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1.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361791

RESUMO

As a key enzyme regulating postprandial blood glucose, α-Glucosidase is considered to be an effective target for the treatment of diabetes mellitus. In this study, a simple, rapid, and effective method for enzyme inhibitors screening assay was established based on α-glucosidase catalyzes reactions in a personal glucose meter (PGM). α-glucosidase catalyzes the hydrolysis of maltose to produce glucose, which triggers the reduction of ferricyanide (K3[Fe(CN)6]) to ferrocyanide (K4[Fe(CN)6]) and generates the PGM detectable signals. When the α-glucosidase inhibitor (such as acarbose) is added, the yield of glucose and the readout of PGM decreased accordingly. This method can achieve the direct determination of α-glucosidase activity by the PGM as simple as the blood glucose tests. Under the optimal experimental conditions, the developed method was applied to evaluate the inhibitory activity of thirty-four small-molecule compounds and eighteen medicinal plants extracts on α-glucosidase. The results exhibit that lithospermic acid (52.5 ± 3.0%) and protocatechualdehyde (36.8 ± 2.8%) have higher inhibitory activity than that of positive control acarbose (31.5 ± 2.5%) at the same final concentration of 5.0 mM. Besides, the lemon extract has a good inhibitory effect on α-glucosidase with a percentage of inhibition of 43.3 ± 3.5%. Finally, the binding sites and modes of four active small-molecule compounds to α-glucosidase were investigated by molecular docking analysis. These results indicate that the PGM method is feasible to screening inhibitors from natural products with simple and rapid operations.


Assuntos
Benzaldeídos/farmacologia , Benzofuranos/farmacologia , Glicemia/análise , Catecóis/farmacologia , Depsídeos/farmacologia , Diabetes Mellitus Tipo 2/diagnóstico , Inibidores de Glicosídeo Hidrolases/farmacologia , Monitorização Ambulatorial/métodos , alfa-Glucosidases/sangue , Acarbose/química , Acarbose/farmacologia , Benzaldeídos/química , Benzaldeídos/isolamento & purificação , Benzofuranos/química , Benzofuranos/isolamento & purificação , Sítios de Ligação , Técnicas Biossensoriais/instrumentação , Catecóis/química , Catecóis/isolamento & purificação , Depsídeos/química , Depsídeos/isolamento & purificação , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores de Glicosídeo Hidrolases/química , Humanos , Hidrólise , Cinética , Maltose/metabolismo , Simulação de Acoplamento Molecular , Monitorização Ambulatorial/instrumentação , Extratos Vegetais/química , Plantas Medicinais , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Termodinâmica , Dispositivos Eletrônicos Vestíveis , alfa-Glucosidases/química
2.
Molecules ; 26(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203179

RESUMO

In this study, a polydopamine (PDA)-modified hollow fiber-immobilized xanthine oxidase (XOD) was prepared for screening potential XOD inhibitors from flavonoids. Several parameters for the preparation of PDA-modified hollow fiber-immobilized XOD, including the dopamine concentration, modification time, XOD concentration and immobilization time, were optimized. The results show that the optimal conditions for immobilized XOD activity were a dopamine concentration of 2.0 mg/mL in 10.0 mM Tris-HCl buffer (pH 8.5), a modification time of 3.0 h, an XOD concentration of 1000 µg/mL in 10.0 mM phosphate buffer (pH 7.5) and an immobilization time of 3.0 h. Subsequently, the enzymatic reaction conditions such as the pH value and temperature were investigated, and the enzyme kinetics and inhibition parameters were determined. The results indicate that the optimal pH value (7.5) and temperature (37 °C) of the PDA-modified hollow fiber-immobilized XOD were consistent with the free enzyme. Moreover, the PDA-modified hollow fiber-immobilized XOD could still maintain above 50% of its initial immobilized enzyme activity after seven consecutive cycles. The Michaelis-Menten constant (Km) and the half-maximal inhibitory concentration (IC50) of allopurinol on the immobilized XOD were determined as 0.25 mM and 23.2 µM, respectively. Furthermore, the PDA-modified hollow fiber-immobilized XOD was successfully applied to evaluate the inhibitory activity of eight flavonoids. Quercetin, apigenin, puerarin and epigallocatechin showed a good inhibition effect, and their percentages of inhibition were (79.86 ± 3.50)%, (80.98 ± 0.64)%, (61.15 ± 6.26)% and (54.92 ± 0.41)%, respectively. Finally, molecular docking analysis further verified that these four active compounds could bind to the amino acid residues in the XOD active site. In summary, the PDA-modified hollow fiber-immobilized XOD is an efficient method for the primary screening of XOD inhibitors from natural products.


Assuntos
Inibidores Enzimáticos/química , Enzimas Imobilizadas , Flavonoides/química , Indóis/química , Polímeros/química , Xantina Oxidase , Enzimas Imobilizadas/antagonistas & inibidores , Enzimas Imobilizadas/química , Simulação de Acoplamento Molecular , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/química
3.
Anal Bioanal Chem ; 413(9): 2457-2466, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33674935

RESUMO

In this study, an effective and portable method for enzyme activity detection and inhibitory activity evaluation was developed based on the alkaline phosphatase (ALP)-mediated reaction in a personal glucose meter (PGM). In this method, ALP catalyzes the hydrolysis of substrate amifostine (WR-2721) to produce ethanethiol (WR-1065), which can trigger the reduction of ferricyanide (K3[Fe(CN)6]), an electron transfer mediator in glucose test strips, to ferrocyanide ([K4Fe(CN)6]) and generate a PGM-detectable signal. Thus, WR-1065 can be directly quantified by a PGM as simply as detecting glucose in blood. After being systematically optimized, the method was applied to evaluate the inhibitory activity of ten small-molecule compounds and six Cordyceps sinensis (CS) extracts on ALP. The results showed that adenosine-5-monophosphate and theophylline had high inhibitory activity, but two CS extracts have promotion potency on ALP with the values of -20.7 ± 1.3% and -46.6 ± 2.1%, respectively. Moreover, the binding sites and modes of small-molecule compounds to ALP were investigated by molecular docking, while a new substrate competitor with theoretically good inhibitory activity against ALP was designed by scaffold hopping. Finally, the accuracy of the PGM method for enzyme activity detection was assessed by detecting ALP from milk samples, and the recovery ranged from 87.7% to 116.9%. These results indicate that it is feasible to evaluate enzyme activity and the inhibitory activity of small-molecule compounds and CS extracts on ALP using a PGM based on ALP-mediated reaction. Graphical abstract.


Assuntos
Fosfatase Alcalina/metabolismo , Técnicas Biossensoriais/métodos , Glicemia/análise , Ensaios Enzimáticos/métodos , Fosfatase Alcalina/antagonistas & inibidores , Técnicas Biossensoriais/instrumentação , Ensaios Enzimáticos/instrumentação , Inibidores Enzimáticos/farmacologia , Desenho de Equipamento , Humanos , Modelos Moleculares
4.
J Pharm Biomed Anal ; 193: 113743, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33221573

RESUMO

In this study, a method based on adsorbed hollow fiber immobilized tyrosinase (TYR) was developed to screening potential TYR inhibitors from Pueraria lobate extract. Kojic acid and ranitidine were used as positive and negative control to verify the reliability of the proposed method, respectively. Several significant parameters of the screening process, including the amount of P. lobata extract, adsorption time and incubation time, were optimized. After investigating the repeatability of the developed method, seven potential active compounds in P. lobata extract were successfully detected and their chemical structures were tentatively identified by liquid chromatography - mass spectrometry analysis. Furthermore, the inhibitory activity of four identified compounds on TYR was tested in vitro, and three of them, namely, puerarin, puerarin-6″-O-xyloside and puerarin apioside were verified to have good TYR inhibitory activity with IC50 value of 478.5, 513.8, and 877.3 µM, respectively. In addition, the molecular docking results indicated that these compounds could bind to the amino acid residues in TYR catalytic pocket. These results proved that the proposed method is a feasible approach for screening of TYR inhibitors from plant extract.


Assuntos
Isoflavonas , Pueraria , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase , Extratos Vegetais/farmacologia , Reprodutibilidade dos Testes
5.
Anal Chim Acta ; 1142: 19-27, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33280697

RESUMO

In this study, a simple and portable enzyme activity assay and inhibitor screening method was developed based on ß-Glucosidase-mediated cascade reaction in a personal glucose meter (PGM). The inhibition of castanospermine (ß-Glucosidase inhibitor) on ß-Glucosidase leads to reducing the yields of glucose and saligenin produced by the catalysis hydrolysis of D (-)-Salicin. The ferricyanide (K3 [Fe(CN)6]) can be reduced by the products of glucose and saligenin to form ferrocyanide ([K4[Fe(CN)6]) in the glucose strips, and thereby get the electron to generate PGM detectable signals. This strategy can realize the direct determination of glucose and saligenin using PGM as simple as measuring the glucose in blood. Under the optimum experimental conditions, quantitative detection of ß-Glucosidase in crude almond sample was achieved within the ranges of 1.0-9.0 U/mL with the limit of detection of 0.45 U/mL. The recoveries of ß-Glucosidase spiked with two different concentrations (3.0 and 6.0 U/mL) in the crude bitter almond extracts were determined as 96.2% and 84.3%, respectively. Furthermore, gallic acid, protocatechualdehyde, cryptochlorogenic acid, epigallocatechin, epicatechin and vanillic acid exhibited good inhibitory effect (all higher than 40%) on ß-Glucosidase. In addition, tea polyphenol extracts of raw Pu-erh and Fuding white tea had good inhibition potency and the % of inhibition were (29.0 ± 3.5)% and (21.1 ± 2.2)% on ß-Glucosidase, respectively. Finally, molecular docking study indicated that hydrogen bonding plays an important role in the interaction between the compounds and ß-Glucosidase. The enzyme activity assay and inhibitor screening method developed in present study using PGM based on ß-Glucosidase-mediated cascade reaction would be of value for expanding the application of PGM in non-glucose target analysis.


Assuntos
Glucose , beta-Glucosidase , Automonitorização da Glicemia , Hidrólise , Simulação de Acoplamento Molecular
6.
J Sep Sci ; 44(6): 1220-1230, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33369071

RESUMO

In this study, a zirconium terephthalate metal-organic framework-coated magnetic nanoparticle (UiO-66@PA@PEI@Fe3 O4 ) was synthesized for the extraction of berberine prior to high-performance liquid chromatography analysis. The phytic acid, which could be grafted onto the magnetic nanoparticle through electrostatic interaction with the abundant amino groups of polyethylenimine, possesses outstanding metal ion coordination ability for the immobilization of metal-organic frameworks UiO-66. The physicochemical properties of the obtained nanoparticle were thoroughly investigated by a series of characterization techniques. Then, the factors that will affect the extraction efficiency and recovery of berberine were investigated. Results indicated that the material had good stability and reusability, and high adsorption capacity (50.01 mg/g) to berberine through single-layer adsorption. In addition, a molecular docking study indicated that the interactions between the material and berberine were mainly π-π stacking and hydrophobic interaction. Finally, the material was successfully applied to the extraction of berberine in Rhizoma Coptidis and Cortex Phellodendri extracts with the recoveries of 76.1% and 71.6%, respectively.

7.
Inorg Chem ; 55(13): 6504-10, 2016 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-27308962

RESUMO

A novel small-molecule compound of lithium iodine and 3-hydroxypropionitrile (HPN) has been successfully synthesized. Our combined experimental and theoretical studies indicated that LiIHPN is a Li-ion conductor, which is utterly different from the I(-)-anion conductor of LiI(HPN)2 reported previously. Solid-state lithium-air batteries based on LiIHPN as the electrolyte exhibit a reversible discharge capacity of more than 2100 mAh g(-1) with a cyclic performance over 10 cycles. Our findings provide a new way to design solid-state electrolytes toward high-performance lithium-air batteries.

8.
Structure ; 23(11): 2076-86, 2015 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-26592798

RESUMO

The human TEAD family of transcription factors (TEAD1-4) is required for YAP-mediated transcription in the Hippo pathway. Hyperactivation of TEAD's co-activator YAP contributes to tissue overgrowth and human cancers, suggesting that pharmacological interference of TEAD-YAP activity may be an effective strategy for anticancer therapy. Here we report the discovery of a central pocket in the YAP-binding domain (YBD) of TEAD that is targetable by small-molecule inhibitors. Our X-ray crystallography studies reveal that flufenamic acid, a non-steroidal anti-inflammatory drug (NSAID), binds to the central pocket of TEAD2 YBD. Our biochemical and functional analyses further demonstrate that binding of NSAIDs to TEAD inhibits TEAD-YAP-dependent transcription, cell migration, and proliferation, indicating that the central pocket is important for TEAD function. Therefore, our studies discover a novel way of targeting TEAD transcription factors and set the stage for therapeutic development of specific TEAD-YAP inhibitors against human cancers.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Proteínas de Ligação a DNA/química , Fatores de Transcrição/química , Sequência de Aminoácidos , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/química , Sítios de Ligação , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Dados de Sequência Molecular , Ligação Proteica , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
9.
Chempluschem ; 80(8): 1250-1254, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31973307

RESUMO

Bacterial resistance to antibiotics remains a serious threat to global health. The gyrase B enzyme is a well-validated target for developing antibacterial drugs. Despite being an attractive target for antibiotic development, there are currently no gyrase B inhibitory drugs on the market. A fragment screen using 1,800 compounds identified 14 fragments that bind to Escherichia coli (E. coli) gyrase B. The detailed characterization of binding is described for all 14 fragments. With the aid of X-ray crystallography, modifications on a low-affinity fragment (KD =253 µM, IC50 =634 µM) has led to the development of a new class of potent phenyl aminopyrazole inhibitors against E. coli gyrase B (IC50 =160 nM). The study presented here combines the use of a set of biophysical techniques including differential scanning fluorimetry, nuclear magnetic resonance, isothermal titration calorimetry, and X-ray crystallography to methodically identify, quantify, and optimize fragments into new chemical leads.

10.
Org Lett ; 14(15): 3955-7, 2012 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-22830594

RESUMO

A stereoselective allylic alkylation of isatin-derived Morita-Baylis-Hillman (MBH) carbonates with nitroalkanes has been developed. In the presence of 10 mol % ß-isocupreidine (ß-ICD), 3,3'-disubstituted oxindoles were prepared with moderate diastereoselectivities and excellent enantioselectivities.


Assuntos
Alcanos/química , Carbonatos/química , Indóis/síntese química , Isatina/análogos & derivados , Isatina/química , Nitrocompostos/química , Alquilação , Catálise , Hidroxiquinolinas/química , Indóis/química , Estrutura Molecular , Oxindóis , Quinuclidinas/química , Estereoisomerismo
11.
Org Lett ; 14(14): 3764-7, 2012 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-22789100

RESUMO

A highly enantioselective [3 + 2] annulation of MBH carbonates and maleimides catalyzed by chiral phosphines has been developed. In the presence of 5 mol % of L-Thr-L-Val-derived phosphine 6, functionalized bicyclic imides were prepared in excellent yields, and with high diastereoselectivities and nearly perfect enantioselectivities.


Assuntos
Carbonatos/química , Dipeptídeos/síntese química , Imidas/química , Maleimidas/síntese química , Fosfinas/química , Dipeptídeos/química , Maleimidas/química , Estrutura Molecular , Estereoisomerismo
12.
J Am Chem Soc ; 134(24): 10222-7, 2012 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-22621622

RESUMO

Phthalides were used for the first time in the allylic alkylation reactions with MBH carbonates for the creation of chiral 3,3-disubstituted phthalides. Highly enantioselective regiodivergent synthesis of γ-selective or ß-selective allylic alkylation products was achieved by employing bifunctional chiral phosphines or multifunctional tertiary amine-thioureas as the catalyst, respectively. It was demonstrated that proper selection of catalysts and reaction conditions would differentiate an S(N)2'-S(N)2' pathway and an addition-elimination process, yielding different regioisomers of the allylic alkylation products in a highly enantiomerically pure form.


Assuntos
Compostos Alílicos/química , Benzofuranos/química , Carbonatos/química , Alquilação , Estereoisomerismo
13.
Org Lett ; 13(22): 6070-3, 2011 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-22035214

RESUMO

A highly enantioselective and regioselective substitution reaction of the Morita-Baylis-Hillman (MBH) carbonates with nitroalkanes catalyzed by a quinidine-derived tertiary amine-thiourea catalyst has been developed. The described method, which is different from most organocatalytic allylic substitutions of the MBH adducts to date, represents a novel approach to regioselectively functionalize the MBH adducts.


Assuntos
Alcanos/química , Carbonatos/química , Nitrocompostos/química , Catálise , Estrutura Molecular , Estereoisomerismo
14.
Org Lett ; 13(1): 82-5, 2011 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-21138329

RESUMO

The first tertiary amine catalyzed enantioselective Morita-Baylis-Hillman (MBH) reaction of isatins with acrylates has been demonstrated, allowing asymmetric synthesis of biologically significant 3-substituted-3-hydroxy-2-oxindoles in good yields and with excellent enantioselectivities. The C6'-OH group of ß-isocupreidine (ß-ICD) is believed to facilitate the key proton transfer step in the MBH reaction, via an intramolecular proton relay process.


Assuntos
Acrilatos/química , Indóis/síntese química , Isatina/química , Catálise , Hidroxilação , Estrutura Molecular , Oxindóis , Estereoisomerismo
16.
Shanghai Kou Qiang Yi Xue ; 13(2): 121, 125, 2004 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-15133556

RESUMO

Branchial cyst is a rarely seen inheritent cyst commonly located in the lateral face and neck.A giant branchial cyst with infection in a newborn infant was reported in this paper. Surgical enucleate of the cyst was performed at 17 days of the infant with good result. The patient has been followed up for 2 years without recurrence.


Assuntos
Branquioma/cirurgia , Neoplasias de Cabeça e Pescoço/cirurgia , Infecções/etiologia , Branquioma/complicações , Branquioma/patologia , Neoplasias de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Recém-Nascido , Masculino
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