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1.
Biomed Chromatogr ; 33(12): e4678, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31412148

RESUMO

We aimed to investigate the pharmacokinetics, bioavailability and urinary excretion of scopolin and its metabolite scopoletin in rats. An LC-tandem mass spectrometry (MS/MS) method for simultaneous determination of scopolin and scopoletin in rat biomatrices was developed and validated over a plasma and urine concentration range of 5.0-2000 ng/mL. Chromatographic separation was performed on a Hypersil GOLD C18 column with acetonitrile and 0.1% formic acid in water as mobile phase with gradient elution. Detection was performed in the positive ionization and selected reaction monitoring mode. The intra- and inter-batch precision and accuracy, extraction recovery and matrix effect and stability of scopolin and scopoletin were well within the acceptable limits of variation. There was no gender-related difference in the pharmacokinetic profiles of scopolin. There were significant differences in total area under the concentration-time curve (AUC), time required to achieve a maximal concentration (Tmax ) and apparent clearance from plasma (Cl/F) of scopoletin between the male and female rats (p < .05). The bioavailability (F) of scopolin was exceptionally low. The maximal excretion rates were 7.61 µg/h and 7.15 µg/h for scopolin and 31.68 µg/h and 25.58 µg/h for scopoletin in male and female rats, respectively. The LC-MS/MS method was successfully applied to the pharmacokinetic, bioavailability and urinary excretion studies of scopolin and its metabolite scopoletin following a single administration of scopolin to rats.


Assuntos
Cromatografia Líquida/métodos , Cumarínicos/farmacocinética , Cumarínicos/urina , Glucosídeos/farmacocinética , Glucosídeos/urina , Escopoletina/farmacocinética , Escopoletina/urina , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Disponibilidade Biológica , Cumarínicos/administração & dosagem , Feminino , Glucosídeos/administração & dosagem , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Escopoletina/administração & dosagem
2.
Int J Pharm ; 568: 118529, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31323368

RESUMO

Rapamycin as a novel macrolide immunosuppressive agent has been commonly used in organ transplantation owing to its stronger immunosuppressive effect, non-nephrotoxicity and lower side effect. However its drawbacks of low bioavailability and big individual difference remain to be improved in clinical application. Here rapamycin loaded TPGS-Lecithins-Zein nanoparticles (RTLZ-NPs) with core-shell structure were prepared by the phase separation method. The RTLZ-NPs were approximately 190.3 nm in size, with PDI and zeta potential about 0.256 and -19.71 mV respectively. Drug entrapment and loading achieved were about 86.64 and 25.73% respectively. Meanwhile RTLZ-NPs exhibited favorable enzymolysis resistance abilities in gastrointestinal environments and enhanced uptake in Caco-2 cells. The optimum absorption sites of rapamycin in the intestine were duodenum and jejunum as single-pass intestinal perfusion assay. Upon also considering the results of Caco-2 cell assay, it could be speculated that the transport of rapamycin in vivo involved active transport as well as P-glycoprotein (P-gp) based efflux. Finally, the relative oral bioavailability of RTLZ-NPS was 4.33 fold higher than free rapamycin in SD rat. Altogether the designed nanoparticles can be an efficient oral delivery strategy for rapamycin analogues to prevent the attacks from destructive enzymes, reduce cell efflux, increase cell uptake, and then enhance the oral bioavailability.


Assuntos
Portadores de Fármacos/administração & dosagem , Lecitinas/administração & dosagem , Nanopartículas/administração & dosagem , Sirolimo/administração & dosagem , Vitamina E/administração & dosagem , Zeína/administração & dosagem , Administração Oral , Animais , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/administração & dosagem , Cumarínicos/química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Humanos , Absorção Intestinal/efeitos dos fármacos , Lecitinas/química , Lecitinas/farmacocinética , Masculino , Nanopartículas/química , Ratos Sprague-Dawley , Sirolimo/química , Sirolimo/farmacocinética , Tiazóis/administração & dosagem , Tiazóis/química , Vitamina E/química , Vitamina E/farmacocinética , Zeína/química , Zeína/farmacocinética
3.
J Agric Food Chem ; 67(32): 8810-8818, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31318199

RESUMO

Citrus grandis (L.) Osbeck is a popular fruit cultivated around the world, and its peels are sometimes used for the treatment of cough, abdominal pain, and indigestion in China. However, the peel is discarded after fruit consumption in most cases, and its chemical constituents and biological activities have not been validated before. The present study focused on evaluation of the chemical and pharmacological profile of coumarins from peels of C. grandis against inflammation. The extracts and phytochemicals from peels of C. grandis were prepared, and anti-inflammatory activities were carried out in vivo and in vitro, including inhibiting xylene-induced ear edema and carrageenan-induced paw edema in mice and the production of inflammatory cytokines (interleukin 1ß, prostaglandin 2, and tumor-necrosis factor α) in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Results indicated that methanolic extract, ethyl acetate fraction, and four major coumarins (compounds 7, 8, 13, and 16) inhibited swelling induced by xylene and carrageenan, separately, in vivo. Furthermore, 18 coumarins inhibited inflammatory factor secretion in macrophages primed by LPS, in which compounds 4, 6, 7, 10, 17 showed the most pronounced change, which were comparable to dexamethasone. In summary, peel of C. grandis showed an anti-inflammatory effect and coumarin compounds were responsible for regulating inflammatory mediators and cytokines, which might provide a novel nutritional strategy for inflammatory diseases.


Assuntos
Anti-Inflamatórios/administração & dosagem , Citrus/química , Cumarínicos/administração & dosagem , Edema/tratamento farmacológico , Frutas/química , Extratos Vegetais/administração & dosagem , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Cumarínicos/química , Cumarínicos/isolamento & purificação , Dinoprostona/imunologia , Edema/genética , Edema/imunologia , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Células RAW 264.7 , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Resíduos/análise
4.
Mol Pharmacol ; 96(3): 393-400, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31308264

RESUMO

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by cutaneous lesions and intense pruritus. The warm temperature-activated Ca2+-permeable transient receptor potential vanilloid (TRPV)3 channel is abundantly expressed in keratinocytes, and gain-of-function mutations of TRPV3 cause skin lesions and pruritus in rodents and humans, suggesting an involvement of TRPV3 in the pathogenesis of AD. Here we report that pharmacological and genetic inhibition of TRPV3 attenuates skin lesions and dermatitis in mice. We found that TRPV3 proteins, together with inflammatory factors tumor necrosis factor (TNF)-α and interleukin (IL)-6, were upregulated in the skin of mice in a AD-like model induced by topical application of chemical 2,4-dinitrofluorobenzene, as detected by Western blot analysis and immunostaining assays. Pharmacological activation of TRPV3 by channel agonist and skin sensitizer carvacrol resulted in the development of AD in wild-type mice but not in TRPV3 knockout mice. Furthermore, inhibition of TRPV3 by natural osthole reversed the severity of inflammatory dorsal skin and ear edema in a dose-dependent manner and also decreased expression of inflammatory factors TNF-α and IL-6. Taken together, our findings demonstrate the involvement of overactive TRPV3 in the progressive pathology of AD in mice, and topical inhibition of TRPV3 channel function may represent an effective option for preventing and treating AD or inflammatory skin diseases. SIGNIFICANCE STATEMENT: The overactive transient receptor potential vanilloid TRPV3 channel is critically involved in the pathogenesis of atopic dermatitis. Inhibition of TRPV3 channel function by topical natural osthole may represent an effective therapy for management of atopic dermatitis aimed at preventing or alleviating skin lesions and severe itching.


Assuntos
Cumarínicos/administração & dosagem , Dermatite Atópica/metabolismo , Dinitrofluorbenzeno/efeitos adversos , Canais de Cátion TRPV/metabolismo , Administração Tópica , Animais , Cumarínicos/farmacologia , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Temperatura Alta , Humanos , Interleucina-6/metabolismo , Masculino , Camundongos , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos
5.
Int J Pharm ; 568: 118474, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31279055

RESUMO

Development of topically administered drug delivery systems for the treatment of ocular diseases have majorly focused on enhancing bioavailability of drugs in the ocular tissues. However, control of spatial distribution of topically administered drugs so as to restrict/avoid drug bioavailability at sensitive ocular tissues that are prone to drug induced adverse effects has not been explored. In this study, we aimed to reduce the bioavailability of topically administered corticosteroid, triamcinolone acetonide (TA) in lens via controlled spatial distribution in order to minimize TA induced posterior subcapsular cataract (PSC). For this, a negatively charged polymeric core-shell nanoparticulate drug delivery system composed of polycaprolactone (PCL) core and pluronic® F-68 (PF68) shell was fabricated. For in vivo studies, coumarin-6 (COU) loaded nanoparticles (NPs) were fabricated and studied for their biodistribution after topical administration in mice eyes and compared with free COU biodistribution. The administered COU loaded NPs differentially distributed in mice eyes and showed lower bioavailability in lens compared to free COU. Further, in vivo efficacy of the delivery system for its ability to minimize the rate of PSC progression was evaluated in diabetic rats. The results demonstrated that TA loaded PCL-PF68 NPs decreased PSC progression compared to free TA when administered topically.


Assuntos
Catarata/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Glucocorticoides/administração & dosagem , Triancinolona Acetonida/administração & dosagem , Administração Oftálmica , Animais , Disponibilidade Biológica , Caderinas/metabolismo , Catarata/induzido quimicamente , Catarata/metabolismo , Catarata/patologia , Cumarínicos/administração & dosagem , Cumarínicos/química , Cumarínicos/farmacocinética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Liberação Controlada de Fármacos , Olho/efeitos dos fármacos , Olho/metabolismo , Olho/patologia , Glucocorticoides/química , Masculino , Camundongos Endogâmicos C57BL , Poloxâmero/administração & dosagem , Poloxâmero/química , Poliésteres/administração & dosagem , Poliésteres/química , Ratos Sprague-Dawley , Tiazóis/administração & dosagem , Tiazóis/química , Tiazóis/farmacocinética , Triancinolona Acetonida/química
6.
Food Funct ; 10(6): 3135-3141, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31041969

RESUMO

Urolithin A (Uro-A) is an anti-inflammatory and cancer chemopreventive metabolite produced by the gut microbiota from the polyphenol ellagic acid. However, in vivo conjugation of Uro-A to Uro-A glucuronide (Uro-A glur) dramatically hampers its activity. We describe here for the first time the tissue deconjugation of Uro-A glur to Uro-A after lipopolysaccharide (LPS)-induced inflammation, which could explain the systemic in vivo activity of free Uro-A in microenvironments subjected to inflammatory stimuli.


Assuntos
Cumarínicos/farmacocinética , Glucuronídeos/farmacocinética , Inflamação/tratamento farmacológico , Animais , Cumarínicos/administração & dosagem , Cumarínicos/química , Ácido Elágico/metabolismo , Microbioma Gastrointestinal , Trato Gastrointestinal/microbiologia , Glucuronídeos/administração & dosagem , Glucuronídeos/química , Humanos , Inflamação/metabolismo , Inflamação/microbiologia , Masculino , Ratos , Ratos Sprague-Dawley
7.
Int J Mol Sci ; 20(7)2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30987181

RESUMO

(1) Background: Chemokine-like factor 1 (CKLF1) is a chemokine with potential to be a target for stroke therapy. Compound IMM-H004 is a novel coumarin derivative screened from a CKLF1/C-C chemokine receptor type 4 (CCR4) system and has been reported to improve cerebral ischemia/reperfusion injury. This study aims to investigate the protective effects of IMM-H004 on cerebral ischemia injury and its infectious cardiopulmonary complications in adult and aged rats from the CKLF1 perspective. (2) Methods: The effects of IMM-H004 on the protection was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining, behavior tests, magnetic resonance imaging (MRI) scans, enzyme-linked immunosorbent assay (ELISA), Nissl staining, histo-pathological examination, and cardiopulmonary function detection. Immunohistological staining, immunofluorescence staining, quantitative real-time PCR (qPCR), and western blotting were used to elucidate the underlying mechanisms. (3) Results: IMM-H004 protects against cerebral ischemia induced brain injury and its cardiopulmonary complications, inhibiting injury, and inflammation through CKLF1-dependent anti-inflammation pathway in adult and aged rats. IMM-H004 downregulates the amount of CKLF1, suppressing the followed inflammatory response, and further protects the damaged organs from ischemic injury. (4) Conclusions: The present study suggested that the protective mechanism of IMM-H004 is dependent on CKLF1, which will lead to excessive inflammatory response in cerebral ischemia. IMM-H004 could also be a therapeutic agent in therapy for ischemic stroke and cardiopulmonary complications in the aged population.


Assuntos
Envelhecimento/patologia , Isquemia Encefálica/tratamento farmacológico , Quimiocinas/metabolismo , Cumarínicos/uso terapêutico , Inflamação/patologia , Pulmão/patologia , Proteínas com Domínio MARVEL/metabolismo , Miocárdio/patologia , Fármacos Neuroprotetores/uso terapêutico , Animais , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/etiologia , Lesões Encefálicas/patologia , Isquemia Encefálica/complicações , Cumarínicos/administração & dosagem , Cumarínicos/química , Cumarínicos/farmacologia , Inflamação/metabolismo , Masculino , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Ratos Sprague-Dawley , Acidente Vascular Cerebral/complicações
8.
Biomed Pharmacother ; 115: 108893, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31022598

RESUMO

The comorbidity of coronary heart disease (CHD) and depression in patients is extremely prevalent, with a rate from 20 to 50%, while depression-like behaviors exist in a larger percentage of patients. Therefore, the study of comorbidities is particularly urgent. Chaihu-Shugan-San (CSS), a classical traditional Chinese medicine formula, has been used to treat CHD with depression for hundreds of years. However, the mechanism of its action on comorbidities remains unclear. Here, we focused on the behavioral changes in ApoE-/- mice fed a high-fat diet (HFD) and elucidated the mechanism of CSS and its main absorbed component, meranzin hydrate (MH), as an anti-atherosclerosis and anti-depression agent. In the present study, mice were fed an HFD for 16 weeks and were intragastrically administered high and low doses of CSS and MH. Depressive-like behaviors were evaluated by the sucrose preference test, the open-field test, the light-dark test and the tail-suspension test, after which atherosclerotic plaques, plasma lipids, inflammatory cytokine levels and the expression of BDNF/TrkB were measured. We demonstrated that the atherosclerosis model group exhibited significant depressant behaviors. Moreover, CSS inhibited depressive-like behavioral changes, reduced atherosclerotic plaque areas, plasma total cholesterol, triglycerides, LDL-cholesterol levels and inflammatory cytokines including TNF-α, IL-1ß, and IL-6 in plasma and hippocampi, increased the protein and mRNA expression of BDNF and TrkB in the aorta and the hippocampus. Interestingly, MH, the main component in CSS that is absorbed in the plasma and hippocampus, exerted effects similar to those of CSS. In addition, MH increased the protein and mRNA expression of BDNF and TrkB in human umbilical vein endothelial cells (HUVECs) induced by LPS. Collectively, these results suggest that MH represents the CSS decoction, induces anti-atherosclerosis effects and improves depression-like behaviors in HFD-fed ApoE-/- mice. Moreover, the regulation of proinflammatory factors and BDNF-TrkB signaling are possibly involved in this process. Our findings indicate that MH is a potential phytochemical compound for the prevention of the comorbidity of atherosclerosis and depression.


Assuntos
Aterosclerose/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cumarínicos/farmacologia , Glicoproteínas de Membrana/metabolismo , Extratos Vegetais/farmacologia , Proteínas Tirosina Quinases/metabolismo , Animais , Anti-Inflamatórios , Fator Neurotrófico Derivado do Encéfalo/genética , Cumarínicos/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout para ApoE , Extratos Vegetais/administração & dosagem , Proteínas Tirosina Quinases/genética , Transdução de Sinais/efeitos dos fármacos
9.
Hum Exp Toxicol ; 38(7): 775-784, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30943761

RESUMO

Our aim was to investigate the effects of resveratrol, auraptene, and curcumin on the spatial learning and spatial memory retention in the Morris water maze (MWM). The effects of 4-day bilateral intrahippocampal (i.h.) infusions of dimethyl sulfoxide (DMSO), H-89 as a protein kinase AII inhibitor, auraptene/H-89, resveratrol/H-89, and curcumin/H-89 were investigated on spatial memory acquisition in MWM. The rats were trained for 4 days; each day included one block of four trials. Post-training probe tests were performed on day 5 in acquisition test. For retention assessments, different animals were trained for 4 days and then infused (i.h.) with either DMSO, H-89, auraptene/H-89, resveratrol/H-89, or curcumin/H-89. The retention test was performed 48 h after the last training trial. The bilateral infusion of H-89 led to a significant impairment in spatial memory in acquisition and retention tests accompanied with a significant decrease in expressions of cAMP response-element binding (CREB) and pCREB proteins in hippocampus. Resveratrol and curcumin reversed the H-89-induced spatial memory acquisition and retention impairments with significant increases in both CREB and pCREB proteins expressions compared to H-89-treated animals. Auraptene showed significant effects in reversing H-89-induced impairments in spatial memory retention but not spatial memory acquisition.


Assuntos
Cumarínicos/administração & dosagem , Curcumina/administração & dosagem , Transtornos da Memória/tratamento farmacológico , Memória/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Resveratrol/administração & dosagem , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Infusões Parenterais , Isoquinolinas/toxicidade , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Ratos Wistar , Sulfonamidas/toxicidade
10.
J Nutr Sci Vitaminol (Tokyo) ; 65(1): 66-71, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30814414

RESUMO

Cerebral ischemia/reperfusion leads to delayed neuronal cell death, resulting in brain damage. Auraptene (AUR) and naringin (NGIN), which exert neuroprotective effects in ischemic brain, are abundant in the peel of Citrus kawachiensis. Although parts of AUR/NGIN are transited from the peel to the juice during the squeezing of this fruit, these amounts in juice might be too low to exert effects. We thus prepared the AUR/NGIN-rich fruit juice of C. kawachiensis by addition of peel paste to the raw juice. The present study revealed that orally administration of the dried powder of this AUR/NGIN-rich fruit juice (2.5 g/kg/d) for 7 d to ischemic mice significantly suppressed the ischemia-induced neuronal cell death in the hippocampus, which was coincidently with the reduction of hyperactivation of microglia and astrocytes. These results suggest that AUR/NGIN-rich juice of C. kawachiensis may possess therapeutic potential for the prevention of neurodegenerative diseases via inhibition of inflammatory processes.


Assuntos
Anti-Inflamatórios/farmacologia , Isquemia Encefálica/tratamento farmacológico , Citrus , Cumarínicos/farmacologia , Flavanonas/farmacologia , Fitoterapia/métodos , Preparações de Plantas/farmacologia , Animais , Encéfalo/metabolismo , Isquemia Encefálica/induzido quimicamente , Morte Celular/efeitos dos fármacos , Cumarínicos/administração & dosagem , Flavanonas/administração & dosagem , Sucos de Frutas e Vegetais , Hipocampo , Camundongos , Fármacos Neuroprotetores/farmacologia , Pós
11.
J Enzyme Inhib Med Chem ; 34(1): 808-817, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30879350

RESUMO

The bromodomain and extra-terminal (BET) bromodomains, particularly BRD4, have been identified as promising therapeutic targets in the treatment of many human disorders such as cancer, inflammation, obesity, and cardiovascular disease. Recently, the discovery of novel BRD4 inhibitors has garnered substantial interest. Starting from scaffold hopping of the reported compound dihydroquinazolinone (PFI-1), a series of coumarin derivatives were designed and synthesised as a new chemotype of BRD4 inhibitors. Interestingly, the representative compounds 13 exhibited potent BRD4 binding affinity and cell proliferation inhibitory activity, and especially displayed a favourable PK profile with high oral bioavailability (F = 49.38%) and metabolic stability (T1/2 = 4.2 h), meaningfully making it as a promising lead compound for further drug development.


Assuntos
Cumarínicos/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Administração Oral , Proteínas de Ciclo Celular , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cumarínicos/administração & dosagem , Cumarínicos/farmacocinética , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Concentração Inibidora 50 , Quinazolinonas/química , Relação Estrutura-Atividade
12.
J Thromb Thrombolysis ; 47(4): 495-504, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30859370

RESUMO

In patients with active cancer and acute venous thromboembolism (VTE), the low-molecular-weight-heparin (LMWH) dalteparin is more effective than vitamin K antagonist (VKA) in reducing the risk of recurrent venous thromboembolism (rVTE) without increasing the risk of bleeding. However, the relative benefit of LMWH versus VKA in patients with active cancer at high or low risk of rVTE and bleeding is unclear. This post hoc analysis used data from the CLOT study to explore the efficacy and safety of LMWH versus VKA in preventing recurrent thrombosis in high- and low-risk patients with active cancer. High-risk patients were defined by metastatic disease and/or antineoplastic treatment at baseline; low-risk patients presented with neither. Among high-risk patients, rVTE occurred in 25/318 (8%) (LMWH) versus 53/314 (17%) (VKA) (hazard ratio, 0.44; p = 0.001). No significant difference was detected in the rate of major or any bleeding. The 6-month mortality rate was 40% (LMWH) versus 41% (VKA). In low-risk patients, 2/20 (10%) (LMWH) had rVTE versus 0/24 (0%) (VKA) (hazard ratio, not estimable; p = 0.998). No significant difference was detected in the rate of major or any bleeding. The 6-month mortality rate was 20% (LMWH) versus 29% (VKA). In patients with cancer-associated thrombosis at high risk of rVTE and bleeding, the LMWH dalteparin was more effective than VKA in reducing the risk of rVTE without increasing the risk of bleeding. No difference in rate of rVTE or bleeding was observed between LMWH and VKA among low-risk patients.


Assuntos
Cumarínicos/administração & dosagem , Dalteparina/administração & dosagem , Neoplasias/tratamento farmacológico , Trombose/tratamento farmacológico , Tromboembolia Venosa/tratamento farmacológico , Idoso , Cumarínicos/efeitos adversos , Dalteparina/efeitos adversos , Intervalo Livre de Doença , Feminino , Hemorragia/induzido quimicamente , Hemorragia/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/mortalidade , Neoplasias/patologia , Taxa de Sobrevida , Trombose/mortalidade , Trombose/patologia , Tromboembolia Venosa/mortalidade , Tromboembolia Venosa/patologia
13.
J Sci Food Agric ; 99(9): 4397-4406, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30861122

RESUMO

BACKGROUND: Compounds of the inner shell of chestnut (Castanea crenata) have diverse biological activities, including anti-cancer and anti-oxidant activities. Here we explored the effects of an extract of chestnut inner shells and of its bioactive component scoparone on vascular smooth muscle cell migration and vessel damage. RESULTS: The ethanol extract of chestnut inner shells, containing 11 major compounds, inhibited platelet-derived growth factor (PDGF)-BB-induced migration of rat aortic smooth muscle cells (RASMCs). Among these compounds, scoparone (6,7-dimethoxycoumarin) suppressed RASMC migration and wound healing in response to PDGF-BB but did not affect RASMC proliferation. In RASMCs, scoparone inhibited the PDGF-BB-induced rat aortic sprout outgrowth and attenuated the PDGF-BB-mediated increase in phosphorylation of mitogen-activated protein kinases (MAPKs), p38 MAPK and extracellular signal-regulated kinase 1/2. The in vivo administration of scoparone resulted in the attenuation of neointima formation in balloon-injured carotid arteries of rats. CONCLUSION: These findings demonstrate that scoparone, found in chestnut inner shells, may inhibit cell migration through suppression of the phosphorylation of MAPKs in PDGF-BB-treated RASMCs, probably contributing to the reduction of neointimal hyperplasia induced after vascular injury. Therefore, scoparone and chestnut inner shell may be a potential agent or functional food, respectively, for the prevention of vascular disorders such as vascular restenosis or atherosclerosis. © 2019 Society of Chemical Industry.


Assuntos
Becaplermina/metabolismo , Cumarínicos/administração & dosagem , Fagaceae/química , Hiperplasia/tratamento farmacológico , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , Neointima/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cumarínicos/química , Humanos , Hiperplasia/fisiopatologia , Masculino , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Neointima/metabolismo , Neointima/fisiopatologia , Nozes/química , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley
14.
J Pharmacol Sci ; 139(3): 151-157, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30733181

RESUMO

Glucocorticoids are widely prescribed for lots of pathological conditions, however, can produce 'Cushingoid' side effects including central obesity, glucose intolerance, insulin resistance and so forth. Our study is intended to investigate the improving effects of coumarins on diabetogenic action of dexamethasone in vivo and in vitro and elucidate potential mechanisms. ICR mice treated with dexamethasone for 21 days exhibited decreased body weight, increased blood glucose and impaired glucose tolerance, which were prevented by fraxetin (40 mg/kg/day), esculin (40 mg/kg/day) and osthole (20 mg/kg/day), respectively. Esculin, fraxetin and osthole also could promote glucose uptake in normal C2C12 myotubes, and improve insulin resistance in myotubes induced by dexamethasone. Western blotting results indicated that esculin, fraxetin and osthole could boost Akt activation, stimulate GLUT4 translocation, thus alleviate insulin resistance. Esculin and osthole also could activate AMPK, thereby phosphorylate TBC1D1 at Ser237, and consequently ameliorate diabetogenic action of dexamethasone. Our study indicates coumarins as potential anti-diabetic candidates or leading compounds for drug development.


Assuntos
Glicemia/efeitos dos fármacos , Cumarínicos/farmacologia , Dexametasona/toxicidade , Músculo Esquelético/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Western Blotting , Linhagem Celular , Cumarínicos/administração & dosagem , Dexametasona/administração & dosagem , Esculina/farmacologia , Glucocorticoides/administração & dosagem , Glucocorticoides/toxicidade , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Molecules ; 24(4)2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30791539

RESUMO

Wedelolactone is a coumarin ether with significant hepatoprotective effects. However, there are few pharmacokinetic studies of wedelolactone, which will affect the studies of its efficacy and potential toxicity. In this study, a selective ultra-performance liquid chromatography (UPLC) method was developed to confirm the pharmacokinetic parameters of wedelolactone in rat plasma. The chromatographic separation was carried out on a Kromasil C18 UPLC column (250 × 4.6 mm; 5.0 µm) by gradient mobile phase of methanol-water containing 0.5% acetic acid (v/v). Perfect linearity was obtained and the samples were stable under different conditions. The intra-day and inter-day precisions (relative standard deviation, %) were within 3.81% and accuracies (relative error, %) ranged from -4.01% to 7.12%. The extraction recoveries in rat plasma ranged from 95.98% to 108.93%. This rapid method was successfully applied in the pharmacokinetic study of wedelolactone in rat plasma. Following the oral administration of 5.00 mg/kg wedelolactone, the wedelolactone was rapidly absorbed. Pharmacokinetic parameters were used to quantitatively describe the dynamic changes of wedelolactone in vivo, providing a theoretical basis for pharmacological research on drugs and preclinical medication. The study of wedelolactone can provide a theoretical basis and quick analysis for the study of other traditional Chinese medicine. This may lead to breakthroughs in the pharmacokinetic study of complex Chinese medicines.


Assuntos
Cromatografia Líquida de Alta Pressão , Cumarínicos/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão/métodos , Cumarínicos/administração & dosagem , Cumarínicos/química , Estabilidade de Medicamentos , Medicamentos de Ervas Chinesas , Estrutura Molecular , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Extratos Vegetais/farmacocinética , Ratos , Reprodutibilidade dos Testes
16.
Clin Rehabil ; 33(5): 904-912, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30757911

RESUMO

OBJECTIVE: To evaluate the effectiveness and safety of oral administration of Linfadren® in addition to conventional treatment in patients with post-trauma/surgery persistent hand edema. DESIGN: Parallel-group randomized controlled trial. SETTING: Outpatient rehabilitation center. SUBJECTS: A total of 60 outpatients (mean age 48.5 (standard deviation (SD) = 12.3) years) with post-trauma/surgery persistent hand edema. INTERVENTIONS: Patients were randomized to either receive six-week conventional treatment plus Linfadren® (Study Group) or conventional treatment (Control Group). MAIN MEASURES: Primary outcome was hand edema as measured by figure-of-eight method. Secondary outcomes were hand function, patient's overall perceived treatment effectiveness and rescue medication request. Tolerability of Linfadren® was also evaluated. Assessments were performed at baseline, at the end of treatment and three months after the end of treatment. RESULTS: All patients completed the six-week program and 57 patients (95%) completed the three-month follow-up. At six weeks, the Study Group had significantly greater improvement in hand edema (423.3 (SD = 23.8) mm vs 439.4 (SD = 22.6) mm; P = 0.009) and upper limb function ( Quick Disabilities of Arm, Shoulder and Hand questionnaire: 23.6 (SD = 13.6) vs 37.7 (SD = 15.9); P = 0.005) compared to the Control Group. Moreover, the percentage of patients who perceived treatment as effective was significantly higher in the Study Group than in the Control Group both after treatment (70% vs 37%, P = 0.002) and at follow-up (77% vs 30%, P < 0.0001). The rescue medication request was not different between groups. No adverse events were recorded. CONCLUSION: Linfadren® in addition to conventional treatment was safe and more effective than conventional treatment alone in patients with post-trauma/surgery persistent hand edema.


Assuntos
Arbutina/administração & dosagem , Cumarínicos/administração & dosagem , Diosmina/administração & dosagem , Edema/terapia , Mãos/fisiopatologia , Modalidades de Fisioterapia , Adulto , Idoso , Criança , Terapia Combinada , Combinação de Medicamentos , Edema/fisiopatologia , Feminino , Traumatismos da Mão/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Complicações Pós-Operatórias/fisiopatologia
17.
Virus Res ; 263: 112-118, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30658072

RESUMO

As an efficient pathogen resulting in economic impact in aquaculture, spring viremia of carp virus (SVCV) causes devastating disease in cyprinids. Based on the previous study that 7-(6-(2-methyl-imidazole))-coumarin (D5) exhibited anti-SVCV activity in fish cells, we hypothesized that D5 may be useful as a potential therapeutic agent for controlling SVCV infection in vivo. In this study, we verified that D5 inhibited SVCV replication in zebrafish, with reducing 22.5% mortality of SVCV-infected fish. Further data suggested that coumarin D5 was more stable with a prolonged inhibitory half-life in the early stage of virus infection (1-4 days). Consistent with above results, D5 decreased the viral titer in fish body and repressed SVCV glycoprotein gene expression in virus sensitive tissues (kidney and spleen) in the early stage of virus infection. In addition, the results replied that D5 elicited an innate immune response in non-viral infected zebrafish by up-regulating the expression of interferon genes (IFNγ, IFNφ1, IFNφ2 and RIG-1). D5 also enhanced the levels of antioxidant-related gene transcription and enzyme activities in SVCV-infected zebrafish, suggesting that D5 exhibited an antioxidant protection on fish by keeping the balance of redox state. Therefore, D5 is a potential therapeutic agent for the devastating fish rhabdovirus infections.


Assuntos
Antivirais/administração & dosagem , Cumarínicos/administração & dosagem , Imidazóis/administração & dosagem , Fatores Imunológicos/administração & dosagem , Infecções por Rhabdoviridae/tratamento farmacológico , Rhabdoviridae/isolamento & purificação , Animais , Antivirais/química , Antivirais/farmacocinética , Cumarínicos/química , Cumarínicos/farmacocinética , Modelos Animais de Doenças , Meia-Vida , Imidazóis/química , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/química , Fatores Imunológicos/farmacocinética , Infecções por Rhabdoviridae/virologia , Análise de Sobrevida , Resultado do Tratamento , Carga Viral , Peixe-Zebra
18.
Support Care Cancer ; 27(4): 1471-1480, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30343411

RESUMO

PURPOSE: To assess the effectiveness and safety of a product containing diosmin, coumarin, and arbutin (Linfadren®) in addition to complex decongestive therapy (CDT) on the management of patients with a breast cancer-related lymphedema (BCRL). METHODS: Fifty outpatients (average age of 56.2 ± 2.7 years, range 28-71) with a BCRL were enrolled for this study. Patients were randomly assigned (1:1 ratio) to receive either CDT consisting of skin care, manual lymphatic drainage, remedial exercises, and elastic compression garment (control group, n = 25) or CDT plus Linfadren® (study group, n = 25). Patients were evaluated before and after treatment and 3 months after the end of treatment. Primary outcomes were reduction of upper limb excess volume (EV) and percentage reduction of excess volume (%REV). Secondary outcomes were improvement in Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire, and patient's perception of treatment effectiveness (PPTE). RESULTS: Addition of Linfadren® to CDT yielded an additional reduction of primary outcomes both after treatment (EV, - 521 ml vs. - 256 ml, P < 0.0001; %REV, - 66.4% vs. - 34%, P = 0.02) and at 3-month follow-up (EV, - 59 ml vs. + 24 ml, P < 0.0001; %REV, - 73.6% vs. - 31.4%, P = 0.004). Moreover, statistically significant differences were found between the two groups for the secondary outcomes after treatment (QuickDASH, P = 0.006; PPTE, P = 0.03) and at 3-month follow-up (QuickDASH, P = 0.006; PPTE, P = 0.02). No patient showed adverse events. CONCLUSIONS: Linfadren® in addition to CDT was a safe and effective therapy for reducing BCRL and was better than CDT alone.


Assuntos
Arbutina/administração & dosagem , Linfedema Relacionado a Câncer de Mama/terapia , Cumarínicos/administração & dosagem , Diosmina/administração & dosagem , Adulto , Idoso , Arbutina/efeitos adversos , Linfedema Relacionado a Câncer de Mama/epidemiologia , Terapia Combinada/efeitos adversos , Bandagens Compressivas/efeitos adversos , Cumarínicos/efeitos adversos , Diosmina/efeitos adversos , Drenagem/efeitos adversos , Drenagem/métodos , Terapia por Exercício/efeitos adversos , Terapia por Exercício/métodos , Feminino , Humanos , Massagem/efeitos adversos , Massagem/métodos , Pessoa de Meia-Idade , Higiene da Pele/efeitos adversos , Higiene da Pele/métodos , Resultado do Tratamento , Extremidade Superior
19.
Mol Cancer Ther ; 18(2): 301-311, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30404927

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy and is highly resistant to standard treatment regimens. Targeted therapies against KRAS, a mutation present in an overwhelming majority of PDAC cases, have been largely ineffective. However, inhibition of downstream components in the KRAS signaling cascade provides promising therapeutic targets in the management of PDAC and warrants further exploration. Here, we investigated Urolithin A (Uro A), a novel natural compound derived from pomegranates, which targets numerous kinases downstream of KRAS, in particular the PI3K/AKT/mTOR signaling pathways. We showed that treatment of PDAC cells with Uro A blocked the phosphorylation of AKT and p70S6K in vitro, successfully inhibited the growth of tumor xenografts, and increased overall survival of Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice compared with vehicle or gemcitabine therapy alone. Histologic evaluation of these Uro A-treated tumor samples confirmed mechanistic actions of Uro A via decreased phosphorylation of AKT and p70S6K, reduced proliferation, and increased cellular apoptosis in both xenograft and PKT mouse models. In addition, Uro A treatment reprogrammed the tumor microenvironment, as evidenced by reduced levels of infiltrating immunosuppressive cell populations such as myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Overall, this work provides convincing preclinical evidence for the utility of Uro A as a therapeutic agent in PDAC through suppression of the PI3K/AKT/mTOR pathway.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Carcinoma Ductal Pancreático/tratamento farmacológico , Cumarínicos/administração & dosagem , Lythraceae/química , Neoplasias Pancreáticas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos Fitogênicos/farmacologia , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/farmacologia , Humanos , Camundongos , Neoplasias Pancreáticas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Nutr Neurosci ; 22(3): 185-195, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28784051

RESUMO

OBJECTIVES: Urolithins, ellagitannin-gut microbial-derived metabolites, have been reported to mediate pomegranate's neuroprotective effects against Alzheimer's disease (AD), but there are limited data on their effects against neuroinflammation. Herein, we: (1) evaluated whether urolithins (urolithins A and B and their methylated derivatives) attenuate neuroinflammation in murine BV-2 microglia and human SH-SY5Y neurons, and (2) evaluated hippocampus of transgenic AD (R1.40) mice administered a pomegranate extract (PE; 100 or 200 mg/kg/day for 3 weeks) for inflammatory biomarkers. METHODS: Effects of urolithins (10 µM) on inflammatory biomarkers were evaluated in lipopolysaccharide (LPS)-stimulated BV-2 microglia. In a non-contact co-culture cell model, SH-SY5Y cell viability was assessed after exposure to media collected from LPS-BV-2 cells treated with or without urolithins. Effects of urolithins on apoptosis and caspase 3/7 and 9 release from H2O2-induced oxidative stress of BV-2 and SH-SY5Y cells were assessed. Hippocampal tissues of vehicle and PE-treated transgenic R1.40 mice were evaluated for gene expression of inflammatory biomarkers by qRT-PCR. RESULTS: Urolithins decreased media levels of nitric oxide, interleukin 6 (IL-6), prostaglandin E2, and tumor necrosis factor alpha from LPS-BV-2 microglia. In the co-culture cell model, media from LPS-BV-2 cells treated with urolithins preserved SH-SY5Y cell viability greater than media from cells treated without urolithins. Urolithins mitigated apoptosis and caspase 3/7 and 9 release from H2O2-induced oxidative stress of BV-2 and SH-SY5Y cells. While not statistically significant, inflammatory biomarkers (TNF-α, COX-2, IL-1, and IL-6) appeared to follow a decreasing trend in the hippocampus of high-dose PE-treated animals compared to controls. DISCUSSION: The attenuation of neuroinflammation by urolithins may contribute, in part, toward pomegranate's neuroprotective effects against AD.


Assuntos
Cumarínicos/administração & dosagem , Encefalite/metabolismo , Microbioma Gastrointestinal , Taninos Hidrolisáveis/metabolismo , Lythraceae/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Encefalite/induzido quimicamente , Encefalite/prevenção & controle , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Mediadores da Inflamação , Lipopolissacarídeos/administração & dosagem , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/administração & dosagem
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