Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.520
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Chem Biol Interact ; 311: 108778, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31377058

RESUMO

The aim of the present study was to evaluate the diuretic effect of 1,3,5,6-tetrahydroxyxanthone (THX), isolated from preparations of Garcinia achachairu Rusby (Clusiaceae) branches, in rats. Wistar normotensive (NTR) and spontaneously hypertensive rats (SHR) received a single oral treatment with THX, hydrochlorothiazide (HCTZ) or just vehicle (VEH). The effects of THX in combination with diuretics of clinical use, as well as with l-NAME, atropine, and indomethacin were also explored. Cumulative urine volume and urinary parameters were measured at the end of the 8-h or 24-h experiment. THX was able to stimulate 8-h and 24-h diuresis in both NTR and SHR, as well as urinary Na+ and K+ excretion, at a dose of 0.1 mg/kg; while 8-h urinary Cl- levels were only significantly increased in the group of animals treated with THX at the dose of 0.3 mg/kg. In addition, Ca2+ content was reduced in the 24-h urine of THX-treated NTR and SHR, like that obtained in the HCTZ (10 mg/kg) group. The combination with HCTZ or furosemide, but not with amiloride, significantly enhanced THX-induced diuresis. The diuretic effect with HCTZ plus THX treatment was accompanied by an increase of the urinary Na+, K+, and Cl- excretion. On the other hand, when given THX in combination with amiloride, there was a significant increase in Na+ and a decrease in K+ excretion, an effect characteristic of this class of diuretics. Moreover, the diuretic effect of THX was heightened after pretreatment with l-NAME, and its ability to induce diuresis was prevented neither in the presence of indomethacin nor in the presence of atropine. However, the pretreatment with atropine completely avoided the saluretic effect stimulated by THX, suggesting, at least in part, the role of muscarinic receptors in the renal effects of THX disclosed in this study.


Assuntos
Diurese/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Xantonas/farmacologia , Animais , Atropina/farmacologia , Clusiaceae/química , Clusiaceae/metabolismo , Feminino , Hidroclorotiazida/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Potássio/urina , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Sódio/urina , Xantonas/uso terapêutico
2.
Int J Nanomedicine ; 14: 6179-6195, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31447559

RESUMO

Background and purpose: Gambogic acid (GA) is a natural compound that exhibited a promising multi-target antitumor activity against several types of cancer. However, the clinical application of this drug is limited due to its poor solubility and low tumor cell-specific delivery. In this study, the monomeric and dimeric Cyclo (Arg-Gly-Asp) c(RGD) tumor targeting peptides (c(RGDfK) and E-[c(RGDfK)2]) were used to modify GA loaded nanostructured lipid carriers (NLC) to reduce the limitations associated with GA and improve its antitumor activity. Methods: GA-NLC was prepared by emulsification and solvent evaporation methods and the surface of the NLC was conjugated with the c(RGD) peptides via an amide bond. The formulations were characterized for particle size, morphology and zeta potential, encapsulation efficiency and drug loading. The in-vitro cytotoxicity and cell uptake studies were conducted using 4T1 cell. Furthermore, the in-vivo antitumor activity and bio-distribution study were performed on female BALB/c nude mice. Results: The c(RGD) peptides modified GA-NLC was successfully prepared with the particles size about 20 nm. The HPLC analysis, FT-IR and 1H-NMR spectra confirmed the successful conjugation of the peptides with the NLC. The in-vitro cytotoxicity study on 4T1 cells revealed that c(RGD) peptides modified GA-NLCs showed significantly higher cytotoxicity at 0.25 and 0.5 µg/mL as compared to unmodified GA-NLC. Furthermore, the cell uptake study demonstrated that better accumulation of E-[c(RGDfK)2] peptides modified NLC in 4T1 cell after 12 h incubation. Moreover, the in-vivo study showed that c(RGD)s functionalized GA-NLC exhibited better accumulation in tumor tissue and tumor growth inhibition. In contrast to the monomeric c(RGD) peptide, the dimeric c(RGD) peptide (E-[c(RGDfK)2]) conjugated GA-NLC showed the improved antitumor activity and tumor targeting ability of GA-NLC. Conclusion: These data provide further support for the potential clinical applications of E-[c(RGDfK)2]-GA-NLC in breast cancer therapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Lipídeos/química , Nanoestruturas/química , Oligopeptídeos/química , Xantonas/uso terapêutico , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanoestruturas/ultraestrutura , Tamanho da Partícula , Multimerização Proteica , Distribuição Tecidual/efeitos dos fármacos , Xantonas/farmacologia
3.
Int J Nanomedicine ; 14: 4649-4666, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31303753

