Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 164
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Food Funct ; 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32242562

RESUMO

The formation and disappearance of aldehydes during simulated gastrointestinal digestion (SD) of fried clams was investigated in order to shed light on the underlying mechanism. Results from the thiobarbituric acid reactive substance (TBARS) and fluorometric assays using a specific aldehyde probe indicated that the SD (with lipase) of fried clams initially reduced (at the gastric stage), but subsequently increased (mainly at the intestinal stage) the contents of total aldehydes. Meanwhile, eight specific aldehydes including propanal, acrolein, trans-2-pentenal, hexanal, trans,trans-2,4-octadienal, trans,trans-2,4-decadienal, 4-hydroxy-hexenal and 4-hydroxy-nonenal in the digested meal were determined by using a high-performance liquid chromatography-tandem electrospray ionization mass spectrometry (HPLC-ESI-MS/MS) method. Results indicated that the changes in the trend of the contents of the eight aforementioned aldehydes were similar to those of total aldehydes during SD (with lipase) of fried clams. However, a similar SD process without lipase time-dependently reduced the contents of total and individual aldehydes. Moreover, lipid classes and free fatty acids (FFAs) in the digested meal were determined to reveal the degree of hydrolysis of lipids during the SD process. Results indicated that the SD (with lipase) of fried clams significantly hydrolyzed triacylglycerols (TAG) and polar lipids (PL) and produced FFAs, but the SD process without lipase resulted in negligible lipid hydrolysis. Thus, our results demonstrated a positive correlation between lipid hydrolysis and aldehyde generation during the SD of fried clams. Alternatively, unsaturated FFAs instead of TAG and PL could have served as the main precursors for aldehyde generation due to their high oxidative susceptibility.

2.
Drug Dev Res ; 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32220026

RESUMO

Scutellarin is the major and active constituent of Dengzhan Xixin Injection (DZXX), a traditional Chinese medicine prepared from the aqueous extract of Erigeron breviscapus and widely used for the treatment of various cerebrovascular diseases in clinic. In present study, the possible pharmacokinetic differences of scutellarin after intravenous administration of scutellarin alone or DZXX were explored. Additional, the potential roles of ß-glucuronidase (GLU) and OATP2B1 in drug-drug interaction (DDI) between scutellarin and constituents of DZXX were further evaluated in vitro. The plasma concentration, urinary and biliary excretion of scutellarin in rats after administration of DZXX, were significantly higher than those received scutellarin, while pharmacokinetic profile of Apigenin 7-O-glucuronide (AG) in rats was similar no matter AG or DZXX group. Furthermore, higher concentration in brain and plasma, however, lower level of scutellarin in intestine were observed after intravenous administration of DZXX. Finally, AG and caffeoylquinic acid esters were found to significantly inhibit GLU and OATP2B1 in vitro, which might explain, at least in part, the pharmacokinetic DDI between scutellarin and other chemical constituents in DZXX. The findings provided deep insight into the prescription-formulating principle in DZXX for treating the cerebrovascular diseases.

3.
Bioorg Chem ; 96: 103637, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32032849

RESUMO

The inhibition of soluble epoxide hydrolase (sEH) is a promising therapeutic approach to treat inflammation and other disorders. In our present investigation on searching for sEH inhibitors from traditional Chinese medicines, we found that Alisma orientale displayed inhibition of sEH. We constructed a small library of protostane-type triterpenoids (1-25) isolated from A. orientale, and screened their inhibitory activities. Alismanin B (1), 11-deoxy-25-anhydro alisol E (4), 11-deoxy alisol B (5), and 25-O-ethyl alisol A (15) displayed concentration-dependently inhibitory activities against sEH with IC50 values from 3.40 ± 0.57 µM to 9.57 ± 0.88 µM. 11-Deoxy-25-anhydro alisol E (4) and 11-deoxy alisol B (5) were defined as mixed-type competitive inhibitors with Ki values of 12.6 and 3.48 µM, respectively, based on the result of inhibition kinetics. The potential interaction mechanism of 11-deoxy alisol B (5) with sEH was analyzed by molecular docking and molecular dynamics, revealing that amino acid residues Trp336 and Tyr466 were vital for its inhibitory activity.

