Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 38
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Med Chem ; 65(1): 163-190, 2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-34939411

RESUMO

DCN1, a co-E3 ligase, interacts with UBC12 and activates cullin-RING ligases (CRLs) by catalyzing cullin neddylation. Although DCN1 has been recognized as an important therapeutic target for human diseases, its role in the cardiovascular area remains unknown. Here, we first found that DCN1 was upregulated in isolated cardiac fibroblasts (CFs) treated by angiotensin (Ang) II and in mouse hearts after pressure overload. Then, structure-based optimizations for DCN1-UBC12 inhibitors were performed based on our previous work, yielding compound DN-2. DN-2 specifically targeted DCN1 at molecular and cellular levels as shown by molecular modeling studies, HTRF, cellular thermal shift and co-immunoprecipitation assays. Importantly, DN-2 effectively reversed Ang II-induced cardiac fibroblast activation, which was associated with the inhibition of cullin 3 neddylation. Our findings indicate a potentially unrecognized role of DCN1 inhibition for anticardiac fibrotic effects. DN-2 may be used as a lead compound for further development.


Assuntos
/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Fibrose/tratamento farmacológico , Cardiopatias/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Pirimidinas/química , Enzimas de Conjugação de Ubiquitina/antagonistas & inibidores , Animais , Proteínas Culina/metabolismo , Inibidores Enzimáticos/química , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibrose/metabolismo , Fibrose/patologia , Cardiopatias/metabolismo , Cardiopatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína NEDD8/metabolismo , Ratos , Ratos Sprague-Dawley , Ubiquitinas
2.
Carbohydr Polym ; 277: 118867, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34893272

RESUMO

The role of polysaccharides in quality control of ginseng is underestimated. Large-scale comparison on the polysaccharides of Panax ginseng (PG), P. quinquefolius (PQ), P. notoginseng (PN), Red ginseng (RG), P. japonicus (ZJS), and P. japonicus var. major (ZZS), was performed by both chemical and biological approaches. Holistic fingerprinting at polysaccharide and the hydrolyzed oligosaccharide and monosaccharide levels utilized various chromatography methods, while OGD and OGD/R models on H9c2 cells were introduced to evaluate the protective effects on cell viability and mitochondrial function. Polysaccharides from six ginseng species exhibited remarkable content difference (RG > PG/ZZS/ZJS/PQ > PN), but weak differentiations in molecular weight distribution and oligosaccharide profiles, while Glc and GalA were richer for monosaccharide compositions of PG and RG polysaccharides, respectively. RG polysaccharides (25/50/100 µg/mL) showed significant cardiomyocyte protection by regulating mitochondrial functions. These new evidences may provide support for the supplementary role of polysaccharides in quality control of ginseng.


Assuntos
Miócitos Cardíacos/efeitos dos fármacos , Panax/química , Plantas Medicinais/química , Polissacarídeos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Configuração de Carboidratos , Linhagem Celular , Peso Molecular , Polissacarídeos/química , Substâncias Protetoras/química , Ratos
3.
Food Chem Toxicol ; 151: 112151, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33774095

RESUMO

This study was to analyze the pyrrolizidine alkaloids (PAs) in Eupatorium fortunei herbs and its derived finished products with a view to evaluating their effects on the proliferation and oligodendrogenesis of neural progenitor cells (NPCs). Using a LC-MS/MS method with 32 PAs reference standards, 8 PAs including intermedine, intermedine N-oxide, lycopsamine, lycopsamine N-oxide, retronecine, seneciphylline and senkirkine and 7-acetylintermedine N-oxide were identified with intermedine N-oxide and lycopsamine N-oxide being most abundant. The total PA amounts were found to vary from 0.18 to 61.81 µg/g in 30 batches of herbs and from 0.86 to 36.96 µg/g in 4 commercial finished products, respectively. Risk assessments indicated that the short-term intake seemed unlikely lead to acute toxic effects but the chronic use warranted cautions. Using NPCs derived from mouse induced pluripotent stem cells as an in vitro testing model, intermedine, intermedine N-oxide and lycopsamine N-oxide appeared to decrease cell viability at 30 µM whereas intermedine N-oxide inhibited oligodendrogenesis of NPCs at 10 µM. The present results suggested that the PAs in the majority of E. fortunei herbs and the derived products not only resulted in their exposure far exceeding the acceptable intake limit (i. e. 1.0 µg PA per day for adults) in herbal medicinal products recommended by the European Medicines Agency but also induced neurotoxicity to NPCs in vitro.


Assuntos
Eupatorium/química , Oligodendroglia/efeitos dos fármacos , Alcaloides de Pirrolizidina/análise , Alcaloides de Pirrolizidina/toxicidade , Animais , Cromatografia Líquida/métodos , Técnicas In Vitro , Camundongos , Células-Tronco Neurais/citologia , Oligodendroglia/citologia , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
4.
Neural Plast ; 2021: 8815144, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33603780

RESUMO

Purpose: This study is aimed at investigating brain structural changes and structural network properties in complete spinal cord injury (SCI) patients, as well as their relationship with clinical variables. Materials and Methods: Structural MRI of brain was acquired in 24 complete thoracic SCI patients (38.50 ± 11.19 years, 22 males) within the first postinjury year, while 26 age- and gender-matched healthy participants (38.38 ± 10.63 years, 24 males) were enrolled as control. The voxel-based morphometry (VBM) approach and graph theoretical network analysis based on cross-subject grey matter volume- (GMV-) based structural covariance networks (SCNs) were conducted to investigate the impact of SCI on brain structure. Partial correlation analysis was performed to explore the relationship between the GMV of structurally changed brain regions and SCI patients' clinical variables, including injury duration, injury level, Visual Analog Scale (VAS), American Spinal Injury Association Impairment Scale (AIS), International Classification of Functioning, Disability and Health (ICF) scale, Self-rating Depression Scale (SDS), and Self-rating Anxiety Scale (SAS), after removing the effects of age and gender. Results: Compared with healthy controls, SCI patients showed higher SDS score (t = 4.392 and p < 0.001). In the VBM analysis, significant GMV reduction was found in the left middle frontal cortex, right superior orbital frontal cortex (OFC), and left inferior OFC. No significant difference was found in global network properties between SCI patients and healthy controls. In the regional network properties, significantly higher betweenness centrality (BC) was noted in the right anterior cingulum cortex (ACC) and left inferior OFC and higher nodal degree and efficiency in bilateral middle OFCs, while decreased BC was noted in the right putamen in SCI patients. Only negative correlation was found between GMV of right middle OFC and SDS score in SCI patients (r = -0.503 and p = 0.017), while no significant correlation between other abnormal brain regions and any of the clinical variables (all p > 0.05). Conclusions: SCI patients would experience depressive and/or anxious feelings at the early stage. Their GMV reduction mainly involved psychology-cognition related rather than sensorimotor brain regions. The efficiency of regional information transmission in psychology-cognition regions increased. Greater GMV reduction in psychology region was related with more severe depressive feelings. Therefore, early neuropsychological intervention is suggested to prevent psychological and cognitive dysfunction as well as irreversible brain structure damage.


Assuntos
Encéfalo/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Traumatismos da Medula Espinal/diagnóstico por imagem , Adulto , Encéfalo/fisiopatologia , Feminino , Substância Cinzenta/fisiopatologia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Medula Espinal , Traumatismos da Medula Espinal/fisiopatologia , Adulto Jovem
5.
Eur J Med Chem ; 210: 112970, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33153765

RESUMO

To discover novel anticancer agents with potent and low toxicity, we designed and synthesized a range of new thiosemicarbazone-indole analogues based on lead compound 4 we reported previously. Most compounds displayed moderate to high anticancer activities against five tested tumor cells (PC3, EC109, DU-145, MGC803, MCF-7). Specifically, the represented compound 16f possessed strong antiproliferative potency and high selectivity toward PC3 cells with the IC50 value of 0.054 µM, compared with normal WPMY-1 cells with the IC50 value of 19.470 µM. Preliminary mechanism research indicated that compound 16f could significantly suppress prostate cancer cells (PC3, DU-145) growth and colony formation in a dose-dependent manner. Besides, derivative 16f induced G1/S cycle arrest and apoptosis, which may be related to ROS accumulation due to the activation of MAPK signaling pathway. Furthermore, molecule 16f could effectively inhibit tumor growth through a xenograft model bearing PC3 cells and had no evident toxicity in vivo. Overall, based on the biological activity evaluation, analogue 16f can be viewed as a potential lead compound for further development of novel anti-prostate cancer drug.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Indóis/farmacologia , Tiossemicarbazonas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Tiossemicarbazonas/química , Células Tumorais Cultivadas
6.
Colloids Surf B Biointerfaces ; 193: 111069, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32371286

RESUMO

Cajaninstilbene acid (CSA) exerts wide pharmacological activities, such as anti-inflammation, hypoglycaemic activity, analgesic effect and cognition improvement. However, it underwent severe phase II metabolism mediated by UDP-glucuronosyltransferase (UGT) in the gastrointestinal (GI) tract after oral administration, affecting its oral bioavailability. In the present study, we utilize UGT inhibitory excipient containing self-microemulsion (SME) delivery system to reduce the production of glucuronide metabolites and increase its oral bioavailability. The present results showed that although similar properties in physiochemical, cytotoxicity, cellular uptake, absorption and transport across rat everted gut sacs between SME-1 (inhibitory excipient containing SME) and SME-2 (control SME, without inhibitory excipient), an improved absolute bioavailability of 57.3 % was conferred by SME-1, significantly higher than the value of 35.4 % by SME-2 and 34.0 % by free CSA. Noticeably, the significantly lower AUC value of CSA glucuronide was determined in rats treated with SME-1 than those either treated with SME-2 or free CSA. Thus, the ability of SME-1 to enhance oral bioavailability of CSA is mainly attributed to the inhibition of phase II metabolism in the GI tract.


Assuntos
Inibidores Enzimáticos/farmacologia , Glucuronosiltransferase/antagonistas & inibidores , Salicilatos/farmacologia , Estilbenos/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Emulsões/administração & dosagem , Emulsões/farmacologia , Inibidores Enzimáticos/administração & dosagem , Glucuronosiltransferase/metabolismo , Humanos , Masculino , Ratos , Ratos Wistar , Salicilatos/administração & dosagem , Estilbenos/administração & dosagem , Células Tumorais Cultivadas
7.
ACS Nano ; 14(2): 1958-1970, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32023048

RESUMO

Size-transformable nanomedicine has the potential to overcome systemic and local barriers, leading to efficient accumulation and penetration throughout the tumor tissue. However, the design of this type of nanomedicine was seldom based on active targeting and intracellular size transformation. Here, we report an intracellular size-transformable nanosystem, in which small and positively charged nanoparticles (<30 nm) prepared from the self-assembly of an amphiphilic hexadecapeptide derivative was coated by folic acid- and dopamine-decorated hyaluronan (HA) to form large and negatively charged nanoparticles (∼130 nm). This nanosystem has been proven to improve the blood circulation half-life of the drug and prevent premature intravascular drug leakage from the nanocarrier. Once accumulated in the tumor, the nanoparticles were prone to HA- and folic acid-mediated cellular uptake, followed by intracellular size transformation and discharge of transformed small nanoparticles. The size-transformable nanosystem facilitated the transcytosis-mediated tumor penetration and improved the internalization of nanoparticles by cells and the intracellular release of 7-ethyl-10 hydroxycamptothecin. With an indocyanine green derivative as the intrinsic component of the amphiphilic polymer, the nanosystem has exhibited additional theranostic functions: photoacoustic imaging, NIR-laser-induced drug release, and synergistic chemotherapy and phototherapy, leading to a 50% complete cure rate in a subcutaneous B16 melanoma model. This nanosystem with multimodalities and efficient tumor penetration has shown potentials in improving anticancer efficacy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ácido Hialurônico/química , Irinotecano/farmacologia , Melanoma Experimental/terapia , Nanopartículas/química , Peptídeos/química , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Sobrevivência Celular , Terapia Combinada , Modelos Animais de Doenças , Dopamina/química , Feminino , Ácido Fólico/química , Verde de Indocianina/administração & dosagem , Verde de Indocianina/química , Injeções Intravenosas , Irinotecano/administração & dosagem , Irinotecano/química , Masculino , Melanoma Experimental/diagnóstico por imagem , Camundongos , Camundongos Endogâmicos C57BL , Imagem Óptica , Tamanho da Partícula , Peptídeos/síntese química , Ratos , Ratos Wistar , Propriedades de Superfície
8.
Int J Pharm ; 572: 118839, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31715359

RESUMO

This study intended to investigate the in vivo pulmonary fate of intratracheally dosed nanosuspensions of fluticasone propionate (FP). Three FP suspensions, including a microsuspension and two nanosuspensions with different dissolution profiles, were prepared and they exhibited comparable aerodynamic performances after nebulization via a jet nebulizer. Following intratracheal administration to rats, the microsuspension underwent extensive mucociliary clearance, leading to a limited absorption time whereas the nanosuspensions decreased the mucociliary clearance and allowed dissolution rate-limiting and extended pulmonary absorption, resulting in prolonged pulmonary retention and long-acting anti-inflammatory efficacy in a lipopolysaccharide induced lung injury model. Delaying the FP dissolution of a nanosuspension by phospholipid coating increased AUC value in lung tissues to 1.72-fold of a conventional nanosuspension, but led to a decreased pharmacological efficacy. This study demonstrated that inhalable nanosuspensions were a feasible means for the sustained pulmonary delivery of FP and the local anti-inflammatory efficacy was highly dependent on the dissolution profiles.


Assuntos
Anti-Inflamatórios/administração & dosagem , Fluticasona/administração & dosagem , Lesão Pulmonar/tratamento farmacológico , Nanopartículas , Administração por Inalação , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Área Sob a Curva , Preparações de Ação Retardada , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Fluticasona/farmacocinética , Fluticasona/farmacologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nebulizadores e Vaporizadores , Ratos , Ratos Wistar , Suspensões , Distribuição Tecidual
9.
Chin Med Sci J ; 34(3): 177-183, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31601300

RESUMO

Objective To evaluate the instant effects and five-year clinical outcomes of coronary artery disease patients complicated with diabetes mellitus after StentBoost-optimized percutaneous coronary intervention (PCI). Methods From March 2009 to July 2010, 184 patients undergoing PCI at our hospital were found stent underexpansion or malapposition by StentBoost after stents implantation and were divided into the diabetic (n=73, 39.67%) and the non-diabetic group (n=111, 60.33%). All patients received StentBoost-guided post-dilatation after stent implantation. The instant procedural results were measured and clinical outcome after five-year follow-up was analyzed in each group. Between-group comparisons were performed using Chi-square test or Student's t test. Multivariate logistic regression analysis was carried out to reveal the independent predictors for long-term clinical outcomes of StentBoost-optimized PCI . Results After StentBoost-guided post-dilatation, the minimum diameter (MinLD), maximum diameter (MaxLD) and average diameter in both groups increased significantly than before (P<0.001), the (MaxLD-MinLD)/MaxLD ratio and the in-stent residual stenosis decreased accordingly (P<0.001). The five-year follow-up showed similar mortality rate (4.92% vs. 2.86%, P=0.67) and major adverse cardiac event rate (11.48% vs. 11.43%, P = 1.0) between the diabetic and the non-diabetic group, whereas the recurrence of angina pectoris was higher in the diabetic group compared to the non-diabetic group (47.54% vs. 29.52%; P=0.02). A multivariate logistic regression analysis revealed that age and left ventricular ejection fraction rather than diabetes mellitus were independent predictors for long-term clinical outcomes. Conclusions StentBoost could effectively improve instant PCI results; the long-term clinical outcomes of StentBoost-optimized PCI were similar between diabetic and non-diabetic patients. Age and left ventricular ejection fraction were the independent predictors for long-term clinical outcomes.


Assuntos
Doença da Artéria Coronariana , Complicações do Diabetes , Intervenção Coronária Percutânea , Idoso , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/cirurgia , Complicações do Diabetes/mortalidade , Complicações do Diabetes/cirurgia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
10.
Exp Ther Med ; 16(6): 4393-4400, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30542389

RESUMO

Inexpensive and simple non-invasive indexes for predicting liver inflammation are urgently required, but have been poorly studied in chronic hepatitis B (CHB) patients with alanine transaminase (ALT) ≤2 times the upper limit of normal (ULN). A total of 356 CHB patients with ALT ≤2 ULN who presented at Huashan Hospital (n=181) and the First Hospital of Quanzhou (n=175) were enrolled and randomly divided into an experimental assessment cohort (n=238) and validation cohort (n=118) at a ratio of 2:1. Histological analysis of liver tissue was performed to determine the pathological stage according to the Scheuer scoring system. For the experimental assessment cohort, univariate and multivariate analysis identified aspartate aminotransferase (AST) and albumin (ALB) as independent predictors of liver necroinflammation [liver necroinflammation grade (G)≥2] in patients with ALT ≤2 ULN. Therefore, a novel index, the AST-to-ALB ratio (ATAR), was proposed, which had a better diagnostic performance [area under receiver operating characteristic curve (AUC)=0.721] than that of ALB (AUC=0.632; P=0.039 vs. ATAR) and AST (AUC=0.682; P=0.082 vs. ATAR). In the validation cohort, the AUC of ATAR (0.728) to identify patients with a G≥2 was slightly greater than that of AST (0.660; P=0.149 vs. ATAR) and ALB (0.672; P=0.282 vs. ATAR). Furthermore, a similar diagnostic superiority was also demonstrated in patients with ALT ≤1 ULN. Thus, ATAR may be a promising non-invasive surrogate marker for liver necroinflammation CHB patients with ALT ≤2 ULN and thereby determine whether anti-viral treatment should be initiated.

11.
Int J Pharm ; 549(1-2): 21-30, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30048776

RESUMO

The pulmonary fate of inhaled poorly water-soluble drugs is not entirely clear. In this study, the main objective was to investigate the in vivo inhalation biopharmaceutics in the aspects of dissolution, mucociliary clearance, absorption and tissue binding using intratracheally administered budesonide and ciclesonide suspensions as model drugs. In doing so, this study first developed a method to differentiate between dissolved and undissolved ciclesonide in the lungs for evaluating in vivo dissolution. Following deposited in rat airways, the drug particles underwent rapid dissolution and mucociliary clearance, leading to the complete removal of drugs from the airways within 2 h and a limited absorption time less than 2 h. Upon dissolution, budesonide and ciclesonide were taken up and retained in the lung tissues for up to 12 h and 24 h, respectively. The in vivo dissolution profiles in the airways exhibited the sameness as the in vitro counterparts in a 0.5% sodium dodecyl sulfate solution as indicated by the similarity factor f2. The efficacy results in a lipopolysaccharide induced lung injury model showed that the duration of local anti-inflammatory was dependent on the drug levels in the lung tissues, but not on the in vitro/in vivo dissolution and plasma pharmacokinetics. The present results demonstrated that ciclesonide suspension has the potential to achieve once-daily dosing for nebulization therapy and the in vitro dissolution profile has limited usefulness in predicting in vitro-in vivo correlation.


Assuntos
Budesonida/administração & dosagem , Glucocorticoides/administração & dosagem , Pulmão/metabolismo , Pregnenodionas/administração & dosagem , Lesão Pulmonar Aguda/tratamento farmacológico , Administração por Inalação , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Budesonida/farmacocinética , Budesonida/farmacologia , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Glucocorticoides/farmacocinética , Glucocorticoides/farmacologia , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nebulizadores e Vaporizadores , Pregnenodionas/farmacocinética , Pregnenodionas/farmacologia , Ratos , Ratos Wistar , Solubilidade , Suspensões , Fatores de Tempo , Distribuição Tecidual
12.
Infect Dis Poverty ; 7(1): 34, 2018 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-29699585

RESUMO

BACKGROUND: Primary pulmonary amoeba is very rare and here we report a case of a 68-year-old man presenting with primary pulmonary amoeba after undergoing chemotherapy for lung adenocarcinoma. CASE PRESENTATION: In October 2016, the man aged 68 was admitted to our hospital because of repeated cough for 8 months and hemoptysis for 1 month. He was diagnosed lung adenocarcinoma and underwent surgery in 2012 without receiving chemotherapy. In March 2016, the patients suffered recurrence of cancer and was treated with chemotherapy. After 2 months of chemotherapy, the patient had consistent cough with white sputum, and chest CT showed a local lung nodule. The physicians suspected that the patient had pulmonary infectious diseases, and he was treated with empirical antibacterial treatment. However, his symptom wasn't relieved and later the percutaneous lung biopsy found trophozites of Entamoeba histolytica. After administration of metronidazole, the symptoms of the patient were markedly relieved and the lesions were absorbed. CONCLUSIONS: In such cases where patients with pulmonary nodules were in immunodeficiency state and had adequate but ineffective anti-bacterial treatment, Entamoeba histolytica infection could be one of the rare causes. Percutaneous lung biopsy should be recommended and specific dying for parasites should be done when necessary.


Assuntos
Amebíase/diagnóstico , Antiprotozoários/uso terapêutico , Entamoeba histolytica/isolamento & purificação , Pneumopatias Parasitárias/diagnóstico , Metronidazol/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Adenocarcinoma de Pulmão , Idoso , Amebíase/tratamento farmacológico , Amebíase/parasitologia , Antineoplásicos/uso terapêutico , China , Humanos , Pneumopatias Parasitárias/tratamento farmacológico , Pneumopatias Parasitárias/parasitologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Masculino
13.
Eur J Pharm Sci ; 114: 303-309, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29292019

RESUMO

Self-microemulsifying (SME) drug delivery system has been developed to increase oral bioavailabilities, and inhibitory excipients are capable of improving oral bioavailability by inhibiting enzyme mediated intestinal metabolism. However, the potential of enzyme inhibitory excipients containing SME in boosting resveratrol bioavailability remains largely uninvestigated. In this study, we set out to prepare SME-1 with UGT inhibitory excipients (excipients without inhibitory activities named SME-2 as control) to increase the bioavailability of RES by inhibiting intestinal metabolism. Results demonstrated that similar physicochemical properties such as size, polydistribution index and in vitro release, cellular uptake and permeability in Caco-2 cells as well as in vivo lymphatic distribution between inhibitory SME-1 and non-inhibitory SME-2 were observed. In vivo study demonstrated that the molar ratios of RES-G/RES were 7.25±0.48 and 5.06±2.42 for free drug and SME-2, respectively, and the molar ratio decreased to 0.36±0.10 in SME-1 group. Pharmacokinetic study confirmed that the inhibitory excipients containing SME demonstrated potential in increasing bioavailability of RES from 6.5% for the free RES and 12.9% for SME-2 to 76.1% in SME-1 through modulating the glucuronidation by UGT inhibitory excipients.


Assuntos
Excipientes/metabolismo , Glucuronosiltransferase/antagonistas & inibidores , Glucuronosiltransferase/metabolismo , Estilbenos/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Emulsões , Excipientes/administração & dosagem , Absorção Gastrointestinal/efeitos dos fármacos , Absorção Gastrointestinal/fisiologia , Humanos , Masculino , Ratos , Ratos Wistar , Resveratrol , Estilbenos/administração & dosagem
14.
Hepatol Res ; 48(3): E133-E145, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28707778

RESUMO

AIM: Chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) levels are not free from significant hepatic lesions. Recently, there has been an improved understanding of the clinical significance of quantitative hepatitis B core antibody levels (qAnti-HBc) during CHB management. In this cross-sectional study, we evaluated the utility of qAnti-HBc in identifying significant liver inflammation in CHB patients. METHODS: A total of 469 patients (training set, n = 363; validation set, n = 106) who underwent liver biopsy (LB) were included. The qAnti-HBc levels were quantified and the relationship between histology and serum markers was systematically analyzed. RESULTS: In the training set, qAnti-HBc levels were found to have significant diagnostic value for moderate to severe liver inflammation (≥G2) in all patients (area under the receiver operating characteristic curve [AUROC] = 0.768; 95% confidence interval [CI], 0.721-0.810; P < 0.001) and in patients with normal or near-normal ALT levels (AUROC = 0.767; 95% CI, 0.697-0.828; P < 0.001). Our novel index (AC index) for the identification of ≥G2 inflammation, which combined the qAnti-HBc and ALT levels, significantly improved diagnostic performance (AUROC = 0.813; 95% CI, 0.768-0.852) compared to the use of ALT alone (AUROC = 0.779; 95% CI, 0.732-0.821) in all patients. In the validation set, the AC index showed an improved AUROC of 0.890 (95% CI, 0.814-0.942) and 0.867 (95% CI, 0.749-0.943) in all patients and patients with normal ALT levels, respectively. CONCLUSIONS: The qAnti-HBc level predicts significant liver inflammation well, even in patients with normal or near-normal ALT levels. Compared with the conventional ALT level, the AC index is a more reliable non-invasive biomarker for significant liver inflammation in CHB patients.

15.
Bioorg Med Chem Lett ; 27(20): 4682-4686, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28919340

RESUMO

Twenty-five novel pregnenolone/2-cyanoacryloyl conjugates (6-30) were designed and prepared, with the aim of developing novel anticancer drugs with dual NF-κB inhibitory and anti-proliferative activities. Compounds 22 and 27-30 showed inhibition against TNF-α-induced NF-κB activation in luciferase assay, which was confirmed by Western blotting. Among them, compound 30 showed potent NF-κB inhibitory activity (IC50=2.5µM) and anti-proliferative against MCF-7, A549, H157, and HL-60 cell lines (IC50=6.5-36.2µM). The present study indicated that pregnenolone/2-cyanoacryloyl conjugate I can server asa novel scaffold for developing NF-κB inhibitors and anti-proliferative agents in cancer chemotherapy.


Assuntos
Antineoplásicos/síntese química , Cianoacrilatos/química , Desenho de Fármacos , NF-kappa B/metabolismo , Pregnenolona/química , Células A549 , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Células MCF-7 , NF-kappa B/antagonistas & inibidores , Relação Estrutura-Atividade
16.
Drug Dev Ind Pharm ; 43(9): 1460-1471, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28402143

RESUMO

In this study, furbiprofen/hydroxypropyl-ß-cyclodextrin (HPßCD) inclusion complexes were prepared to improve the drug dissolution and facilitate its application in hydrophilic gels. Inclusion complexes were prepared using a supercritical fluid processing and a conventional optimized co-lypholization method was employed as a reference. The entrapment efficacy and drug loading of both methods were investigated. Evaluation of drug dissolution enhancement was conducted in deionized water as well as buffer solutions of different pH. Carbopol 940 gels of both flurbiprofen and flurbiprofen/HPßCD inclusion complexes, with or without penetration enhancers, were prepared and percutaneous permeation studies were performed using rat abdominal skin samples. Formation of flurbiprofen/HPßCD inclusion complexes was confirmed by Fourier transform-infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. The results obtained showed that SCF processing produced a higher EE (81.91 ± 1.54%) and DL (6.96 ± 0.17%) compared with OCL with values of 69.11 ± 2.23% and 4.00 ± 1.01%, respectively. A marked instantaneous release of flurbiprofen/HPßCD inclusion complexes prepared by SCF processing (103.04 ± 2.66% cumulative release within 5 min, a 10-fold increase in comparison with flurbiprofen alone) was observed. In addition, this improvement in dissolution was shown to be pH-independent (the percentage cumulative release at pH 1.2, 4.5, 6.8 and 7.4 at 5 min was 95.19 ± 1.71, 101.75 ± 1.44, 105.37 ± 4.58 and 96.84 ± 0.56, respectively). Percutaneous permeability of flurbiprofen-in-HPßCD-in-gels could be significantly accelerated by turpentine oil and was related to the water content in the system. An in vivo pharmacokinetic study showed a 2-fold increase in Cmax and a shortened Tmax as well as a comparable relative bioavailability when compared with the commercial flurbiprofen Cataplasms (Zepolas®). With their superior dissolution, these flurbiprofen/HPßCD inclusion complexes prepared by SCF processing could provide improved applications for flurbiprofen.


Assuntos
Flurbiprofeno/química , Flurbiprofeno/farmacocinética , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacocinética , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Química Farmacêutica , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Microscopia Eletrônica de Varredura , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
17.
Eur J Pharm Biopharm ; 114: 29-37, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28093351

RESUMO

Polymeric micelles are considered promising carriers for pulmonary drug delivery. Their interaction with the respiratory epithelium, however, is mostly unknown. In the present study, methoxypoly (ethylene glycol) (mPEG)-poly (lactic-co-glycolic acid) (PLGA) micelles containing curcumin acetate (CA) or a mixture of CA and Nile Red (NR) were prepared using the solvent evaporation method. Calu-3 and NCI-H441 human respiratory epithelial cell monolayers were used as in vitro models of upper and lower respiratory tract epithelium barrier, respectively, to study the cellular uptake and transport of the vesicles. The results show that Calu-3 and NCI-H441 cells internalized micellar particles and that micelles were able to translocate across the cell monolayers. Micelles were more readily internalized into and permeated across Calu-3 cell monolayers when compared to NCI-H441 cells. Furthermore, the presence of inhibitors of endocytic processes, such as methyl-ß-cyclodextrin, NaN3 and hypertonic sucrose attenuated the cellular uptake and trafficking of micelles. In conclusion, this study demonstrated that mPEG-PLGA micelles translocate human respiratory epithelium in vitro through clathrin-, energy- and cholesterol-mediated endocytosis.


Assuntos
Células Epiteliais/metabolismo , Poliésteres/farmacocinética , Polietilenoglicóis/farmacocinética , Mucosa Respiratória/metabolismo , Transporte Biológico Ativo , Linhagem Celular , Curcumina/administração & dosagem , Curcumina/farmacocinética , Endocitose/efeitos dos fármacos , Humanos , Micelas , Mucosa Respiratória/citologia , Mucosa Respiratória/efeitos dos fármacos
18.
BMC Complement Altern Med ; 17(1): 69, 2017 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-28109297

RESUMO

BACKGROUND: Daylily flowers, the flower and bud parts of Hemerocallis citrina or H. fulva, are well known as Wang-You-Cao in Chinese, meaning forget-one's sadness plant. However, the major types of active constituents responsible for the neurological effects remain unclear. This study was to examine the protective effects of hydroalcoholic extract and fractions and to identify the active fractions. METHODS: The extract of daylily flowers was separated with AB-8 resin into different fractions containing non-phenolic compounds, phenolic acid derivatives and flavonoids as determined using UPLC-DAD chromatograms. The neuroprotective activity was measured by evaluating the cell viability and lactate dehydrogenase release using PC12 cell damage models induced by corticosterone and glutamate. The neurological mechanisms were explored by determining their effect on the levels of dopamine (DA), 5-hydroxy tryptamine (5-HT), γ-aminobutyric acid (GABA), noradrenaline (NE) and acetylcholine (ACh) in the cell culture medium measured using an LC-MS/MS method. RESULTS: Pretreatment of PC12 cells with the extract and phenolic fractions of daylily flowers at concentrations ranging from 0.63 to 5 mg raw material/mL significantly reversed corticosterone- and glutamate-induced neurotoxicity in a dose-dependent manner. The fractions containing phenolic acid derivatives (0.59% w/w in the flowers) and/or flavonoids (0.60% w/w) exerted similar dose-dependent neuroprotective effect whereas the fractions with non-phenolic compounds exhibited no activity. The presence of phenolic acid derivatives in the corticosterone- and glutamate-treated PC12 cells elevated the DA level in the cell culture medium whereas flavonoids resulted in increased ACH and 5-HT levels. CONCLUSION: Phenolic acid derivatives and flavonoids were likely the active constituents of daylily flowers and they conferred a similar extent of neuroprotection, but affected the release of neurotransmitters in a different manner.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Hemerocallis/química , Fármacos Neuroprotetores/farmacologia , Animais , China , Cromatografia Líquida , Corticosterona/farmacologia , Medicamentos de Ervas Chinesas/química , Flores/química , Ácido Glutâmico/farmacologia , Fármacos Neuroprotetores/isolamento & purificação , Células PC12 , Fenol , Ratos
19.
J Biomed Nanotechnol ; 13(1): 99-09, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29373003

RESUMO

The main objective of this study was to test the hypothesis that inhaled nanocrystals of a highly lipophilic drug could be used as a novel approach for producing sustained pulmonary delivery. Curcumin acetate, an ester prodrug of curcumin, was utilized as a highly lipophilic model drug. Curcumin acetate was subjected to wet ball milling to produce different particle sizes of nanocrystals and microparticles, and the milled curcumin acetate was spray-dried to yield similar inhalable microparticles. Following intrapulmonary administration in rats, pharmacokinetic experiments indicated that curcumin acetate significantly extended the pulmonary absorption time by 7.2-fold compared to curcumin, possibly due to the high lipophilicity of the former. The biodistribution data showed that aerosolized curcumin acetate nanocrystals 123.7 nm in size not only prolonged pulmonary retention, with the AUC value of curcumin acetate being 7.62-fold higher than that of the microparticles 1120 nm in size, but also increased the local in vivo release rate by 3.3-fold and the local availability of converted curcumin by 25.1-fold. In addition, the improved local availability resulted in better pharmacological efficacy in a monocrotaline-induced rat model of pulmonary arterial hypertension. This study was the first to demonstrate that inhalable nanocrystals are a feasible means for the sustained pulmonary delivery of highly lipophilic drugs.


Assuntos
Curcumina/farmacocinética , Portadores de Fármacos/farmacocinética , Pulmão/efeitos dos fármacos , Nanopartículas/química , Administração por Inalação , Animais , Curcumina/administração & dosagem , Curcumina/análise , Curcumina/química , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Pulmão/química , Pulmão/metabolismo , Nanopartículas/administração & dosagem , Tamanho da Partícula , Ratos , Ratos Wistar , Distribuição Tecidual
20.
Curr Pharm Des ; 22(17): 2532-48, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26818873

RESUMO

BACKGROUND: Systemic pulmonary delivery is considered to have advantages over oral or intravenous administration for certain drugs. METHODS: In this article, we review the effects of intrinsic drug properties and drug loading carriers on the pharmacokinetic parameters of inhaled drugs in the context of use in systemic pulmonary delivery. RESULTS: The delivery of drugs via inhalation can be advisable to achieve a fast onset of action; enhance the systemic bioavailability of drugs with poor oral absorption, including peptides and proteins; avoid invasive administration and improve patient compliance. To optimize the functioning of this delivery system, there is high demand for a systematic understanding of the pharmacokinetic characteristics, which are closely related to the pharmacodynamic and toxicological effects. CONCLUSION: The pharmacokinetic parameters of inhaled drug products are affected by many factors, including physiological and pathological variables and the intrinsic drug and formulation properties.


Assuntos
Sistemas de Liberação de Medicamentos , Preparações Farmacêuticas/administração & dosagem , Farmacocinética , Administração por Inalação , Disponibilidade Biológica , Composição de Medicamentos , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...