RESUMO

Introduction: Herein, a hyaluronic acid (HA)-coated redox-sensitive chitosan-based nanoparticle, HA(HECS-ss-OA)/GA, was successfully developed for tumor-specific intracellular rapid delivery of gambogic acid (GA). Materials and methods: The redox-sensitive polymer, HECS-ss-OA, was prepared through a well-controlled synthesis procedure with a satisfactory reproducibility and stable resulted surface properties of the assembled cationic micelles. GA was solubilized into the inner core of HECS-ss-OA micelles, while HA was employed to coat outside HECS-ss-OA/GA for CD44-mediated active targeting along with protection from cation-associated in vivo defects. The desirable redox-sensitivity of HA(HECS-ss-OA)/GA was demonstrated by morphology and particle size changes alongside in vitro drug release of nanoparticles in different simulated reducing environments. Results: The results of flow cytometry and confocal microscopy confirmed the HA-receptor mediated cellular uptake and burst drug release in highly reducing cytosol of HA(HECS-ss-OA)/GA. Consequently, HA(HECS-ss-OA)/GA showed the highest apoptosis induction and cytotoxicity over the non-sensitive (HA(HECS-cc-OA)/GA) and HA un-coated (HECS-ss-OA/GA) controls against A549 NSCLC model both in vitro and in vivo. Furthermore, a diminished systemic cytotoxicity was observed in HA(HECS-ss-OA)/GA treated mice compared with those treated by HA un-coated cationic ones and GA solution.


Assuntos
Quitosana/química , Sistemas de Liberação de Medicamentos/métodos , Ácido Hialurônico/química , Micelas , Neoplasias/tratamento farmacológico , Xantonas/administração & dosagem , Xantonas/uso terapêutico , Células A549 , Animais , Antineoplásicos/farmacologia , Apoptose , Varredura Diferencial de Calorimetria , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quitosana/síntese química , Humanos , Ácido Hialurônico/síntese química , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Neoplasias/patologia , Oxirredução , Propionatos/síntese química , Propionatos/química , Espectroscopia de Prótons por Ressonância Magnética , Reprodutibilidade dos Testes , Distribuição Tecidual/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Xantonas/farmacologia
4.
Chem Biol Interact ; 311: 108755, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31319077

RESUMO

Effective control of white adipose tissue accumulation would provide a therapeutic strategy for obesity, which poses a growing global problem. The plant chemical mangiferin stimulates adenosine monophosphate-activated protein kinase (AMPK), which inhibits adipogenesis and has therefore been considered a therapeutic target for obesity and related diseases. We previously reported the anti-inflammatory properties of 6'-O-acetyl mangiferin (OAM). In this study, we evaluated the potential of OAM as an AMPK activator in vitro in 3T3-L1 preadipocytes. OAM inhibited adipogenesis as indicated by lower intracellular lipid and triglyceride accumulation as well as reduced adipogenic gene and protein expression upon treatment. OAM-treated 3T3-L1 cells excreted more glycerol, indicating increased lipolysis, which was supported by increased expression of lipolysis-related genes, including adipose triglyceride lipase and hormone-sensitive lipase. We determined that OAM upregulates lipolysis via phosphorylation-dependent activation of AMPK. Further, OAM upregulated the ß-oxidation pathway as indicated by enhanced expression of phosphorylated acetyl-CoA-carboxylase and long-chain acyl-CoA synthetase 1. In conclusion, OAM markedly decreased intracellular lipid accumulation by enhancing lipolysis via AMPK activation and by upregulating ß-oxidation. Thus, OAM has potential as a drug for the prevention and/or improvement of obesity and related diseases and deserves further study.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipogenia/efeitos dos fármacos , Iris (Planta)/química , Lipólise/efeitos dos fármacos , Xantonas/farmacologia , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Iris (Planta)/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , PPAR gama/genética , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacos , Triglicerídeos/metabolismo
5.
Cell Physiol Biochem ; 53(1): 258-280, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31313541