4.
Bioorg Chem ; 94: 103360, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31668462

RESUMO

The bioactive chemical constituents of Euphorbia ebracteolata have been investigated in the present work using various techniques. On the basis of chromatographic methods, such as silica gel, RP C-18 column chromatography, five novel rosane type diterpenoids with an aromatic A-ring (1-5) have been isolated from the roots of Euphorbia ebracteolata. Their structures were elucidated by widely spectroscopic data, including HRESI-MS, 1D and 2D NMR. Additionally, the inhibitory effects on lipase of these isolated diterpenoids were evaluated in vitro. Compound 1 as a new diterpenoid displayed significant inhibitory effect on lipase (IC50 = 1.0 µM). And, the inhibitory kinetics has been studied fully, which determined a competitive inhibition model for compound 1 on the enzymatic activity of lipase (Ki = 1.8 µM).

5.
Appl Physiol Nutr Metab ; 45(2): 187-192, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31287965

RESUMO

The aim of the study was to investigate whether the slow component of oxygen uptake was concurrent with the recruitment of large α-motoneuron muscle fibres by using wavelet and principal component analysis (PCA) of electromyography (EMG) during heavy and severe cycling exercise. Eleven male subjects participated in the study. After establishing each subject's maximum value of oxygen uptake through an incremental test on the cycle ergometer, the subjects performed 6-min cycling tests at heavy and severe intensity. EMG signals were collected from rectus femoris, biceps femoris long head, tibialis anterior, and medial gastrocnemius and processed by combined use of wavelet and PCA analysis. The time delays to the onset of slow component occurred significantly earlier during severe (105.22 ± 5.45 s) compared with during heavy (138.78 ± 15.09 s) exercise. ANOVA with repeated measures showed that for all muscles tested, the angle θ formed by the first and second principal components decreased significantly between time windows during heavy and severe exercise. However, significant increases of EMG mean power frequency (MPF) were found only during heavy exercise. Our results show the concurrence of the oxygen uptake slow component with the additional recruitment of muscle fibres, presumably less efficient large α-motoneuron fibres. Novelty The expected rise in MPF may be offset by muscle fatigue occurring in the later time windows of the slow component during severe exercise. The gradual shift to higher EMG frequencies throughout the slow-component phase was reflected in the progressive and significant decrease of angle θ.

6.
Int J Biol Macromol ; 143: 349-358, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31830453

RESUMO

ß-Glucuronidase plays a vital role in the metabolism of drugs and endogenous substance. Herein, we assayed the inhibitory effects of thirty-six flavonoids (1-36) toward ß-glucuronidase (Escherichia coli) using the probe reaction of DDAO-glu hydrolysis. The results showed that kushenol X (6), (2S)-farrerol (10), 5,7,2'-trihydroxy-8,6'-dimethoxy flavone (20), demethylbellidifolin (31), and gentisin (32) exhibited potent inhibitory activities toward ß-glucuronidase with the IC50 values of 2.07 ± 0.26, 8.95 ± 0.74, 4.97 ± 0.61, 0.91 ± 0.11, and 0.68 ± 0.10 µM, respectively. Furthermore, the inhibition kinetics studies indicated that demethylbellidifolin (31) and gentisin (32) exhibited mixed-type inhibiton toward ß-glucuronidase, the Ki values were caculated to be 4.05 and 2.02 µM, respectively. Additionally, the circular change of dichroism (CD) spectrum verified the interaction between demethylbellidifolin (31) and gentisin (32) with ß-glucuronidase; following by the molecular docking and molecular dynamics further revealed the potential interaction amino acid site in ß-glucuronidase. All our findings not only developed some potent novel ß-glucuronidase inhibitors but also indicated the potential herb drug interaction (HDI) effects of flavonoids with some clinical drugs which had enterohepatic circulation and further revealed the vital pharamcophoric requirement of natural flavonoids for ß-glucuronidase inhibition activity.

7.
J Nat Prod ; 82(12): 3302-3310, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31789520

RESUMO

Nine new monoterpenoid indole alkaloids, uncarialins A-I (1-9), were isolated from Uncaria rhynchophylla as well as 14 known analogues (10-23). Their structures were determined by HRESIMS, 1D and 2D NMR, and experimental and calculated electronic circular dichroism data. Compounds 5, 7, 15, and 22 displayed significant agonistic effects against the 5-HT1A receptor with EC50 values of 2.2 ± 0.1, 0.1 ± 0.1, 1.6 ± 0.3, and 2.0 ± 0.5 µM, respectively. The mechanisms of action of these four compounds with the 5-HT1A receptor were investigated by molecular docking, and the results suggested that amino acid residues Asp116, Thr196, Asn386, and Tyr390 played critical roles in the observed activity of the above-mentioned compounds.

8.
Future Med Chem ; 11(22): 2891-2903, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702381

RESUMO

Aim: CYP3A5 plays a vital role in the drug metabolism, it displays varied expression levels among individuals and is easily influenced by genetic polymorphisms and some diseases. Methodology & results: A dual function probe isobutyryl-11-keto-ß-boswellic acid (IKBA) was developed; it possessed a high selectivity toward CYP3A5 and CYP3A enzymes for its two individual metabolites, respectively. The probe has the high accuracy and wide applicability in measuring the real activity of CYP3A5. Finally, IKBA was successfully used for the evaluation of the activity of CYP3A5 and CYP3A enzymes in various bio samples. Conclusion: IKBA could serve as a useful tool for exploring the physiology and pathology functions of CYP3A5 and give some useful guidance for the rational use of clinical drugs.

9.
Anal Chem ; 91(24): 15840-15845, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31713417

RESUMO

Carboxylesterase 2 (CES2), an endoplasmic reticulum (ER) located phase I enzyme, plays a vital role in the metabolism of various endogenous and exogenous substances, and is regarded as an important target for the design of prodrugs. Unfortunately, superior highly selective ER targeting fluorescent probes for monitoring of CES2 are not currently available. Herein, we report an ER targeting CES2 selective and sensitive ratiometric fluorescent probe ERNB based on the ER localizing group p-toluenesulfonamide. ERNB possessed high specificity, sensitivity, and exhibited excellent subcellular localization when compared to commercial ER tracker, and was used to image CES2 in the ER of living cells. Additionally, using ERNB we evaluated the CES2 regulation under d,l-dithiothreitol and tunicamycin-induced ER stress. Furthermore, we determined the down regulation of CES2 activity and expression in the acetaminophen-induced acute liver injury model. On the basis of these results, we conclude that ERNB is a promising tool for highlighting the role of CES2 in the ER and in exploring the role of CES2 in the development of diseases associated with ER stress.

10.
Acta Pharm Sin B ; 9(5): 986-996, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31649848

RESUMO

Imipenem is a carbapenem antibiotic. However, Imipenem could not be marketed owing to its instability and nephrotoxicity until cilastatin, an inhibitor of renal dehydropeptidase-I (DHP-I), was developed. In present study, the potential roles of renal organic anion transporters (OATs) in alleviating the nephrotoxicity of imipenem by cilastatin were investigated in vitro and in rabbits. Our results indicated that imipenem and cilastatin were substrates of hOAT1 and hOAT3. Cilastatin inhibited hOAT1/3-mediated transport of imipenem with IC50 values comparable to the clinical concentration, suggesting the potential to cause a clinical drug-drug interaction (DDI). Moreover, imipenem exhibited hOAT1/3-dependent cytotoxicity, which was alleviated by cilastatin and probenecid. Furthermore, cilastatin and probenecid ameliorated imipenem-induced rabbit acute kidney injury, and reduced the renal secretion of imipenem. Cilastatin and probenecid inhibited intracellular accumulation of imipenem and sequentially decreased the nephrocyte toxicity in rabbit primary proximal tubule cells. Renal OATs, besides DHP-I, was also the target of interaction between imipenem and cilastatin, and contributed to the nephrotoxicity of imipenem. This therefore gives in part the explanation about the mechanism by which cilastatin protected against imipenem-induced nephrotoxicity. Thus, OATs can potentially be used as a therapeutic target to avoid the renal adverse reaction of imipenem in clinic.

12.
Eur J Med Chem ; 182: 111652, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494470

RESUMO

Farnesoid X receptor (FXR) is a key regulator in charge of bile acid synthesis, transport, and metabolism. Activation of FXR represses bile acid synthesis and increases its excretion and transport, consequently protecting the liver functions. Thus, FXR is considered as a critical therapeutic target of cholestasis and nonalcoholic steatohepatitis. Herein, we isolated and identified fourteen new protostane-type triterpenoids (1-14) and four known analogues (15-18) from Alisma orientale, and finally constructed a small library of protostane-type triterpenoids (1-70) to investigate their structure-activity relationship with FXR, further leading to obtain compound 15 with potent agonistic activity against FXR (EC50 = 90 nM). Extensive in vitro investigation confirmed high efficacy of compound 15 against FXR in living cell, and revealed its underlying mechanism for FXR activation (amino acid residues Arg331 and Ser332) by molecular docking and site-directed mutagenesis technology.


Assuntos
Produtos Biológicos/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Terpenos/farmacologia , Alisma/química , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Células Cultivadas , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Mutagênese Sítio-Dirigida , Receptores Citoplasmáticos e Nucleares/genética , Relação Estrutura-Atividade , Terpenos/química , Terpenos/isolamento & purificação
13.
J Mater Chem B ; 7(32): 4983-4989, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31411622

RESUMO

Glutathione transferase (GST) is a very important metabolic enzyme that mediates the wide metabolism of endogenous and xenobiotic compounds; it usually has a significant over expression in cancer cells, which is a key reason resulting in drug resistance, and will show an obvious down regulation during liver injury, thus it was also regarded as a vital biomarker in clinical diagnosis. Herein, based on boron-dipyrromethene (BODIPY) dye, a two-photon probe BNPA was designed for the real-time detection of GST activities and fluorescence imaging in both cancer cells and liver tissues. Importantly, BNPA exhibited a high selectivity, ultrahigh imaging resolution and showed a classic Michaelis-Menten kinetics toward GSTs. Furthermore, it was successfully used for monitoring the GST activities in living cells and deep tissues by two-photon imaging, as well as detecting the down regulation of GST activities during α-naphthylisothiocyanate (ANIT) induced liver injury. Our results fully demonstrated that BNPA could serve as a promising tool for evaluating the GST function and the process of cellular GSTs in living systems, and also provided a new approach for studying GST-associated liver diseases, which would be greatly useful for rational drug use and disease diagnosis in clinics.

16.
Chem Biol Interact ; 311: 108793, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31421117

RESUMO

Polyphyllin I (PPI), a bioactive component extracted from Paris polyphylla, was reported to have potent anticancer activities in previous studies. However, there were few reports on the effects and underlying mechanism of PPI in human acute myeloid leukemia cells. The present study demonstrated that PPI had an inhibitory effect through inducing apoptosis and autophagy in THP-1 and NB4 cells. PPI induced apoptosis via activating JNK pathway, as evidenced by the decreased Bcl-2 levels and increased Bax, cleaved-caspase-3 and phosphorylated-JNK expressions. In addition, PPI promoted autophagy as evidenced with increased expressions of LC3-II and Beclin-1 in western blot and autophagic vacuoles in MDC staining, which was associated with the inhibition of AKT-mTOR pathway. Furthermore, JNK inhibitor SP600125 and autophagy inhibitor 3-MA were employed to evaluate the role of apoptosis and autophagy in PPI-induced cell death. We found that autophagy and apoptosis were both causes of cell death induced by PPI. These data suggested that PPI could be a potent therapeutic agent for the treatment of human acute myeloid leukemia.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Diosgenina/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Diosgenina/farmacologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Leucemia Mieloide Aguda/patologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima/efeitos dos fármacos
17.
Food Funct ; 10(9): 5768-5778, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31454000

RESUMO

In this study, we aimed at investigating the antiinflammatory activity of the freeze-dried fruit powder of Actinidia arguta (FAA) on dextran sulphate sodium (DSS)-induced ulcerative colitis (UC) in mice and the effect of its extract on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. For pharmacodynamic studies, the oral administration of FAA (300 or 600 mg kg-1) could decrease the disease activity index (DAI), reduce the incidence of colon and spleen edemas (caused by inflammation), and alleviate the pathological changes in UC. For research involving biochemical indicators, FAA could decrease the expression of inflammatory markers (such as myeloperoxidase (MPO)) and attenuate the oxidative stress levels. ELISA results revealed that the expressions of proinflammatory cytokines (IL-1ß, IL-6, and TNF-α) were downregulated by FAA. Furthermore, the expression levels of the inflammation-induced activation of p38, JNK, and ERK were decreased by FAA. Hence, it was concluded that FAA could alleviate the UC symptoms in mice and the inflammatory response of macrophages via the MAPK signal pathway. Overall, FAA might have the potential to treat UC when used as a dietary supplement.


Assuntos
Actinidia/química , Anti-Inflamatórios/metabolismo , Colite Ulcerativa/dietoterapia , Colite Ulcerativa/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/imunologia , Preparações de Plantas/metabolismo , Actinidia/metabolismo , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/imunologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Feminino , Frutas/química , Frutas/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Preparações de Plantas/química , Pós/química , Pós/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
19.
Phytochemistry ; 166: 112062, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31299395

RESUMO

Tripterygium wilfordii Hook. f. is a perennial woody vine member of the Celastraceae family. As a traditional Chinese medicine, it contains complex chemical components and exerts various pharmacological activities. In the present study, we identified a glucosyltransferase, TwUGT1, that can catalyze the synthesis of an abietane-type diterpene glucoside, namely, triptophenolide14-O-beta-D-glucopyranoside, and investigated the pharmacological activity of triptophenolide glucoside in diverse cancer cells. Triptophenolide glucoside exhibited significant inhibitory effects on U87-MG, U251, C6, MCF-7, HeLa, K562, and RBL-2H3 cells as determined by pharmacological analysis. The triptophenolide glucoside content of T. wilfordii was analyzed using Agilent Technologies 6490 Triple Quad LC/MS. The glucosyltransferase TwUGT1 belongs to subfamily 88 and group E in family 1. Molecular docking and site-directed mutagenesis of TwUGT1 revealed that the His30, Asp132, Phe134, Thr154, Ala370, Leu376, Gly382, His387, Glu395 and Gln412 residues play crucial roles in the catalytic activity of triptophenolide 14-O-glucosyltransferase. In addition, TwUGT1 was also capable of glucosylating phenolic hydroxyl groups, such as those in liquiritigenin, pinocembrin, 4-methylumbelliferone, phloretin, and rhapontigenin.


Assuntos
Biocatálise , Diterpenos/química , Diterpenos/metabolismo , Glucosídeos/química , Glucosiltransferases/metabolismo , Tripterygium/química , Glucosiltransferases/química , Simulação de Acoplamento Molecular , Conformação Proteica
20.
Bioorg Chem ; 90: 103101, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31291611

RESUMO

In this study, forty-nine kinds of traditional Chinese medicines (TCMs) were evaluated for their inhibitory activities against human carboxylesterase 2 (HCE 2) using a human liver microsome (HLM) system. Swertia bimaculata showed significant inhibition on HCE 2 at 10 µg/mL among forty-nine kinds of TCMs. The extract of Swertia bimaculata was separated by preparative HPLC to afford demethylbellidifolin (1) identified by MS, 1H NMR, and 13C NMR spectra. Demethylbellidifolin (1) was assayed for its inhibitory HCE 2 effect by HCE 2-mediated DDAB hydrolysis, and its potential IC50 value was 3.12 ±â€¯0.64 µM. Demethylbellidifolin (1) was assigned as a mixed-type competitive inhibitor with the inhibiton constant Ki value of 6.87 µM by Lineweaver-Burk and slope plots. Living cell imaging was conducted to corroborate its inhibitory HCE 2 activity. Molecular docking indicated potential interactions of demethylbellidifolin (1) with HCE 2 through two hydrogen bonds of the C-3 and C-5 hydroxy groups with amino acid residues Glu227 and Ser228 in the catalytic cavity, respectively.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA