraron que la sobredosis de APAP inducía daño renal, como lo demuestran las alteraciones sustanciales en la ultraestructura del túbulo contorneado proximal, y además, de un aumento significativo (p <0,05) de la urea, creatinina, factor de necrosis tumoral alfa y niveles sanguíneos de malondialdehído, protegidos por RES + QUR. Estos hallazgos indican que APAP induce alteraciones en la ultraestructura tubular renal, inhibida por el resveratrol más quercetina, que también disminuye los niveles sanguíneos de biomarcadores de daño renal.


Assuntos
Animais , Ratos , Quercetina/administração & dosagem , Resveratrol/administração & dosagem , Túbulos Renais/efeitos dos fármacos , Acetaminofen/toxicidade , Quercetina/farmacologia , Ureia/sangue , Ratos Sprague-Dawley , Creatinina/sangue , Microscopia Eletrônica de Transmissão , Modelos Animais de Doenças , Overdose de Drogas , Resveratrol/farmacologia , Túbulos Renais/patologia , Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem
14.
Biochem Pharmacol ; 178: 114123, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32593613

RESUMO

Commonly used drugs for treating many conditions are either natural products or derivatives. In silico modelling has identified several natural products including quercetin as potential highly effective disruptors of the initial infection process involving binding to the interface between the SARS-CoV-2 (Covid-19) Viral Spike Protein and the epithelial cell Angiotensin Converting Enzyme-2 (ACE2) protein. Here we argue that the oral route of administration of quercetin is unlikely to be effective in clinical trials owing to biotransformation during digestion, absorption and metabolism, but suggest that agents could be administered directly by alternative routes such as a nasal or throat spray.


Assuntos
Betacoronavirus/efeitos dos fármacos , Produtos Biológicos/farmacologia , Peptidil Dipeptidase A/metabolismo , Quercetina/farmacologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Betacoronavirus/metabolismo , Betacoronavirus/fisiologia , Produtos Biológicos/administração & dosagem , Produtos Biológicos/química , Ensaios Clínicos como Assunto/métodos , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Avaliação Pré-Clínica de Medicamentos/métodos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Estrutura Molecular , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Ligação Proteica/efeitos dos fármacos , Quercetina/administração & dosagem , Quercetina/química , Internalização do Vírus/efeitos dos fármacos
15.
PLoS One ; 15(6): e0234375, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555682

RESUMO

Renal dysplasia, the major cause of childhood renal failure, is characterized by defective branching morphogenesis and nephrogenesis. Beta-catenin, a transcription factor and cell adhesion molecule, is markedly increased in the nucleus of kidney cells in human renal dysplasia and contributes to its pathogenesis by altering target genes that are essential for kidney development. Quercetin, a naturally occurring flavonoid, reduces nuclear beta-catenin levels and reduces beta-catenin transcriptional activity. In this study, we utilized wild type and dysplastic mouse kidney organ explants to determine if quercetin reduces beta-catenin activity during kidney development and whether it improves the severity of renal dysplasia. In wild type kidney explants, quercetin treatment resulted in abnormal branching morphogenesis and nephrogenesis in a dose dependent manner. In wild type embryonic kidneys, quercetin reduced nuclear beta-catenin expression and decreased expression of beta-catenin target genes Pax2, Six2, and Gdnf, which are essential for kidney development. Our RDB mouse model of renal dysplasia recapitulates the overexpression of beta-catenin and histopathological changes observed in human renal dysplasia. RDB kidneys treated with quercetin resulted in improvements in the overall histopathology, tissue organization, ureteric branching morphogenesis, and nephrogenesis. Quercetin treatment also resulted in reduced nuclear beta-catenin and reduced Pax2 expression. These improvements were associated with the proper organization of vimentin, NCAM, and E-cadherin, and a 45% increase in the number of developing and maturing nephrons. Further, our results show that in human renal dysplasia, beta-catenin, vimentin, and e-cadherin also have abnormal expression patterns. Taken together, these data demonstrate that quercetin treatment reduces nuclear beta-catenin and this is associated with improved epithelial organization of developing nephrons, resulting in increased developing nephrons and a partial rescue of renal dysplasia.


Assuntos
Rim/anormalidades , Rim/efeitos dos fármacos , Quercetina/farmacologia , beta Catenina/metabolismo , Animais , Antígenos CD/metabolismo , Caderinas/metabolismo , Núcleo Celular/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Rim/metabolismo , Masculino , Camundongos , Camundongos Mutantes , Morfogênese/efeitos dos fármacos , Morfogênese/genética , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Técnicas de Cultura de Órgãos , Gravidez , Vimentina/metabolismo , beta Catenina/química , beta Catenina/genética
16.
Life Sci ; 254: 117735, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32360572

RESUMO

AIMS: Recurrent pregnancy loss (RPL) is one of the most common obstetrical diseases, which is a manifestation of antiphospholipid syndrome (APS) with no effective therapy methods. Autophagy and inflammatory responses both play an important role in the pathogenesis of RPL and hyperoside has been demonstrated to have multifarious bioactivities including enhancing autophagy and anti-inflammation. This study aims to investigate the effect of hyperoside on anticardiolipin (aCL)-IgG fractions-induced pregnancy loss. MAIN METHODS: In the present study, the effect of hyperoside was evaluated in a rat model of pregnancy loss induced by aCL-IgG fractions isolated from serum of APS patients. The fetuses were counted and the placentas were weighted and the protein expressions of inflammation and autophagy were measured by western blot analysis. KEY FINDINGS: Treatment with hyperoside (40 mg/kg) improved pregnancy outcome manifest as increasing the weight of fetuses and decreasing the fetal resorption rate. In addition, hyperoside treatment downregulated the expressions of phosphorylated mammalian target of rapamycin (mTOR), phosphorylated p70S6 Kinase (S6K) and inhibited the expressions of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and NF-kB p-p65 in pregnancy loss animal models. SIGNIFICANCE: Hyperoside attenuated pregnancy loss through regulating mTOR/S6K and TLR4/MyD88/NF-kB signaling pathways, which may provide a potential drug candidate for recurrent pregnancy loss therapy.


Assuntos
Aborto Habitual/prevenção & controle , Autofagia/efeitos dos fármacos , Inflamação/prevenção & controle , Quercetina/análogos & derivados , Animais , Modelos Animais de Doenças , Feminino , Masculino , Gravidez , Resultado da Gravidez , Quercetina/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
17.
Adv Exp Med Biol ; 1195: 1-11, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468451

RESUMO

Parkinson's disease (PD) is a major cause of morbidity and mortality among older individuals. Several researchers have suggested that iron chelators which cross the blood-brain barrier (BBB) might have clinical efficacy in treating PD. Therefore, efforts are made not only in order to improve the effect of L-dopa but also to introduce drugs which provide anti-parkinsonian and neuroprotective effects. In this study, quercetin, a flavonoid, exhibited noticeable neuroprotective effects via iron induced-oxidative stress-dependent apoptotic pathways. Our results suggested that quercetin significantly decreased the catalepsy and exhibited neuroprotective effects in rotenone-induced Parkinson. A model of rotenone-induced Parkinsonism in rats produced the decrease in glutathione, SOD, catalase, and serum iron concentration and the increase in H2O2 and lipid peroxidation activity. Quercetin efficiently halted the deleterious toxic effects of L-dopa, revealing normalization of catalepsy and rotarod score, in addition to amelioration of neurochemical parameters, indicating benefit of both symptomatic and neuroprotective therapies. In silico molecular docking studies have also shown that quercetin could be an ideal potential drug target for aromatic L-amino acid decarboxylase and human catechol-O-methyltransferase. In conclusion, quercetin possesses strong iron-chelating abilities and could be recommended as a disease-modifying therapy when administered in combination with L-dopa, early on in the course of Parkinson's disease.


Assuntos
Antiparkinsonianos/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Quercetina/uso terapêutico , Animais , Antiparkinsonianos/farmacologia , Descarboxilases de Aminoácido-L-Aromático/metabolismo , Catecol O-Metiltransferase/metabolismo , Humanos , Levodopa/efeitos adversos , Levodopa/antagonistas & inibidores , Simulação de Acoplamento Molecular , Quercetina/farmacologia
19.
Aging (Albany NY) ; 12(8): 6511-6517, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: covidwho-30425

RESUMO

COVID-19, also known as SARS-CoV-2, is a new emerging zoonotic corona virus of the SARS (Severe Acute Respiratory Syndrome) and the MERS (Middle East Respiratory Syndrome) family. COVID-19 originated in China and spread world-wide, resulting in the pandemic of 2020. For some reason, COVID-19 shows a considerably higher mortality rate in patients with advanced chronological age. This begs the question as to whether there is a functional association between COVID-19 infection and the process of chronological aging. Two host receptors have been proposed for COVID-19. One is CD26 and the other is ACE-2 (angiotensin-converting enzyme 2). Interestingly, both CD26 and the angiotensin system show associations with senescence. Similarly, two proposed therapeutics for the treatment of COVID-19 infection are Azithromycin and Quercetin, both drugs with significant senolytic activity. Also, Chloroquine-related compounds inhibit the induction of the well-known senescence marker, Beta-galactosidase. Other anti-aging drugs should also be considered, such as Rapamycin and Doxycycline, as they behave as inhibitors of protein synthesis, blocking both SASP and viral replication. Therefore, we wish to speculate that the fight against COVID-19 disease should involve testing the hypothesis that senolytics and other anti-aging drugs may have a prominent role in preventing the transmission of the virus, as well as aid in its treatment. Thus, we propose that new clinical trials may be warranted, as several senolytic and anti-aging therapeutics are existing FDA-approved drugs, with excellent safety profiles, and would be readily available for drug repurposing efforts. As Azithromycin and Doxycycline are both commonly used antibiotics that inhibit viral replication and IL-6 production, we may want to consider this general class of antibiotics that functionally inhibits cellular protein synthesis as a side-effect, for the treatment and prevention of COVID-19 disease.


Assuntos
Envelhecimento/efeitos dos fármacos , Antivirais , Betacoronavirus , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Antivirais/farmacologia , Antivirais/uso terapêutico , Azitromicina/farmacologia , Azitromicina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/prevenção & controle , Dipeptidil Peptidase 4/metabolismo , Humanos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Pandemias/prevenção & controle , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Pneumonia Viral/mortalidade , Pneumonia Viral/prevenção & controle , Quercetina/farmacologia , Quercetina/uso terapêutico , Receptores Virais/metabolismo
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