RESUMO

BACKGROUND/AIMS: Although neuroblastoma is a heterogeneous cancer, a substantial portion overexpresses CD71 (transferrin receptor 1) and MYCN. This study provides a mechanistically driven rationale for a combination therapy targeting neuroblastomas that doubly overexpress or have amplified CD71 and MYCN. For this subset, CD71 was targeted by its natural ligand, gambogic acid (GA), and MYCN was targeted with an HDAC inhibitor, vorinostat. A combination of GA and vorinostat was then tested for efficacy in cancer and non-cancer cells. METHODS: Microarray analysis of cohorts of neuroblastoma patients indicated a subset of neuroblastomas overexpressing both CD71 and MYCN. The viability with proliferation changes were measured by MTT and colony formation assays in neuroblastoma cells. Transfection with CD71 or MYCN along with quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect expression changes. For pathway analysis, gene ontology (GO) and Protein-protein interaction analyses were performed to evaluate the potential mechanisms of GA and vorinostat in treated cells. RESULTS: For both GA and vorinostat, their pathways were explored for specificity and dependence on their targets for efficacy. For GA-treated cells, the viability/proliferation loss due to GA was dependent on the expression of CD71 and involved activation of caspase-3 and degradation of EGFR. It relied on the JNK-IRE1-mTORC1 pathway. The drug vorinostat also reduced cell viability/proliferation in the treated cells and this was dependent on the presence of MYCN as MYCN siRNA transfection led to a blunting of vorinostat efficacy and conversely, MYCN overexpression improved the vorinostat potency in those cells. Vorinostat inhibition of MYCN led to an increase of the pro-apoptotic miR183 levels and this, in turn, reduced the viability/proliferation of these cells. The combination treatment with GA and vorinostat synergistically reduced cell survival in the MYCN and CD71 overexpressing tumor cells. The same treatment had no effect or minimal effect on HEK293 and HEF cells used as models of non-cancer cells. CONCLUSION: A combination therapy with GA and vorinostat may be suitable for MYCN and CD71 overexpressing neuroblastomas.


Assuntos
Antígenos CD , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sistemas de Liberação de Medicamentos , Proteína Proto-Oncogênica N-Myc , Neuroblastoma , Receptores da Transferrina , Antígenos CD/genética , Antígenos CD/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Células HEK293 , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Proteína Proto-Oncogênica N-Myc/antagonistas & inibidores , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patologia , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Receptores da Transferrina/antagonistas & inibidores , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo , Vorinostat/farmacologia , Xantonas/farmacologia
6.
Chem Pharm Bull (Tokyo) ; 67(7): 634-639, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257318

RESUMO

The mango tree (Mangifera indica L.) is a tropical, perennial, woody evergreen plant belonging to the Anacardiaceae. In traditional medicine, dried mango tree leaves were considered useful in treating diabetes and respiratory infections. In this paper, we review the phytochemical research on mango leaves and the mechanisms of benzophenones in lipid metabolism regulation. Thirty-six benzophenones have been isolated from mango leaves; among them, mangiferin is the major compound. Structure-activity relationships of benzophenones in lipid accumulation and the mechanisms of action of mangiferin in lipid metabolism are summarized. After oral administration, mangiferin is partly converted to its active metabolite, northyariol, which contributes to the activation of sirtuin-1 and liver kinase B1 and increases the intracellular AMP level and AMP/adenosine triphosphate ratio, followed by AMP-activated protein kinase phosphorylation, leading to increased phosphorylation of sterol regulatory element-binding protein-1c. Current evidence supports ethnopharmacological uses of mango leaves in diabetes and points toward potential future applications.


Assuntos
Benzofenonas/química , Mangifera/química , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Benzofenonas/isolamento & purificação , Benzofenonas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Mangifera/metabolismo , Folhas de Planta/química , Folhas de Planta/metabolismo , Relação Estrutura-Atividade , Xantonas/administração & dosagem , Xantonas/química , Xantonas/metabolismo , Xantonas/farmacologia
7.
Eur J Med Chem ; 177: 362-373, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158750

RESUMO

Inhibiting the decomposition of carbohydrates into glucose or promoting glucose conversion is considered to be an effective treatment for type 2 diabetes. Herein, a series of novel xanthone-triazole derivatives were designed, synthesized, and their α-glucosidase inhibitory activities and glucose uptake in HepG2 cells were investigated. Most of the compounds showed better inhibitory activities than the parental compound a (1,3-dihydroxyxanthone, IC50 = 160.8 µM) and 1-deoxynojirimycin (positive control, IC50 = 59.5 µM) towards α-glucosidase. Compound 5e was the most potent inhibitor, with IC50 value of 2.06 µM. The kinetics of enzyme inhibition showed that compounds 5e, 5g, 5h, 6c, 6d, 6g and 6h were noncompetitive inhibitors, and molecular docking results were consistent with the noncompetitive property that these compounds bind to allosteric sites away from the active site (Asp214, Glu276 and Asp349). On the other hand, the glucose uptake assays exhibited that compounds 5e, 6a, 6c and 7g displayed high activities in promoting the glucose uptake. The cytotoxicity assays showed that most compounds were low-toxic to human normal hepatocyte cell line (LO2). These novel xanthone triazole derivatives exhibited dual therapeutic effects of α-glucosidase inhibition and glucose uptake promotion, thus they could be use as antidiabetic agents for developing novel drugs against type 2 diabetes.


Assuntos
Glucose/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/farmacologia , Triazóis/farmacologia , Xantonas/farmacologia , Sítios de Ligação , Desenho de Drogas , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/toxicidade , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/metabolismo , Hipoglicemiantes/toxicidade , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/toxicidade , Xantonas/síntese química , Xantonas/metabolismo , Xantonas/toxicidade , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
8.
Fitoterapia ; 137: 104194, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31175954

RESUMO

Four unusual heterodimeric tetrahydroxanthones, usneaxanthones A-D (1-4) were isolated from lichen Usnea aciculifera Vain (Parmeliaceae). Their structures and absolute configurations, particularly the central and axial chiralities, were unambiguously demonstrated by a combination of spectroscopic data (1D, 2D NMR, HRESIMS), electronic circular dichroism (ECD) experiments, and single-crystal X-ray crystallographic analyses. Cytotoxic effects of isolated compounds (1, 2 and 4) were evaluated on HT-29 human colorectal cancer cells. Compound 4 showed potent cytotoxicity against HT-29 with IC50 values of 2.41 µM.


Assuntos
Antineoplásicos/farmacologia , Usnea/química , Xantonas/farmacologia , Antineoplásicos/isolamento & purificação , Células HT29 , Humanos , Estrutura Molecular , Vietnã , Xantonas/isolamento & purificação
9.
Vet Res ; 50(1): 49, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221210

RESUMO

An ethanolic extract from Rhodomyrtus tomentosa leaves (RTL) was studied as a natural alternative to control Staphylococcus aureus, which is an important pathogen responsible for bovine mastitis. The minimal inhibitory concentrations (MICs) of the RTL extract and of rhodomyrtone, a pure compound isolated from the plant, were determined by a microdilution method. Rhodomyrtone and the RTL extract exhibited antibacterial activity against S. aureus, including its persistent phenotype (SCV: small-colony variant) and a biofilm hyperproducer strain, with MICs of 0.25-0.5 and 8-16 µg/mL, respectively. Time-kill kinetics showed a strong bactericidal activity for both the RTL extract- and rhodomyrtone-treated bacteria at 2 × MIC as early as 4 h post-exposure. An additive effect of the extract at 0.5 × MIC was observed in a combination with oxytetracycline or pirlimycin against S. aureus by showing a 64- to 128-fold reduction in antibiotic MICs. Moreover, the RTL extract significantly decreased the number of intracellular SCVs inside bovine mammary epithelial cells. However, the extract or its combination with pirlimycin only slightly improved the activity of pirlimycin against the bacterial colonization of mouse mammary glands. In vitro MICs determined in the presence of casein indicated that the limited activity of the RTL extract in the murine model of mastitis could be linked to neutralization of active components by milk proteins. While the RTL extract showed interesting antibacterial properties in vitro, to be considered as an alternative to antibiotics in dairy farms, formulation studies are needed to cope with the observed reduction of activity in vivo.


Assuntos
Antibacterianos/farmacologia , Mastite Bovina/tratamento farmacológico , Myrtaceae/química , Extratos Vegetais/farmacologia , Infecções Estafilocócicas/veterinária , Staphylococcus aureus/efeitos dos fármacos , Animais , Bovinos , Modelos Animais de Doenças , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Feminino , Mastite Bovina/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Xantonas/farmacologia
10.
Food Chem Toxicol ; 129: 257-268, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31034931

RESUMO

Isoxanthohumol (IXN), a prenylflavonoid from hops and beer, gained increasing attention as a potential chemopreventive agent. In the present study, IXN antimetastatic potential in vitro against the highly invasive melanoma cell line B16-F10 and in vivo in a murine metastatic model was investigated. Melanoma cell viability was diminished in a dose-dependent manner following the treatment with IXN. This decrease was a consequence of autophagy and caspase-dependent apoptosis. Additionally, the dividing potential of highly proliferative melanoma cells was dramatically affected by this isoflavanone, which was in correlation with an abrogated cell colony forming potential, indicating changes in their metastatic features. Concordantly, IXN promoted strong suppression of the processes that define metastasis- cell adhesion, invasion, and migration. Further investigation at the molecular level revealed that the abolished metastatic potential of a melanoma subclone was due to disrupted integrin signaling. Importantly, these results were reaffirmed in vivo where IXN inhibited the development of lung metastatic foci in tumor-challenged animals. The results of the present study may highlight the beneficial effects of IXN on melanoma as the most aggressive type of skin cancer and will hopefully shed a light on the possible use of this prenylflavonoid in the treatment of metastatic malignancies.


Assuntos
Humulus/química , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Melanoma Experimental/patologia , Xantonas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos
11.
Phytomedicine ; 59: 152901, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30981189

RESUMO

BACKGROUND: Diabetes mellitus poses serious threat to the global population due to the alarming diabetic complications it leads to. The current therapeutic options available can be improved for better efficiency and maximum benefits. Combination therapy has been commonly used to improve the efficacy and to minimize the side effects of drugs in current clinical use. PURPOSE: The present study aims to assess the interaction between a natural molecule mangiferin with the commercially available oral hypoglycemic drugs metformin and gliclazide in diabetic rats. METHODS: In this study, the in vitro cytotoxicity and glucose uptake studies were performed in HepG2 cells. Based on experimental data, the combination index of the hypoglycemic drugs like metformin and gliclazide in combination with different doses of mangiferin was determined using COMPUSYN software. Further, in vivo studies were performed in HFD + STZ induced diabetic male Sprague Dawley rats. Serum parameters, enzyme markers, hepatic oxidative stress markers, gene and protein expression studies and histopathological analyses were performed in rat liver to identify the mode of action of the combination drug administration. RESULTS: The in vitro studies on HepG2 cells suggest a positive interaction of mangiferin with both metformin and gliclazide at specific concentrations as evidenced by glucose uptake. The hepatic enzymes, oxidative stress markers, carbohydrate metabolizing enzymes, gene (AMPK, Akt, ACC ß and Glut-2) and protein (PPARα, PPARγ) expression confirmed the results of the in vitro studies. Both the combinations of mangiferin with metformin and mangiferin with gliclazide exhibited potent antidiabetic effect. The combination of mangiferin with metformin was insulin dependent (Akt pathway) whereas the combination of mangiferin and gliclazide was insulin independent (AMPK pathway). CONCLUSION: The overall results suggest that combination of mangiferin with both metformin and gliclazide alleviates diabetic conditions potentially at specific doses and modulates the adverse effect of high dose of commonly used OHD's. This combination therapy can be translated for its clinical use as a diabetes management strategy.


Assuntos
Gliclazida/farmacologia , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Xantonas/farmacologia , Administração Oral , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Quimioterapia Combinada , Enzimas/genética , Enzimas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Gliclazida/administração & dosagem , Células Hep G2 , Humanos , Insulina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Metformina/administração & dosagem , Ratos Sprague-Dawley
12.
Mol Med Rep ; 19(6): 4797-4805, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30957183

RESUMO

Perivascular adipose tissue (PVAT) is considered to serve a vital role during the development of endothelial dysfunction. The current study investigated the effect of exosomes derived from mangiferin­stimulated PVAT on endothelial function, including regeneration, migration, apoptosis and inflammation. The number of exosomes secreted by PVAT was increased by stimulation with mangiferin (0.1, 1 or 10 µM), and uptake of these exosomes by endothelial cells was observed. Exosomes produced by stimulation of PVAT with mangiferin reversed the effects of inflammation­induced endothelial dysfunction following palmitic acid (PA) treatment. Furthermore, nuclear factor (NF)­κB signaling in endothelial cells was significantly increased when treated with PA­induced PVAT­derived exosomes, whereas exosomes from the supernatant of PVAT stimulated with mangiferin reduced p65 and p50 phosphorylation levels in the cells, and inhibited p65 transportation to the nucleus. Taken together, the present study demonstrated that exosomes derived from mangiferin­stimulated PVAT supernatant inhibited inflammation­induced endothelial dysfunction via modulation of NF­κB signaling.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Exossomos/metabolismo , Doenças Vasculares/metabolismo , Xantonas/farmacologia , Tecido Adiposo/patologia , Animais , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Inflamação , Masculino , NF-kappa B , Ácido Palmítico/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
13.
Oxid Med Cell Longev ; 2019: 3640753, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31019651

RESUMO

Among a series of xanthones identified from mangosteen, the fruit of Garcinia mangostana L. (Guttifereae), α- and γ-mangostins are known to be major constituents exhibiting diverse biological activities. However, the effects of γ-mangostin on oxidative neurotoxicity and impaired memory are yet to be elucidated. In the present study, the protective effect of γ-mangostin on oxidative stress-induced neuronal cell death and its underlying action mechanism(s) were investigated and compared to that of α-mangostin using primary cultured rat cortical cells. In addition, the effect of orally administered γ-mangostin on scopolamine-induced memory impairment was evaluated in mice. We found that γ-mangostin exhibited prominent protection against H2O2- or xanthine/xanthine oxidase-induced oxidative neuronal death and inhibited reactive oxygen species (ROS) generation triggered by these oxidative insults. In contrast, α-mangostin had no effects on the oxidative neuronal damage or associated ROS production. We also found that γ-mangostin, not α-mangostin, significantly inhibited H2O2-induced DNA fragmentation and activation of caspases 3 and 9, demonstrating its antiapoptotic action. In addition, only γ-mangostin was found to effectively inhibit lipid peroxidation and DPPH radical formation, while both mangostins inhibited ß-secretase activity. Furthermore, we observed that the oral administration of γ-mangostin at dosages of 10 and 30 mg/kg markedly improved scopolamine-induced memory impairment in mice. Collectively, these results provide both in vitro and in vivo evidences for the neuroprotective and memory enhancing effects of γ-mangostin. Multiple mechanisms underlying this neuroprotective action were suggested in this study. Based on our findings, γ-mangostin could serve as a potentially preferable candidate over α-mangostin in combatting oxidative stress-associated neurodegenerative diseases including Alzheimer's disease.


Assuntos
Transtornos da Memória/tratamento farmacológico , Neurotoxinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Xantonas/uso terapêutico , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/patologia , Peróxido de Hidrogênio/toxicidade , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos Endogâmicos ICR , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Picratos/química , Ratos Sprague-Dawley , Escopolamina , Xantonas/química , Xantonas/farmacologia
14.
Nutrients ; 11(4)2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31010128

RESUMO

Beer, the most popular beverage containing hops, is also frequently consumed by cancer patients. Moreover, non-alcoholic beer, owing to its nutritional value and high content of biological active compounds, is sometimes recommended to patients by oncologists. However, the potential benefits and negatives have to date not been sufficiently evaluated. The present study was designed to examine the effects of four main hop-derived prenylflavonoids on the viability, reactive oxygen species (ROS) formation, activity of caspases, and efficiency of the chemotherapeutics 5-fluorouracil (5-FU), oxaliplatin (OxPt) and irinotecan (IRI) in colorectal cancer cell lines SW480, SW620 and CaCo-2. All the prenylflavonoids exerted substantial antiproliferative effects in all cell lines, with xanthohumol being the most effective (IC50 ranging from 3.6 to 7.3 µM). Isoxanthohumol increased ROS formation and the activity of caspases-3/7, but 6-prenylnaringenin and 8-prenylnaringenin exerted antioxidant properties. As 6-prenylnaringenin acted synergistically with IRI, its potential in combination therapy deserves further study. However, other prenylflavonoids acted antagonistically with all chemotherapeutics at least in one cell line. Therefore, consumption of beer during chemotherapy with 5-FU, OxPt and IRI should be avoided, as the prenylflavonoids in beer could decrease the efficacy of the treatment.


Assuntos
Antineoplásicos/uso terapêutico , Cerveja , Neoplasias Colorretais/tratamento farmacológico , Interações de Medicamentos , Flavonoides/uso terapêutico , Humulus/química , Extratos Vegetais/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Antioxidantes , Cerveja/efeitos adversos , Células CACO-2 , Caspases/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Combinação de Medicamentos , Comportamento Alimentar , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Flavonoides/farmacologia , Fluoruracila/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Oxaliplatina/uso terapêutico , Extratos Vegetais/farmacologia , Propiofenonas/farmacologia , Propiofenonas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Resultado do Tratamento , Xantonas/farmacologia , Xantonas/uso terapêutico
15.
Molecules ; 24(7)2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30965682

RESUMO

Protein kinase CK2 is an emerging target for therapeutic intervention in human diseases, particularly in cancer. Inhibitors of this enzyme are currently in clinical trials, indicating the druggability of human CK2. By virtual screening of the ZINC database, we found that the natural compound bikaverin can fit well in the ATP binding site of the target enzyme CK2. By further in vitro evaluation using CK2 holoenzyme, bikaverin turned to be a potent inhibitor with an IC50 value of 1.24 µM. In this work, the cell permeability of bikaverin was determined using a Caco-2 cell permeability assay as a prerequisite for cellular evaluation and the compound turned out to be cell permeable with a Papp- value of 4.46 × 10-6 cm/s. Bikaverin was tested for its effect on cell viability using a MTT assay and cell proliferation using an EdU assay in different cancer cell lines (MCF7, A427 and A431 cells). Cell viability and cell proliferation were reduced dramatically after treatment with 10 µM bikaverin for 24 h. Additionally the IncuCyte® live-cell imaging system was applied for monitoring the cytotoxicity of bikaverin in the three tested cancer cell lines. Finally, molecular dynamic studies were performed to clarify the ligand binding mode of bikaverin at the ATP binding site of CK2 and to identify the amino acids involved.


Assuntos
Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/química , Inibidores de Proteínas Quinases/farmacologia , Xantonas/farmacologia , Células CACO-2 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Células MCF-7 , Modelos Moleculares , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Xantonas/química
16.
Biosci Biotechnol Biochem ; 83(6): 996-999, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30835638

RESUMO

Endolichenic fungi, nonobligate microfungi that live in lichen, are promising as new bioresources of pharmacological compounds. We found that norlichexanthone isolated from the endolichenic fungus in Pertusaria laeviganda exhibited high antioxidant activity. Norlichexanthone produced by endolichenic fungus had the antioxidant activity with same level of ascorbic acid. This is the first report of high antioxidant activity of norlichexanthone. Abbreviations: AAPH: 2,2'-azobis (2-methylpropionamidine) dihydrochloride; DPPH: 2,2-diphenyl-1-picrylhydrazyl; FL: fluorescein sodium salt; HPLC-PDA: high-performance liquid chromatography with photodiode array; LC-ESI-MS: liquid chromatography with electrospray ionization mass spectrometry; ORAC: oxygen radical absorbance capacity; PB: phosphate buffer; ROS: reactive oxygen species; TLC: thin-layer chromatography.


Assuntos
Antioxidantes/farmacologia , Ascomicetos/metabolismo , Líquens/microbiologia , Xantonas/metabolismo , Xantonas/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia em Camada Delgada/métodos , Análise Espectral/métodos , Xantonas/isolamento & purificação
17.
J Pharm Pharmacol ; 71(6): 1017-1028, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30847938

RESUMO

OBJECTIVES: Investigating the antipulmonary fibrosis effect of mangiferin from Mangifera indica and the possible molecular mechanism. METHODS: In vivo, bleomycin (BLM)-induced pulmonary fibrosis experimental model was used for evaluating antipulmonary fibrosis effect of mangiferin. Histopathologic examination and collagen deposition were investigated by HE and Masson staining as well as detecting the content of hydroxyproline. The expression of transforming growth factor-ß1 (TGF-ß1), α-smooth muscle actin (α-SMA), TLR4 and p-P65 in lung tissue was analysed through immunofluorescence. Leucocytes and inflammatory cytokines including IL-1ß, IL-6, TNF-α and MCP-1 in bronchoalveolar lavage fluid were detected by cell counting and enzyme-linked immunosorbent assay. In vitro, TGF-ß1-induced A549 epithelial-mesenchymal transition (EMT) cell model was used for investigating the possible molecular mechanism. Reactive oxygen species (ROS) generation was detected by DCFH-DA assay. Expression of all proteins was examined by Western blot. KEY FINDINGS: Oral administration of mangiferin could attenuate the severity of BLM-induced pulmonary fibrosis through increasing the survival rate, improving histopathological lesion and body weight loss as well as decreasing pulmonary index visibly. Pulmonary hydroxyproline content, TGF-ß1, and α-SMA levels were reduced significantly. The molecular mechanism of mangiferin for inhibiting pulmonary fibrosis is that it could obviously inhibit the occurrence of inflammation and the secretion of inflammatory cytokine through inhibiting activation of TLR4 and phosphorylation of p65. Meanwhile, EMT process was suppressed obviously by mangiferin through blocking the phosphorylation of Smad2/3 and reducing MMP-9 expression. Besides, mangiferin could significantly inhibit the process of oxidant stress through downregulating the intracellular ROS generation. CONCLUSIONS: Mangiferin attenuates BLM-induced pulmonary fibrosis in mice through inhibiting TLR4/p65 and TGF-ß1/Smad2/3 pathway.


Assuntos
Mangifera/classificação , Estresse Oxidativo/efeitos dos fármacos , Fibrose Pulmonar/prevenção & controle , Xantonas/farmacologia , Células A549 , Animais , Bleomicina/toxicidade , Líquido da Lavagem Broncoalveolar , Colágeno/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Xantonas/isolamento & purificação
18.
Life Sci ; 223: 174-184, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30890405

RESUMO

AIM: Atherosclerosis (AS) is a chronic condition of the arterial vessels and a risk factor for myocardial infarction and stroke. Euxanthone is a xanthone compound extracted from Polygala caudata, and shows vasodilatory action. The aim of this study was to determine the potential pharmacological effects of euxanthone against oxidized low-density lipoprotein (ox-LDL)-induced endothelial cell injury. MATERIAL AND METHODS: Human umbilical vein endothelial cells (HUVECs) were exposed to ox-LDL, following pre-treatment with different concentrations of euxanthone. Viability, apoptosis and DNA fragmentation were respectively assessed by CCK-8 assay, Annexin-V/PI staining and TdT-mediated dUTP Nick-End Labeling (TUNEL) assay. The cellular levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were analyzed by enzyme linked immune-sorbent assays (ELISA), and reactive oxygen species (ROS) levels using dichlorodihydrofluorescin diacetate (DCFH) staining. Quantitative RT-PCR and Western blotting were respectively used to analyze the expression levels of specific mRNAs and proteins. HUVECs were transfected with Nrf2 siRNA to induce knockdown of the latter. KEY FINDINGS: Euxanthone pre-treatment rescued the HUVECs from ox-LDL-induced cytotoxicity, apoptosis and DNA fragmentation in a dose-dependent manner. In addition, euxanthone also significantly reversed ox-LDL-triggered loss of mitochondrial membrane potential (MMP), cytochrome C release from mitochondria to cytosol, cleavage of caspase-3 and PARP, and increase in Bax/Bcl-2 ratio. Pre-treatment with euxanthone markedly suppressed ox-LDL-induced ROS generation and inhibition of antioxidant enzymes, as well as the up-regulation of pro-inflammatory factors like MCP-1, IL-1ß and TNF-α in the HUVECs. Euxanthone up-regulated and activated Nrf2 by repressing Keap1, and increased the expression of its downstream genes HO-1 and NQO-1. Nrf2 knockdown abrogated the cyto-protective, anti-apoptotic, anti-oxidant and anti-inflammatory effects of euxanthone in ox-LDL-treated HUVECs. Finally, euxanthone activated Nrf2 via the MAPK pathway and blocking the latter likewise negated the protective effects of euxanthone against cell ox-LDL. SIGNIFICANCE: Euxanthone protected HUVECs against the oxidative and inflammatory damage induced by ox-LDL, indicating its potential as a novel therapeutic agent for AS.


Assuntos
Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Lipoproteínas LDL/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Xantonas/farmacologia , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/metabolismo , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Endoteliais da Veia Umbilical Humana , Humanos , Marcação In Situ das Extremidades Cortadas , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Polygala/química , Xantonas/isolamento & purificação
19.
Eur J Med Chem ; 168: 405-413, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30831408

RESUMO

Inflammatory breast cancer (IBC) is a highly metastatic, lethal form of breast cancer that lacks targeted therapeutic strategies. Inspired by the promising cytotoxicity of gambogic acid and related caged xanthones in spheroidsMARY-X, an in vitro preclinical IBC model, we constructed a library of synthetic analogs and performed structure-activity relationship studies. The studies revealed that functionalizing the A-ring of the caged xanthone framework can significantly affect potency. Specifically, introduction of hydroxyl or fluorine groups at discrete positions of the A-ring leads to enhanced cytotoxicity at submicromolar concentrations. These compounds induce complete dissolution of spheroidsMARY-X with subsequent apoptosis of both the peripherally- and centrally-located cells, proliferative and quiescent-prone (e.g. hypoxic), respectively. These results highlight the structural flexibility and pharmacological potential of the caged xanthone motif for the design of IBC-targeting therapeutics.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Xantonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Neoplasias Inflamatórias Mamárias/patologia , Estrutura Molecular , Relação Estrutura-Atividade , Xantonas/síntese química , Xantonas/química
20.
J Mol Neurosci ; 68(2): 275-286, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30927203

RESUMO

Sevoflurane is a widely used anesthetic. A series of recent studies have shown that exposure to sevoflurane at an early stage is a risk factor for the development of learning and memory dysfunction. Euxanthone is a xanthone derivative obtained from Polygala caudata. This study was designed to investigate whether euxanthone can confer neuroprotective activities against sevoflurane-induced neurotoxicity and to determine the associated molecular mechanisms. Neonatal Sprague-Dawley (male) rats were exposed to sevoflurane with or without euxanthone treatment. The behavioral data of rats were collected at P41 (the beginning of the adult stage). The hippocampal tissue was obtained following exposure to sevoflurane. The reactive oxygen species (ROS) level in the hippocampal tissue was determined by a commercial kit. The expression of apoptotic markers and inflammatory cytokines was determined by western blot. The mRNA and protein expression of Nrf2 were determined by qRT-PCR and western blot, respectively. The rat in vitro model of neurotoxicity was established using isolated hippocampal neurons. Nrf2 expression was repressed by transfection of siRNA. The cell viability was assessed by the CCK-8 assay. The flow cytometry was performed to measure apoptotic cell death. Our data showed that euxanthone treatment at the neonatal stage protected against sevoflurane-induced neurotoxicity in adult rats. At the molecular level, our findings revealed that the neuroprotective activities of euxanthone were associated with decreased sevoflurane-induced apoptosis cell death and neuroinflammation. More importantly, our results provide the experimental evidence that euxanthone confers neuroprotection by upregulating Nrf2 expression. Euxanthone has a therapeutic potential for clinical prevention of sevoflurane-induced neurotoxicity.


Assuntos
Antioxidantes/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Xantonas/farmacologia , Anestésicos Inalatórios/toxicidade , Animais , Células Cultivadas , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Sevoflurano/toxicidade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA