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1.
AAPS PharmSciTech ; 22(3): 110, 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33733385

RESUMO

This study sought to improve the oral bioavailability and enhance the anti-enteritis effect of fraxetin by incorporating it into long circulating liposomes (F-LC-Lipo). The optimal formulation of F-LC-Lipo was obtained via orthogonal design. The particle size, morphology, encapsulation efficiency, stability, and anti-enteritis effect of F-LC-Lipo were evaluated. The particle size of F-LC-Lipo was 166.65 ± 8.75 nm with entrapment efficiency (EE) of 92.18 ± 0.17%. The release rate in different dissolution media (pH 1.2 HCl, DDW, and pH 7.4 PBS) was significantly higher than that of fraxetin solution. Compared with the free fraxetin solution, F-LC-Lipo increased oral bioavailability of fraxetin by 4.43 times (443%). More importantly, F-LC-Lipo could improve the levels of interleukin-1 beta (IL-1ß), IL-6, malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), prostaglandin E2 (PEG2), and IL-10 in rats with enteritis. Overall, these results suggested that LC-Lipo may serve as a potential carrier for improving the solubility and oral bioavailability of fraxetin as well as improving its enteritis effect.


Assuntos
Antioxidantes/administração & dosagem , Antioxidantes/uso terapêutico , Cumarínicos/administração & dosagem , Cumarínicos/uso terapêutico , Enterite/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/uso terapêutico , Disponibilidade Biológica , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Enterite/patologia , Lipossomos , Masculino , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley
2.
Yakugaku Zasshi ; 141(1): 67-79, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33390450

RESUMO

In the 1980s, the authors developed the enzyme immunoassay (EIA) system for mouse nerve growth factor (NGF) to clarify its important physiological roles. Our EIA system was a new and powerful tool for measurement of extremely low levels of NGF in vitro and in vivo, and it contributed to investigation into the regulatory mechanism of NGF synthesis. After that, we demonstrated that the compounds with a low molecular weight, such as 4-methylcatechol, which elicit stimulatory activity toward NGF synthesis, were useful and practical for therapeutic purposes; as NGF has potent activity on neuronal degeneration in both the central nervous system (CNS) and the peripheral nervous system. Since 2008, we have been searching for and isolating neuroprotective component(s) from citrus peels. As a result, our study revealed that 1) 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF) has neuroprotective ability in the CNS by inducing brain-derived neurotrophic factor (BDNF) and by suppressing inflammation; 2) auraptene (AUR) also has neuroprotective ability in the CNS by suppressing inflammation and by probably inducing neurotrophic factor(s). As the content of AUR in the peels of Kawachi Bankan is exceptionally high, 1) we found this peel powder to exert neuroprotective effects in the brain of various pathological model mice; 2) some of the AUR transited from the peel to the juice during the squeezing process to obtain the juice. Therefore, K. Bankan juice, which is enriched in AUR by adding peel paste to the raw juice, was shown to be practical for suppression of cognitive dysfunction of aged healthy volunteers.


Assuntos
Catecóis/farmacologia , Citrus/química , Cumarínicos/farmacologia , Descoberta de Drogas , Fator de Crescimento Neural/biossíntese , Fator de Crescimento Neural/fisiologia , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Animais , Catecóis/isolamento & purificação , Disfunção Cognitiva/tratamento farmacológico , Cumarínicos/administração & dosagem , Cumarínicos/isolamento & purificação , Modelos Animais de Doenças , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Camundongos , Fitoterapia , Ratos
3.
Int J Nanomedicine ; 15: 8369-8382, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33149581

RESUMO

Introduction: Auraptene (AUR), a natural bioactive prenyloxy coumarin, is a highly pleiotropic molecule that can bind to the MT1 receptor and can effectively reduce the proliferation and migration of breast cancer cells. Cisplatin (CDDP), as the first synthetic platinum-based anticancer drug, is widely used in the clinic due to its definite mechanism and therapeutic effect on diverse tumors. However, both of AUR and CDDP exhibit some disadvantages when used alone, including poor solubility, low bioavailability, lack of selectivity and systemic toxicity when they are used singly. Methods: Therefore, the biodegradable materials hyaluronic acid (HA) and ß-cyclodextrin derivative (mono-(6-amino-mono-6-deoxy)-ß-CD, CD) were employed as carriers to load AUR and CDDP to form nanogel (CDDPHA-CD@AUR) capable of dual-targeted delivery and synergistic therapy for breast cancer and cell imaging. Results: With the help of the CDDP-crosslinked CD-loaded structure, the newly synthesized nanogel exhibited excellent physiological stability and fluorescence effects. The release of AUR and CDDP was affected by the pH value, which was beneficial to the selective release in the tumor microenvironment. Cell experiments in vitro demonstrated that the nanogel could be selectively internalized by MCF-7 cells and exhibited low cytotoxicity to HK-2 cells. Antitumor experiments in vivo showed that the nanogel have better antitumor effects and lower systemic toxicity. Conclusion: Based on these, the nanogel loaded with AUR and CDDP have the potential for targeted delivery against breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Cumarínicos/administração & dosagem , Cumarínicos/uso terapêutico , Nanogéis/química , Animais , Neoplasias da Mama/patologia , Morte Celular , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Endocitose , Feminino , Hemólise , Humanos , Ácido Hialurônico/química , Concentração de Íons de Hidrogênio , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanogéis/ultraestrutura , Especificidade de Órgãos , Tamanho da Partícula , Polietilenoglicóis/química , Polietilenoimina/química , Coelhos , Espectrometria de Fluorescência , Espectroscopia de Infravermelho com Transformada de Fourier
4.
Lancet Oncol ; 21(11): 1478-1488, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33128873

RESUMO

BACKGROUND: CH5126766 (also known as VS-6766, and previously named RO5126766), a novel MEK-pan-RAF inhibitor, has shown antitumour activity across various solid tumours; however, its initial development was limited by toxicity. We aimed to investigate the safety and toxicity profile of intermittent dosing schedules of CH5126766, and the antitumour activity of this drug in patients with solid tumours and multiple myeloma harbouring RAS-RAF-MEK pathway mutations. METHODS: We did a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study at the Royal Marsden National Health Service Foundation Trust (London, UK). Patients were eligible for the study if they were aged 18 years or older, had cancers that were refractory to conventional treatment or for which no conventional therapy existed, and if they had a WHO performance status score of 0 or 1. For the dose-escalation phase, eligible patients had histologically or cytologically confirmed advanced or metastatic solid tumours. For the basket dose-expansion phase, eligible patients had advanced or metastatic solid tumours or multiple myeloma harbouring RAS-RAF-MEK pathway mutations. During the dose-escalation phase, we evaluated three intermittent oral schedules (28-day cycles) in patients with solid tumours: (1) 4·0 mg or 3·2 mg CH5126766 three times per week; (2) 4·0 mg CH5126766 twice per week; and (3) toxicity-guided dose interruption schedule, in which treatment at the recommended phase 2 dose (4·0 mg CH5126766 twice per week) was de-escalated to 3 weeks on followed by 1 week off if patients had prespecified toxic effects (grade 2 or worse diarrhoea, rash, or creatinine phosphokinase elevation). In the basket dose-expansion phase, we evaluated antitumour activity at the recommended phase 2 dose, determined from the dose-escalation phase, in biomarker-selected patients. The primary endpoints were the recommended phase 2 dose at which no more than one out of six patients had a treatment-related dose-limiting toxicity, and the safety and toxicity profile of each dosing schedule. The key secondary endpoint was investigator-assessed response rate in the dose-expansion phase. Patients who received at least one dose of the study drug were evaluable for safety and patients who received one cycle of the study drug and underwent baseline disease assessment were evaluable for response. This trial is registered with ClinicalTrials.gov, NCT02407509. FINDINGS: Between June 5, 2013, and Jan 10, 2019, 58 eligible patients were enrolled to the study: 29 patients with solid tumours were included in the dose-escalation cohort and 29 patients with solid tumours or multiple myeloma were included in the basket dose-expansion cohort (12 non-small-cell lung cancer, five gynaecological malignancy, four colorectal cancer, one melanoma, and seven multiple myeloma). Median follow-up at the time of data cutoff was 2·3 months (IQR 1·6-3·5). Dose-limiting toxicities included grade 3 bilateral retinal pigment epithelial detachment in one patient who received 4·0 mg CH5126766 three times per week, and grade 3 rash (in two patients) and grade 3 creatinine phosphokinase elevation (in one patient) in those who received 3·2 mg CH5126766 three times per week. 4·0 mg CH5126766 twice per week (on Monday and Thursday or Tuesday and Friday) was established as the recommended phase 2 dose. The most common grade 3-4 treatment-related adverse events were rash (11 [19%] patients), creatinine phosphokinase elevation (six [11%]), hypoalbuminaemia (six [11%]), and fatigue (four [7%]). Five (9%) patients had serious treatment-related adverse events. There were no treatment-related deaths. Eight (14%) of 57 patients died during the trial due to disease progression. Seven (27% [95% CI 11·6-47·8]) of 26 response-evaluable patients in the basket expansion achieved objective responses. INTERPRETATION: To our knowledge, this is the first study to show that highly intermittent schedules of a RAF-MEK inhibitor has antitumour activity across various cancers with RAF-RAS-MEK pathway mutations, and that this inhibitor is tolerable. CH5126766 used as a monotherapy and in combination regimens warrants further evaluation. FUNDING: Chugai Pharmaceutical.


Assuntos
Cumarínicos/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Administração Oral , Adulto , Idoso , Cumarínicos/efeitos adversos , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Quinases raf/genética , Proteínas ras/genética
5.
Nature ; 579(7799): 421-426, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32188939

RESUMO

Bioorthogonal chemistry capable of operating in live animals is needed to investigate biological processes such as cell death and immunity. Recent studies have identified a gasdermin family of pore-forming proteins that executes inflammasome-dependent and -independent pyroptosis1-5. Pyroptosis is proinflammatory, but its effect on antitumour immunity is unknown. Here we establish a bioorthogonal chemical system, in which a cancer-imaging probe phenylalanine trifluoroborate (Phe-BF3) that can enter cells desilylates and 'cleaves' a designed linker that contains a silyl ether. This system enabled the controlled release of a drug from an antibody-drug conjugate in mice. When combined with nanoparticle-mediated delivery, desilylation catalysed by Phe-BF3 could release a client protein-including an active gasdermin-from a nanoparticle conjugate, selectively into tumour cells in mice. We applied this bioorthogonal system to gasdermin, which revealed that pyroptosis of less than 15% of tumour cells was sufficient to clear the entire 4T1 mammary tumour graft. The tumour regression was absent in immune-deficient mice or upon T cell depletion, and was correlated with augmented antitumour immune responses. The injection of a reduced, ineffective dose of nanoparticle-conjugated gasdermin along with Phe-BF3 sensitized 4T1 tumours to anti-PD1 therapy. Our bioorthogonal system based on Phe-BF3 desilylation is therefore a powerful tool for chemical biology; our application of this system suggests that pyroptosis-induced inflammation triggers robust antitumour immunity and can synergize with checkpoint blockade.


Assuntos
Preparações de Ação Retardada/administração & dosagem , Neoplasias Mamárias Experimentais/imunologia , Piroptose/imunologia , Animais , Cumarínicos/administração & dosagem , Cumarínicos/química , Cumarínicos/metabolismo , Cumarínicos/farmacocinética , Preparações de Ação Retardada/química , Preparações de Ação Retardada/metabolismo , Preparações de Ação Retardada/farmacocinética , Feminino , Proteínas de Fluorescência Verde/administração & dosagem , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Fluorescência Verde/farmacocinética , Células HeLa , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/química , Imunoconjugados/metabolismo , Imunoconjugados/farmacocinética , Inflamassomos/imunologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Oligopeptídeos/administração & dosagem , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Oligopeptídeos/farmacocinética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Proteínas/administração & dosagem , Proteínas/química , Proteínas/metabolismo , Proteínas/farmacocinética , Silanos/administração & dosagem , Silanos/química , Silanos/metabolismo , Silanos/farmacocinética , Linfócitos T/imunologia , Trastuzumab/administração & dosagem , Trastuzumab/química , Trastuzumab/metabolismo , Trastuzumab/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Biomater Sci ; 8(8): 2274-2282, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32162618

RESUMO

Because of their excellent capacity to significantly improve the bioavailability and solubility of chemotherapy drugs, block copolymer micelles are widely utilized for chemotherapy drug delivery. In order to further improve the anti-tumor ability and reduce unwanted side effects of drugs, tumor-targeting peptides were used to functionalize the surface of polymer micelles so that the micelles can target tumor tissues. Herein, we synthesized a kind of PEG-PLA that is maleimide-terminated and then conjugated with a specific peptide F3 which revealed specific capacity binding to nucleolin that is overexpressed on the surface of many tumor cells. Then, F3 conjugated, paclitaxel loaded nanoparticles (F3-NP-PTX) were prepared as stable micelles that displayed an enhanced accumulation via a peptide-mediated cellular association in human breast cancer cells (MCF-7). Furthermore, F3-NP-PTX showed a prominent anti-tumor efficacy compared with non-targeting nanoparticles (NP-PTX) both in vitro and in vivo, and showed great potential as an efficacious targeting drug delivery system for breast cancer treatment.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Cumarínicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Micelas , Paclitaxel/administração & dosagem , Peptídeos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Tiazóis/administração & dosagem , Animais , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/química , Liberação Controlada de Fármacos , Feminino , Humanos , Células MCF-7 , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos Endogâmicos ICR , Paclitaxel/sangue , Paclitaxel/química , Paclitaxel/farmacocinética , Peptídeos/química , Peptídeos/farmacocinética , Polietilenoglicóis/química , Esferoides Celulares/efeitos dos fármacos , Tiazóis/química , Carga Tumoral/efeitos dos fármacos
7.
BMJ Case Rep ; 13(2)2020 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-32041753

RESUMO

In recent years, the number of patients undergoing liver transplant has increased. Successful transplant has resulted in better quality of life and improved fertility in younger women. This is a case study a 31-year-old woman, who had history of Budd-Chiari syndrome and underwent liver transplantation in 2014 with uneventful postoperative course. She was clinically stable on tablet tacrolimus and coumarin with no episode of allograft rejection since transplantation. The patient conceived spontaneously, after 4 years of transplant and during pregnancy, she was managed by multidisciplinary team. During the initial period, the graft and pregnancy continued without complications. However, at 33 weeks, the patient presented with sluggish fetal movements, amniotic fluid index of 3.4 and SD ratio of 3.31 for which she underwent caesarean section. She delivered a healthy female baby of 1.4 kg. This case study concludes that vigilant monitoring of fetal growth is pivotal for optimal fetal outcome.


Assuntos
Síndrome de Budd-Chiari/cirurgia , Transplante de Fígado , Resultado da Gravidez , Adulto , Cesárea , Cumarínicos/administração & dosagem , Feminino , Humanos , Gravidez , Tacrolimo/administração & dosagem
8.
J Nutr ; 150(5): 1240-1251, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31943053

RESUMO

BACKGROUND: Phytoestrogens are plant-derived hormonally active compounds found in soy, cruciferous vegetables, nuts, and seeds. Although phytoestrogens have been associated with altered endogenous hormonal activity, luteal phase deficiency, and reduced endometrial decidualization, the literature reporting examinations of phytoestrogen intake and fertility presents mixed findings. OBJECTIVES: We sought to evaluate prospectively the association between dietary phytoestrogen intake (isoflavones, lignans, and coumestans) and fecundability, the per-cycle probability of conception, in 2 cohorts of women planning pregnancy. METHODS: Pregnancy Study Online (PRESTO) and Snart Foraeldre (SF) are parallel web-based preconception cohort studies of women from North America and Denmark, respectively, who are trying to conceive. Participants complete an online baseline questionnaire on sociodemographic, lifestyle, and medical factors. We ascertained intake of individual phytoestrogens from validated FFQs. We measured fecundability using data on menstruation and pregnancy status from bimonthly follow-up questionnaires. We analyzed data from 4880 PRESTO and 2898 SF female study participants who had been attempting conception for ≤6 cycles at study entry. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% CIs. RESULTS: Phytoestrogen intake varied across cohorts, yet was associated with higher socioeconomic status and healthier behaviors in both cohorts. After adjustment for potential confounders, phytoestrogen intake was not substantially associated with fecundability in either cohort. We observed some evidence of improved fecundability with increasing isoflavone intake among women age ≥30 years in PRESTO (FR: 1.12; 95% CI: 0.94, 1.34, for comparison of ≥90th with <25th percentile intake) and SF (corresponding FR: 1.19; 95% CI: 0.92, 1.55). Lignan intake was associated with slightly increased fecundability in SF (FR for comparison of 75th to 90th with <25th percentile: 1.10; 95% CI: 0.96, 1.26), but decreased fecundability in PRESTO (FR for comparison of ≥90th with <25th percentile: 0.83; 95% CI: 0.72, 0.97). CONCLUSIONS: We did not observe strong associations between phytoestrogen intake and prospectively-measured fecundability among North American or Danish pregnancy planners.


Assuntos
Dieta , Fertilidade/efeitos dos fármacos , Fitoestrógenos/administração & dosagem , Adulto , Índice de Massa Corporal , Estudos de Coortes , Cumarínicos/administração & dosagem , Dinamarca , Escolaridade , Feminino , Fertilização , Humanos , Renda , Isoflavonas/administração & dosagem , Lignanas/administração & dosagem , América do Norte , Gravidez , Estudos Prospectivos
9.
Eur J Pharmacol ; 867: 172799, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31765607

RESUMO

Osteoarthritis (OA) is a common and disabling joint disease mainly characterized by cartilage degradation, with the knees most commonly affected. No effective treatment for the cartilage degradation of OA exists. Preliminary studies have revealed the protective and osteogenic effects of osthole, a natural coumarin first isolated from Cnidium monnieri (Fructus Cnidii); however, no evidence of osthole in an OA-related model has been published to date. This study further explored the effects of osthole in a monoiodoacetate (MIA)-induced OA-related animal model and focused on the molecular mechanism(s) behind the anti-inflammatory and cartilage protective effects of osthole. This study revealed that the cartilage protective effect of osthole in a MIA-induced osteoarthritis (OA) murine model can be explained by downregulation of COX-2 and RUNX2 by inhibition of NF-κB and HIF-2α up-regulated by OA induction, resulting in downregulation of MMP-13, Syndecan IV and ADAMTS-5. In addition, osthole might have anti-inflammatory and analgesic effects due to COX-2 inhibition. Osthole can be considered as a potential component of the treatment of OA, for it possesses a cartilage protective effect, as well as anti-inflammation, analgesic, and movement improving effects. Further preclinical and human clinical studies are needed to examine the efficacy and safety profile of long-term therapy.


Assuntos
Artrite Experimental/tratamento farmacológico , Cartilagem Articular/efeitos dos fármacos , Cumarínicos/administração & dosagem , Osteoartrite/tratamento farmacológico , Substâncias Protetoras/administração & dosagem , Administração Oral , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cartilagem Articular/patologia , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Ácido Iodoacético/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Osteoartrite/induzido quimicamente , Osteoartrite/patologia , Transdução de Sinais/efeitos dos fármacos
10.
Inflamm Res ; 69(1): 115-130, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31786615

RESUMO

OBJECTIVE: To examine whether free (3-PD-5free) and/or liposomal (3-PD-5lipo) 6,7-dihydroxy-3-[3',4'-methylenedioxyphenyl]-coumarin (3-PD-5) (1) modulate the effector functions of neutrophils from patients with rheumatoid arthritis under remission (i-RA) and with active disease (a-RA), in vitro; and (2) exert anti-inflammatory effect in a rat model of zymosan-induced acute joint inflammation. METHODS AND RESULTS: Incorporation of 3-PD-5 into unilamellar liposomes of soya phosphatidylcholine and cholesterol was efficient (57.5 ± 7.9%) and yielded vesicles with low diameter (133.7 ± 18.4 nm), polydispersity index (0.39 ± 0.06), and zeta potential (- 1.22 ± 0.34 mV). 3-PD-5free (1 µM) and 3-PD-5lipo (3 µM) equally suppressed elastase release and reactive oxygen species generation in neutrophils from healthy subjects and i-RA and a-RA patients, stimulated with immune complexes. 3-PD-5free (20 µM) suppressed the release of neutrophil extracellular traps and chemotaxis in vitro, without clear signs of cytotoxicity. 3-PD-5lipo (1.5 mg/kg, i.p.) diminished joint edema and synovial infiltration of total leukocytes and neutrophils, without changing the synovial levels of TNF-α, IL-1ß, and IL-6. CONCLUSION: Altogether, the results reported herein indicate that 3-PD-5 is a promising modulator of the early stages of acute joint inflammation that can help to diminish not only excessive neutrophil infiltration in the synovia but also neutrophil activation and its outcomes in RA patients.


Assuntos
Anti-Inflamatórios/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Cumarínicos/administração & dosagem , Doença Aguda , Adulto , Idoso , Animais , Artrite Reumatoide/imunologia , Armadilhas Extracelulares/efeitos dos fármacos , Feminino , Humanos , Imunomodulação , Lipossomos , Masculino , Pessoa de Meia-Idade , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/fisiologia , Ratos Wistar , Adulto Jovem
11.
Food Funct ; 10(12): 8273-8285, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31720661

RESUMO

Recent studies have found that a high-fat diet (HFD) causes gut microbiota imbalance and colon tissue damage, resulting in increased intestinal permeability, which is one of the main reasons for the existence of constantly circulating low-grade inflammatory cytokines. Pomegranate extracts have been shown to protect from HFD-induced metabolic inflammation (e.g., colitis) and to promote the growth of beneficial bacteria in in vitro stool cultures. However, whether the beneficial effects of pomegranate extracts on the HFD-induced metabolic inflammation are achieved by acting on intestinal tissues has not yet been studied. In our present study, we found that pomegranate peel polyphenols (PPPs) alleviated HFD-induced obesity, elevated circulating pro-inflammatory cytokines, colonic tissue damage, and depressed colonic tight junction protein expression level in rats. Moreover, PPPs normalized the HFD-induced gut microbiota imbalance by increasing the abundance of beneficial bacteria in the colon. Furthermore, we also found that PPPs, punicalagin, and urolithin A (the main microbiota metabolites of pomegranate ellagitannins) all increased the LPS-induced decreased tight junction protein expression level and reversed the LPS-induced inflammatory response in Caco-2 cells. Urolithin A exhibited the best effects among the three pomegranate components. Our results suggested that the protective effects of PPPs in HFD-induced metabolic inflammation can be due to the recovery of colonic tissue damage and the regulation of gut microbiota and that urolithin A is the major component that contributes to the in vivo effects of PPPs.


Assuntos
Colite/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Polifenóis/administração & dosagem , Romã (Fruta)/química , Animais , Colite/etiologia , Colite/imunologia , Colite/microbiologia , Colo/imunologia , Colo/microbiologia , Cumarínicos/administração & dosagem , Cumarínicos/análise , Dieta Hiperlipídica/efeitos adversos , Frutas/química , Humanos , Taninos Hidrolisáveis/administração & dosagem , Taninos Hidrolisáveis/análise , Inflamação , Masculino , Extratos Vegetais/análise , Polifenóis/análise , Ratos , Resíduos/análise
12.
Am J Physiol Renal Physiol ; 317(5): F1255-F1264, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31532243

RESUMO

The popular anticancer drug cisplatin causes many adverse side effects, the most serious of which is acute kidney injury (AKI). Emerging evidence from laboratory and clinical studies suggests that the AKI pathogenesis involves oxidative stress pathways; therefore, regulating such pathways may offer protection. Urolithin A (UA), a gut metabolite of the dietary tannin ellagic acid, possesses antioxidant properties and has shown promise in mouse models of AKI. However, therapeutic potential of UA is constrained by poor bioavailability. We aimed to improve oral bioavailability of UA by formulating it into biodegradable nanoparticles that use a surface-conjugated ligand targeting the gut-expressed transferrin receptor. Nanoparticle encapsulation of UA led to a sevenfold enhancement in oral bioavailability compared with native UA. Treatment with nanoparticle UA also significantly attenuated the histopathological hallmarks of cisplatin-induced AKI and reduced mortality by 63% in the mouse model. Expression analyses indicated that nanoparticle UA therapy coincided with oxidative stress mitigation and downregulation of nuclear factor erythroid 2-related factor 2- and P53-inducible genes. Additionally, normalization of miRNA (miR-192-5p and miR-140-5p) implicated in AKI, poly(ADP-ribose) polymerase 1 levels, antiapoptotic signaling, intracellular NAD+, and mitochondrial oxidative phosphorylation were observed in the treatment group. Our findings suggest that nanoparticles greatly increase the oral bioavailability of UA, leading to improved survival rates in AKI mice, in part by reducing renal oxidative and apoptotic stress.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/tratamento farmacológico , Cisplatino/toxicidade , Cumarínicos/administração & dosagem , Nanopartículas/administração & dosagem , Administração Oral , Animais , Antineoplásicos/toxicidade , Cumarínicos/farmacocinética , Regulação da Expressão Gênica , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos , Estresse Fisiológico
13.
Pharmazie ; 74(9): 529-535, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31484592

RESUMO

8-Methoxycoumarin (8-methoxy-chromen-2-one), isolated from R. graveolens L., is able to alleviate arthritis by inhibition of proinflammatory cytokines. However, its effects on melanogenesis have largely remained unreported. The present study examined the effects of 8-methoxycoumarin on melanogenesis in B16F10 murine cells, together with its effect on the mechanism of melanin synthesis. The cells were treated with different concentrations of 8-methoxycoumarin; α-MSH was used as the positive control. We found 8-methoxycoumarin to significantly increase the melanin content of the cells without exerting any cytotoxicity. In addition, it significantly upregulated the expression of tyrosinase and tyrosinase-related protein-1 and 2 via inducing the expression of microphthalmia-associated transcription factor. Furthermore, we demonstrated the involvement of mitogen-activated protein kinase (MAPK) pathway-mediated phosphorylation of p38 and c-Jun N-terminal kinase (JNK), and inhibition of phosphorylation of extracellular signal-regulated kinase (ERK) to be responsible for enhanced melanin production. Use of SB203580 (p38 inhibitor) and SP600125 (p-JNK inhibitor) corroborated these findings. Additionally, we investigated the effects of 8-methoxycoumarin on protein kinase B (AKT) phosphorylation and protein kinase A (PKA) signaling pathway (using H89, a PKA inhibitor). These results suggested that 8-methoxycoumarin increases melanogenesis via the MAPK signaling pathway. Based on these findings, we conclude that 8-methoxycoumarin could serve as a potential compound for treating hypopigmentation disorders. It could also serve as a promising chemical for hair depigmentation treatment in the cosmetic industry.


Assuntos
Cumarínicos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melaninas/biossíntese , Transdução de Sinais/efeitos dos fármacos , Animais , Antracenos/farmacologia , Cumarínicos/administração & dosagem , Cumarínicos/isolamento & purificação , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Imidazóis/farmacologia , Melanoma Experimental/metabolismo , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/farmacologia , Ruta/química
14.
Food Funct ; 10(9): 6135-6146, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31497826

RESUMO

Osteoarthritis (OA) is a degenerative joint disease, whose progression is closely related to the inflammatory environment. Urolithin A (UA), a natural metabolite of a class of compounds (ellagitannins and ellagic acid) found in pomegranates and other fruits and nuts, has been proved to exert anti-inflammatory effects in a variety of diseases. However, the exact role of UA in OA development is still unclear. In the present study, we examined the latent mechanism of UA and its protective role in the progression of OA by both in vitro and in vivo experiments. In vitro, UA inhibited the interleukin-1 beta (IL-1ß) induced over-production of nitric oxide (NO), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in a concentration-dependent manner in human OA chondrocytes. Furthermore, by downregulating the expression of metalloproteinase 13 (MMP13) and thrombospondin motifs 5 (ADAMTS5), UA attenuated the degradation of the extracellular matrix (ECM) induced by IL-1ß. Mechanistically, UA was found to suppress the activation of PI3K/Akt/NF-κB pathways. In vivo, in a surgically induced mouse OA model, UA-induced protective effects in OA development could be detected. In summary, this research suggested that UA may be adopted as a new therapeutic agent for the treatment of OA.


Assuntos
Cumarínicos/administração & dosagem , Interleucina-1beta/imunologia , NF-kappa B/imunologia , Osteoartrite/tratamento farmacológico , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Dinoprostona/imunologia , Humanos , Interleucina-1beta/genética , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Óxido Nítrico/imunologia , Osteoartrite/genética , Osteoartrite/imunologia , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos
15.
Toxicon ; 171: 35-42, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31526810

RESUMO

Eighty-four male New Zealand White rabbits with average body weight 778 ±â€¯65 g were blocked into four groups to evaluate the ability of sodium bentonite and coumarin in alleviating the toxicity of aflatoxin B1. The first group was fed on a diet without any treatment (CON), while the remaining three diets were added with aflatoxin B1 at 0.25 ppm diet. Diet fed to the third and fourth group of rabbits were further supplemented with sodium bentonite at 5 g/kg (SOB) and coumarin at 5 g/kg (COU) of the diet, respectively. Feeding aflatoxin-contaminated diet (AFL) caused necrosis of liver tissue and reduced the weight gain, average daily gain, feed conversion ratio, nutrient digestibility coefficients, and nitrogen balance of rabbits. This, in turn, was reflected as a reduction in carcass characteristics. The serum collected from rabbits fed aflatoxin-contaminated diet showed decreased levels of total protein, albumin, globulin, glucose, total cholesterol, and triglycerides, and increased concentrations of urea, creatinine, and liver enzymes. Further, aflatoxin diet increased the cecal pH, and decreased the ammonia nitrogen, total volatile fatty acids, and individual fatty acids proportion of cecal fluid. Supplementing sodium bentonite and coumarin at 5 g/kg diet reduced the negative effects of aflatoxin B1 on growth performance, digestibility of nutrients, biochemical parameters, carcass characteristics, and cecal fermentation profile. Furthermore, the coumarin-supplemented group showed better body weight gains and carcass weights compared to the rabbits fed with diets containing sodium bentonite. In conclusion, both sodium bentonite and coumarin supplementation was beneficial in ameliorating the toxicity of aflatoxin B1. Further, the increased body weight gains and better-feed conversion in coumarin-supplemented rabbits project the coumarin as a better anti-aflatoxigenic supplement.


Assuntos
Aflatoxina B1/antagonistas & inibidores , Bentonita/administração & dosagem , Cumarínicos/administração & dosagem , Coelhos/crescimento & desenvolvimento , Aflatoxina B1/toxicidade , Ração Animal/análise , Animais , Ceco/química , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/veterinária , Dieta/veterinária , Contaminação de Alimentos , Masculino , Coelhos/sangue
16.
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
17.
Can J Physiol Pharmacol ; 97(10): 989-998, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31464528

RESUMO

The current study was carried out to evaluate the effect of pretreatment and co-treatment with a newly synthesized coumarin hydrazone, (E)-4-hydroxy-N'-(1-(3-oxo-3H-benzo[f]chromen-2-yl)ethylidene)benzohydrazide (hereinafter EK6), against isoproterenol-induced myocardial infarction in rats. Changes in biochemistry, cardiac biomarkers, electrocardiography, and histopathology after treatment with EK6 or acenocoumarol (Sintrom) were studied. Animals were randomly divided into 4 groups: vehicle control (C), isoproterenol + Sintrom (ISO + Sin), isoproterenol + EK6 (ISO + EK6), and isoproterenol (ISO). Myocardial infarction was induced by subcutaneous ISO administration at a dose of 85 mg·kg-1·day-1 with a drug-free interval of 24 h on days 6 and 7. Treatment with ISO led to significant elevation (p < 0.05) in serum levels of cardiac injury biomarkers, namely cardiac troponin-T, lactate dehydrogenase, creatine kinase-MB, alanine aminotransferase, and aspartate aminotransferase compared with levels in the vehicle control. A change in the lipid profile was also observed as a significant increase in total cholesterol and triglycerides. Furthermore, ISO caused significant alterations in the electrocardiogram pattern, including significant ST-segment elevation, significant decreased R wave amplitude, and significant increase in heart rate (16%) as well as marked changes in the histopathology of the heart tissue. Pretreatment and co-treatment with newly synthesized coumarin hydrazone restored all ISO-induced biochemical, lipid, cardiac, and histopathological changes in rats with myocardial infarction.


Assuntos
Benzopiranos/administração & dosagem , Cardiotônicos/administração & dosagem , Cumarínicos/administração & dosagem , Hidrazonas/administração & dosagem , Infarto do Miocárdio/tratamento farmacológico , Animais , Benzopiranos/síntese química , Biomarcadores/análise , Cardiotônicos/síntese química , Cumarínicos/síntese química , Modelos Animais de Doenças , Eletrocardiografia , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hidrazonas/síntese química , Isoproterenol/toxicidade , Masculino , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/diagnóstico , Miocárdio/patologia , Ratos , Ratos Wistar , Resultado do Tratamento
18.
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
19.
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 , Cimenos/efeitos adversos , 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
20.
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
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