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1.
Int J Nanomedicine ; 14: 6287-6296, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496686

RESUMO

Purpose: We aimed to enhance the solubility, dissolution rate, oral bioavailability, and α-glucosidase inhibition of glimepiride (Glm) by fabricating its nanosuspension using a precipitation-ultrasonication approach. Methods: Glm nanosuspensions were fabricated using optimized processing conditions. Characterization of Glm was performed using Malvern Zetasizer, scanning electron microscopy, transmission electron microscopy, differential scanning calorimetry, and powder X-ray diffraction. Minimum particle size and polydispersity index (PDI) values were found to be 152.4±2.42 nm and 0.23±0.01, respectively, using hydroxypropyl methylcellulose: 6 cPs, 1% w/v, polyvinylpyrrolidone K30 1% w/v, and sodium lauryl sulfate 0.12% w/v, keeping ultrasonication power input at 400 W, with 15 minutes' processing at 3-second pauses. In vivo oral bioavailability was assessed using rabbits as a model. Results: The saturation solubility of the Glm nanosuspensions was substantially enhanced 3.14-fold and 5.77-fold compared to unprocessed drug in stabilizer solution and unprocessed active pharmaceutical ingredient. Also, the dissolution rate of the nanosuspensions ws substantially boosted when compared to the marketed formulation and unprocessed drug candidate. The results showed that >85% of Glm nanosuspensions dissolved in the first 10 minutes compared to 10.17% of unprocessed Glm), 42.19% of microsuspensions, and 19.94% of marketed tablets. In-vivo studies conducted in animals, i.e. rabbits, demonstrated that maximum concentration and AUC0-24 with oral dosing were twofold (5 mg/kg) and 1.74-fold (2.5 mg/kg) and 1.80-fold (5 mg/kg) and 1.63-fold (2.5 mg/kg), respectively, and compared with the unprocessed drug formulation. In-vitro α-glucosidase inhibition results showed that fabricated nanosuspensions had a pronounced effect compared to unprocessed drug. Conclusion: The optimized batch fabricated by ultrasonication-assisted precipitation can be useful in boosting oral bioavailability, which may be accredited to enhanced solubility and dissolution rate of Glm, ultimately resulting in its faster rate of absorption due to nanonization.


Assuntos
Precipitação Química , Inibidores de Glicosídeo Hidrolases/farmacologia , Nanopartículas/química , Compostos de Sulfonilureia/farmacologia , Ultrassom , alfa-Glucosidases/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Derivados da Hipromelose/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Coelhos , Solubilidade , Compostos de Sulfonilureia/administração & dosagem , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacocinética , Suspensões , Difração de Raios X
2.
J Agric Food Chem ; 67(37): 10521-10533, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31461284

RESUMO

This work was designed to comparatively investigate 27 dietary flavonoids that act as α-glucosidase inhibitors and insulin sensitizers. On the basis of the results of an in vitro experiment of α-glucosidase inhibition, myricetin (IC50 = 11.63 ± 0.36 µM) possessed the strongest inhibitory effect, followed by apigenin-7-O-glucoside (IC50 = 22.80 ± 0.24 µM) and fisetin (IC50 = 46.39 ± 0.34 µM). A three-dimensional quantitative structure-activity relationship model of α-glucosidase inhibitors with good predictive capability [comparative molecular field analysis, q2 = 0.529, optimum number of components (ONC) = 10, R2 = 0.996, F = 250.843, standard error of estimation (SEE) = 0.064, and two descriptors; comparative similarity index analysis, q2 = 0.515, ONC = 10, R2 = 0.997, F = 348.301, SEE = 0.054, and four descriptors] was established and indicated that meta positions of ring B favored bulky and minor, electron-withdrawing, and hydrogen bond donor groups. The presence of electron-donating and hydrogen bond acceptor groups at position 4' of ring B could improve α-glucosidase activity. Position 3 of ring C favored minor, electron-donating, and hydrogen bond donor groups, whereas position 7 of ring A favored bulky and hydrogen bond acceptor groups. Molecular docking screened five flavonoids (baicalein, isorhamnetin-3-O-rutinoside, apigenin-7-O-glucoside, kaempferol-7-O-ß-glucoside, and cyanidin-3-O-glucoside) that can act as insulin sensitizers and form strong combinations with four key protein targets involved in the insulin signaling pathway. Apigenin-7-O-glucoside (60 µM) can effectively improve insulin resistance, and glucose uptake increased by approximately 73.06% relative to the model group of insulin-resistant HepG2 cells. Therefore, apigenin-7-O-glucoside might serve as the most effective α-glucosidase inhibitor and insulin sensitizer. This work may guide diabetes patients to improve their condition through dietary therapy.


Assuntos
Flavonoides/química , Inibidores de Glicosídeo Hidrolases/química , Insulina/metabolismo , Flavonoides/metabolismo , Flavonoides/farmacologia , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Saccharomyces cerevisiae/enzimologia , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
3.
Chem Biodivers ; 16(10): e1900341, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31465610

RESUMO

The aim of this work was to investigate the enzyme inhibition, antioxidant activity, and phenolic compounds of Lecokia cretica (Lam.) DC. Acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glycosidase enzymes were strongly inhibited by the L. cretica extracts. IC50 values for the three enzymes were found as 3.21 mg/mL, 2.1 mg/mL, and 2.07 mg/mL, respectively. Antioxidant activities were examined in both aqueous and ethanol (EtOH) extracts using CUPRAC, FRAP, and DPPH method. Also, the phenolic compounds of the endemic plant were identified and quantified by using HPLC/MS/MS. According to the results, the extracts have remarkable antioxidant activities. The most abundant phenolic acids of L. cretica in EtOH extract were determined as quinic acid (12.76 mg/kg of crude extract), chlorogenic acid (3.39 mg/kg), and malic acid (2.38 mg/kg).


Assuntos
Antioxidantes/farmacologia , Antagonistas Colinérgicos/farmacologia , Hipoglicemiantes/farmacologia , Fenóis/farmacologia , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Acetilcolinesterase/metabolismo , Antioxidantes/química , Antioxidantes/isolamento & purificação , Apiaceae/química , Butirilcolinesterase/metabolismo , Antagonistas Colinérgicos/química , Antagonistas Colinérgicos/isolamento & purificação , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/farmacologia , Glicosídeo Hidrolases/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Fenóis/química , Fenóis/isolamento & purificação , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Relação Estrutura-Atividade
4.
Plant Foods Hum Nutr ; 74(3): 430-435, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31302831

RESUMO

The beneficial health effects of apple consumption are well known, however, little is known about the potential of its phenolic fractions to inhibit α-glucosidases and thereafter to treat diseases related to the carbohydrate metabolism, such as postprandial hyperglycemia and diabetes. In the present study, the α-glucosidase inhibition and antioxidant activity of different phenolic fractions of apple were evaluated using the 2,2-diphenyl-1-picrylhydrazyl and hydroxyl radical scavenging activity. Moreover, the phenolic fractions were chemically characterized by LC-MS in order to identify the compounds responsible for the biological properties. The purified extract (not fractionated) had the highest α-glucosidase and hydroxyl radical inhibitions. The purified extract and fractions III and IV were more active against the enzyme activity than the positive control acarbose, the drug used by diabetic patients to treat postprandial hyperglycaemia. Our results show that apple phenolic extracts strongly inhibit α-glucosidase acitivity, validating their potential to be used in the management of type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores de Glicosídeo Hidrolases/farmacologia , Hiperglicemia/tratamento farmacológico , Malus/química , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Metabolismo dos Carboidratos , Fenóis/isolamento & purificação , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/isolamento & purificação , alfa-Glucosidases/metabolismo
5.
Food Chem ; 299: 125102, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31279126

RESUMO

The chemical compositions and α-glucosidase inhibitory activities of anthocyanins extracted from blueberry, blackcurrant and blue honeysuckle fruits and their acid hydrolysates (anthocyanidins) were analysed. Those anthocyanins were glycosidic anthocyanins that converted to anthocyanidins during acid hydrolysis, leading to increases in their α-glucosidase inhibitory activities (expressed as IC50 values) from 0.232, 0.152 and 0.188 to 0.113 to 0.005 and 0.025 mg/mL. The potential inhibitory mechanism of these anthocyanidins was then investigated through inhibition kinetics, fluorescence quenching and docking simulations. The results showed the following: 1) all anthocyanidins were mixed-type inhibitors of α-glucosidase and they bind more tightly to free α-glucosidase as compared to the α-glucosidase-substrate complex; 2) anthocyanidin inhibition of α-glucosidase was a static procedure, presumably driven by hydrophobic associations and hydrogen bonding; and 3) all anthocyanidins were inserted into the active site of α-glucosidase and avoided the entrance of p-nitrophenyl-a-D-glucopyranoside. This study is valuable for anthocyanidins as potential α-glucosidase inhibitors.


Assuntos
Antocianinas/farmacologia , Mirtilos Azuis (Planta)/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Lonicera/química , Ribes/química , Antocianinas/análise , Antocianinas/química , Fluorescência , Frutas/química , Inibidores de Glicosídeo Hidrolases/química , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Cinética , Simulação de Acoplamento Molecular , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
6.
Food Chem ; 299: 124985, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31279127

RESUMO

Dietary protein peptides from quinoa yoghurt beverage (QYB) fermented with probiotic lactic acid bacteria strains play a protective role against diabetes and hypertension. In this study, the α-glucosidase and ACE inhibitory activities of germination-based protein hydrolysates of QYB were investigated. All protein hydrolysates exhibited a dose and strain-dependent inhibition on the enzymes. The inhibition of α-glucosidase was the highest in QLCSY13 (IC50 = 8.86 mg/mL), while ACE inhibition was the highest in QLCZ (IC50 = 0.03 mg/mL). Overall, QLCSY13 had the highest inhibitory activities, which was ascribed to its relatively higher amino acid contents and hydrophobicity. In addition, the ACE and α-glucosidase inhibitory activities of peptide fractions identified by RP-HPLC were 127 ±â€¯4.29 mg/mL and 10.39 ±â€¯4.73 mg/mL respectively. Among the potent inhibitory peptide sequences identified, both LAHMIVAGA and VAHPVF significantly had α-glucosidase and ACE inhibitory activities. Consequently, dietary protein peptides present in QYB had anti-hypertensive and anti-diabetic potentials.


Assuntos
Bebidas/microbiologia , Lactobacillus casei/metabolismo , Peptidil Dipeptidase A/metabolismo , Hidrolisados de Proteína/farmacologia , Iogurte/microbiologia , alfa-Glucosidases/metabolismo , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Fermentação , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Hidrolisados de Proteína/química
7.
Food Chem ; 300: 125245, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31352287

RESUMO

The natural bioactive polysaccharide was regarded as the effective nanocarrier for delivery of active ingredients for its biocompatibility and biodegradability. Moreover, the Fructus Mori polysaccharide has been proved to have good antioxidant and hypoglycemic activities. In this study, the Fructus Mori polysaccharide particles were prepared using antisolvent precipitation method. The bioactive polysaccharide particles exhibited smaller and rounder as the increase of the ethanol/water ratio. The average size, polydispersity index (PDI) and ξ-potential of the bioactive polysaccharide particles were 396.06 nm, 0.38 and -21.23 mV at ethanol/water ratio of 20:1. After spheroidization, the polysaccharide particles exhibited more stable when exposed to heat, increased ionic strength and alkaline conditions. Furthermore, the bioactive polysaccharide particle with the smallest size had the strongest protein adsorption capacity and bioavailability. Especially, the MFP-NP3 showed the ORAC value of 917.06 ±â€¯34.13 µmol TE/g, and the α-glucosidase inhibitory activity of 56.98 ±â€¯1.19% at 0.5 mg/mL. In addition, compared to the native Fructus Mori polysaccharide, the spheroidization enhanced the antioxidant ability and hypoglycemic activity.


Assuntos
Antioxidantes/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Morus/química , Nanopartículas/química , Polissacarídeos/química , Polissacarídeos/farmacocinética , Adsorção , Animais , Antioxidantes/química , Disponibilidade Biológica , Precipitação Química , Etanol , Frutas , Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Concentração Osmolar , Tamanho da Partícula , Ratos , Solventes/química
8.
Comput Biol Chem ; 82: 25-36, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31255972

RESUMO

The prevalence of diabetes mellitus has been incremented in the current century and the need for novel therapeutic compounds to treat this disease has been significantly increased. One of the most promising approaches is to inhibit intestinal alpha glucosidases. Based on our previous studies, four pyrimidine-fused heterocycles (PFH) were selected as they revealed satisfactory inhibitory action against mammalian α-glucosidase. The interaction of these compounds with both active domains of human maltase-glucoamylase (MGAM) and their effect on human Caco-2 cell line were investigated. The docking assessments suggested that binding properties of these ligands were almost similar to that of acarbose by establishing hydrogen bonds especially with Tyr1251 and Arg526 in both C-terminal and N-terminal MGAM, respectively. Also, these compounds indicated a stronger affinity for C-terminal of MGAM. L2 and L4 made tightly complexes with both terminals of MGAM which in turn revealed the importance of introducing pyrimidine scaffold and its hinge compartment. The results of molecular dynamics simulation analyses confirmed the docking data and showed deep penetration of L2 and L4 into the active site of MGAM. Based on cell cytotoxicity assessments, no significant cell death induction was observed. Hence, these functional MGAM inhibitors might be considered as new potential therapeutic compounds in treatment of diabetes and its complications.


Assuntos
Inibidores de Glicosídeo Hidrolases/farmacologia , Pirimidinonas/farmacologia , alfa-Glucosidases/metabolismo , Acarbose/química , Células CACO-2 , Domínio Catalítico , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/toxicidade , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos com 3 Anéis/toxicidade , Humanos , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Pirimidinonas/química , Pirimidinonas/toxicidade , alfa-Glucosidases/química
9.
Eur J Med Chem ; 177: 362-373, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158750

RESUMO

Inhibiting the decomposition of carbohydrates into glucose or promoting glucose conversion is considered to be an effective treatment for type 2 diabetes. Herein, a series of novel xanthone-triazole derivatives were designed, synthesized, and their α-glucosidase inhibitory activities and glucose uptake in HepG2 cells were investigated. Most of the compounds showed better inhibitory activities than the parental compound a (1,3-dihydroxyxanthone, IC50 = 160.8 µM) and 1-deoxynojirimycin (positive control, IC50 = 59.5 µM) towards α-glucosidase. Compound 5e was the most potent inhibitor, with IC50 value of 2.06 µM. The kinetics of enzyme inhibition showed that compounds 5e, 5g, 5h, 6c, 6d, 6g and 6h were noncompetitive inhibitors, and molecular docking results were consistent with the noncompetitive property that these compounds bind to allosteric sites away from the active site (Asp214, Glu276 and Asp349). On the other hand, the glucose uptake assays exhibited that compounds 5e, 6a, 6c and 7g displayed high activities in promoting the glucose uptake. The cytotoxicity assays showed that most compounds were low-toxic to human normal hepatocyte cell line (LO2). These novel xanthone triazole derivatives exhibited dual therapeutic effects of α-glucosidase inhibition and glucose uptake promotion, thus they could be use as antidiabetic agents for developing novel drugs against type 2 diabetes.


Assuntos
Glucose/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/farmacologia , Triazóis/farmacologia , Xantonas/farmacologia , Sítios de Ligação , Desenho de Drogas , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/toxicidade , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/metabolismo , Hipoglicemiantes/toxicidade , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/toxicidade , Xantonas/síntese química , Xantonas/metabolismo , Xantonas/toxicidade , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
10.
Fitoterapia ; 137: 104248, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31247218

RESUMO

Hippophae rhamnoides subsp. Sinensis is a famous traditional medicinal plant in Tibet and Mongolia of China. Three novel flavonoid glycosides and ten known analogues were obtained from the seeds of H. rhamnoides. The structures of new compounds were elucidated by spectroscopics, chemical methods as well as literature data. In vitro assay, compounds 5-9, kaempferol and 70% ethanolic elution fraction showed prominent α-glucosidase inhibitory activities with IC50 values ranging from 8.30 to 112.11 µM, better than that of the positive control, acarbose, whose IC50 value was 1727.07 µM.


Assuntos
Flavonoides/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Glicosídeos/farmacologia , Hippophae/química , China , Flavonoides/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Glicosídeos/isolamento & purificação , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química , Sementes/química , alfa-Glucosidases
11.
Carbohydr Polym ; 219: 219-228, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151520

RESUMO

Coreopsis tinctoria is being widely cultivated in Xinjiang of China, whose consumption is known to prevent diabetes and neurodegenerative diseases. To elucidate the bioactive ingredients responsible for these benefits, the alkaline soluble crude polysaccharide (CTB) was isolated from C. tinctoria. In vitro experiments showed that the inhibition of α-amylase and α-glucosidase by CTB was 13407-fold and 906-fold higher than that by positive control, respectively. Then, a novel arabinogalactan, CTBP-1, was isolated and purified from CTB. Structural analysis showed that CTBP-1 possessed a 1,6-linked ß-d-Galp and 1,5-linked α-l-Araf backbone with branches substituted at the C-3 position of the 1,6-linked ß-d-Galp, and the side chains included 1,5-linked α-l-Araf, T-linked ß-d-Galp and T-linked α-l-Araf. The inhibitory effects of CTBP-1 on α-amylase and α-glucosidase were 2.7 and 17.9 times that of acarbose, respectively. CTBP-1 could avoid indigestion and similar side effects. In addition, CTBP-1 remarkably inhibited the release of nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. In summary, CTBP-1 is a novel arabinogalactan with great potential as a treatment for type 2 diabetes and Alzheimer's disease.


Assuntos
Coreopsis/metabolismo , Galactanos , Inibidores de Glicosídeo Hidrolases/farmacologia , Microglia , Extratos Vegetais/química , alfa-Amilases/antagonistas & inibidores , alfa-Glucosidases/metabolismo , Células Cultivadas , China , Galactanos/química , Galactanos/farmacologia , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Microglia/citologia , Microglia/efeitos dos fármacos , Óxido Nítrico/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
12.
J Agric Food Chem ; 67(25): 7025-7039, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31240933

RESUMO

As a functional food, the unripe fruits of Rubus chingii Hu have been widely used in China for thousands of years. Twenty-five major ellagitannins (ETs) were identified from the unripe fruits, and a novel ellagitannin, chingiitannin A (1), together with four other known ETs (2-5) were isolated and identified by HPLC-QTOF-MS/MS and 2D-NMR. Chingiitannin A showed the highest α-glucosidase and α-amylase inhibitory activities (IC50 2.89 and 4.52 µM, respectively), which occurred in a reversible and noncompetitive manner. Static quenching was indicated in a fluorescence quenching assay. Molecular docking results revealed that chingiitannin A interacted with the enzymes mainly by hydrogen bonding and was bound in the allosteric site. Chingiitannin A was nontoxic, and it increased the glucose uptake in L6 myotubes. The results suggested that the unripe fruits of Rubus chingii Hu are rich sources of ETs, and chingiitannin A might be a good candidate for functional foods or antidiabetic drugs.


Assuntos
Inibidores de Glicosídeo Hidrolases/química , Taninos Hidrolisáveis/química , Hipoglicemiantes/química , Extratos Vegetais/química , Rubus/química , Animais , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Frutas/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Taninos Hidrolisáveis/farmacologia , Hipoglicemiantes/farmacologia , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Mioblastos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ratos , Espectrometria de Massas em Tandem , alfa-Glucosidases/química
13.
Mar Drugs ; 17(6)2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31163670

RESUMO

Three new butenolide derivatives, namely aspernolides N-P (1-3), together with six known analogues (4-9), were isolated from the ethyl acetate (EtOAc) extract of the deep sea-derived fungus Aspergillus terreus YPGA10. The structures of compounds 1-3 were determined on the basis of comprehensive analyses of the nuclear magnetic resonance (NMR) and mass spectroscopy (MS) data, and the absolute configurations of 1 and 2 were determined by comparisons of experimental electronic circular dichroism (ECD) with calculated ECD spectra. Compound 1 represents the rare example of Aspergillus-derived butenolide derivatives featured by a monosubstituted benzene ring. Compounds 6-9 exhibited remarkable inhibitory effects against α-glucosidase with IC50 values of 3.87, 1.37, 6.98, and 8.06 µM, respectively, being much more active than the positive control acarbose (190.2 µM).


Assuntos
4-Butirolactona/análogos & derivados , Organismos Aquáticos/química , Aspergillus/química , Inibidores de Glicosídeo Hidrolases/farmacologia , 4-Butirolactona/química , 4-Butirolactona/isolamento & purificação , 4-Butirolactona/farmacologia , Acetatos/química , Dicroísmo Circular , Ativação Enzimática/efeitos dos fármacos , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Espectroscopia de Ressonância Magnética , Espectrometria de Massas
14.
Food Chem Toxicol ; 129: 337-343, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31071387

RESUMO

This study assesses the ability of anthraquinone derivative, 2-methyl-1,3,6-trihydroxy-9,10-anthraquinone (MTAQ) to decrease postprandial hyperglycemia or enhance glucose uptake and to elucidate the underlying molecular mechanism. We investigated α-glucosidase inhibition, glucose uptake, and translocation of glucose transporter 4 (GLUT4) in C2C12 myotubes. The data indicate that MTAQ strongly inhibited α-glucosidase activity in a concentration-dependent manner, with an IC50 value of 6.49 ±â€¯1.31 µM, and functioned as a reversible competitive inhibitor, with a dissociation constant of 41.88 µM. Moreover, MTAQ significantly augmented basal and insulin-stimulated glucose uptake as well as translocation of GLUT4 to the plasma membrane. It also stimulated the phosphorylation of insulin receptor ß isoform, insulin receptor substrate-1,3-phosphoinositide-dependent protein kinase 1, and protein kinase B (AKT). A pretreatment with an AKT inhibitor, LY294002, attenuated the ability of MTAQ to activate an insulin-like signaling pathway and to enhance basal and insulin-stimulated glucose uptake and stimulate GLUT4 translocation to the plasma membrane. These findings reveal the fact that MTAQ may have potential for the development of new antidiabetic drugs to manage blood glucose levels.


Assuntos
Antraquinonas/farmacologia , Glucose/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Insulina/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Transportador de Glucose Tipo 4/metabolismo , Hipoglicemiantes/farmacologia , Cinética , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Transporte Proteico
15.
Molecules ; 24(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071910

RESUMO

α-glucosidase inhibitors (AGIs) have been an important category of oral antidiabetic drugs being widely exploited for the effective management of type 2 diabetes mellitus. However, the marketed AGIs not only inhibited the disaccharidases, but also exhibited an excessive inhibitory effect on α-amylase, resulting in undesirable gastrointestinal side effects. Compared to these agents, Ramulus Mori alkaloids (SZ-A), was a group of effective alkaloids from natural Morus alba L., and showed excellent hypoglycemic effect and fewer side effects in the Phase II/III clinical trials. Thus, this paper aims to investigate the selective inhibitory effect and mechanism of SZ-A and its major active ingredients (1-DNJ, FA and DAB) on different α-glucosidases (α-amylase and disaccharidases) by using a combination of kinetic analysis and molecular docking approaches. From the results, SZ-A displayed a strong inhibitory effect on maltase and sucrase with an IC50 of 0.06 µg/mL and 0.03 µg/mL, respectively, which was similar to the positive control of acarbose with an IC50 of 0.07 µg/mL and 0.68 µg/mL. With regard to α-amylase, SZ-A exhibited no inhibitory activity at 100 µg/mL, while acarbose showed an obvious inhibitory effect with an IC50 of 1.74 µg/mL. The above analysis demonstrated that SZ-A could selectively inhibit disaccharidase to reduce hyperglycemia with a reversible competitive inhibition, which was primarily attributed to the three major active ingredients of SZ-A, especially 1-DNJ molecule. In the light of these findings, molecular docking study was utilized to analyze their inhibition mechanisms at molecular level. It pointed out that acarbose with a four-ring structure could perform desirable interactions with various α-glucosidases, while the three active ingredients of SZ-A, belonging to monocyclic compounds, had a high affinity to the active site of disaccharidases through forming a wide range of hydrogen bonds, whose affinity and consensus score with α-amylase was significantly lower than that of acarbose. Our study illustrates the selective inhibition mechanism of SZ-A on α-glucosidase for the first time, which is of great importance for the treatment of type 2 diabetes mellitus.


Assuntos
Alcaloides/metabolismo , Simulação de Acoplamento Molecular , Morus/química , alfa-Glucosidases/metabolismo , Alcaloides/química , Animais , Domínio Catalítico , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Cinética , Ligantes , Ratos Wistar , Solventes , Sacarase/metabolismo
16.
Mar Drugs ; 17(5)2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31121891

RESUMO

Hizikia fusiformis (Harvey) Okamura is an edible marine alga that has been widely used in Korea, China, and Japan as a rich source of dietary fiber and essential minerals. In our previous study, we observed that the methanol extract of H. fusiformis and its non-polar fractions showed potent protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase inhibition. Therefore, the aim of the present study was to identify the active ingredient in the methanol extract of H. fusiformis. We isolated a new glycerol fatty acid (13) and 20 known compounds including 9 fatty acids (1-3, 7-12), mixture of 24R and 24S-saringosterol (4), fucosterol (5), mixture of 24R,28R and 24S,28R-epoxy-24-ethylcholesterol (6), cedrusin (14), 1-(4-hydroxy-3-methoxyphenyl)-2-[2-hydroxy -4-(3-hydroxypropyl)phenoxy]-1,3-propanediol (15), benzyl alcohol alloside (16), madhusic acid A (17), glycyrrhizin (18), glycyrrhizin-6'-methyl ester (19), apo-9'-fucoxanthinone (20) and tyramine (21) from the non-polar fraction of H. fusiformis. New glycerol fatty acid 13 was identified as 2-(7'- (2″-hydroxy-3″-((5Z,8Z,11Z)-icosatrienoyloxy)propoxy)-7'-oxoheptanoyl)oxymethylpropenoic acid by spectroscopic analysis using NMR, IR, and HR-ESI-MS. We investigated the effect of the 21 isolated compounds and metabolites (22 and 23) of 18 against the inhibition of PTP1B and α-glucosidase enzymes. All fatty acids showed potent PTP1B inhibition at low concentrations. In particular, new compound 13 and fucosterol epoxide (6) showed noncompetitive inhibitory activity against PTP1B. Metabolites of glycyrrhizin, 22 and 23, exhibited competitive inhibition against PTP1B. These findings suggest that H. fusiformis, a widely consumed seafood, may be effective as a dietary supplement for the management of diabetes through the inhibition of PTP1B.


Assuntos
Extratos Vegetais/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Sargassum/química , alfa-Glucosidases/metabolismo , Suplementos Nutricionais , Ativação Enzimática/efeitos dos fármacos , Ácidos Graxos/química , Ácidos Graxos/isolamento & purificação , Ácidos Graxos/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Metanol/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação
17.
Eur J Med Chem ; 176: 343-377, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31112894

RESUMO

α-Glucosidase enzyme inhibition is an effective therapeutic decorum in the treatment of type 2 diabetes mellitus. Since 1990, three α-glucosidase inhibitors are known to exist clinically, Acarbose, Voglibose and Miglitol. Side effects and long synthetic routes to access them forced the researchers to move their focus to discover simple and small heterocyclic motifs that work as promising α-glucosidase inhibitors and may eventually lead to the management of postprandial hyperglycemic condition in T2DM. In this regards, this review deals with recently discovered heterocyclic molecules that have been evaluated to exhibit inhibition of α-glucosidase enzyme.


Assuntos
Inibidores de Glicosídeo Hidrolases/química , Compostos Heterocíclicos/química , Animais , Linhagem Celular Tumoral , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/toxicidade , Compostos Heterocíclicos/metabolismo , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/toxicidade , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/toxicidade , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
18.
Food Chem Toxicol ; 130: 207-218, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31128218

RESUMO

α-glucosidase inhibition is a rational approach in the effective management of type 2 diabetes. Several inhibitors of this enzyme class are in clinical use, but are riddled with efficacy, potency and safety challenges. For this reason, new effective α-glucosidase inhibitors are under investigation. Compounds with 1, 3, 4-oxadiazole nucleus have shown preclinical efficacy as α-glucosidase inhibitors and as anti-inflammatory agents. Moreover, 1, 3, 4-oxadiazoles also play important role in pesticide chemistry, polymer science, and they are considered as the building blocks in the production of new molecular agents for bioactive molecules. In the present study, computational analyses were carried out for various 1,3,4-oxadiazole (which were divided into BF2 & BF3 series); the most active compound was taken as a potent inhibitor, and pharmacophore were formed from that compound, followed by validation against a test database. The pharmacophore-based virtual screening was performed and, by successive eliminations, six compounds of different interactions with the significant amino acid residues were selected as the lead compounds. It is concluded that these six compounds with 1, 3, 4-oxadiazoles nucleus might be used as promising drug candidates in α-glucosidase inactivation and thus we recommend further in vitro and in vivo pharmacological and safety studies.


Assuntos
Oxidiazóis/química , Oxidiazóis/farmacologia , alfa-Glucosidases/metabolismo , Descoberta de Drogas , Inibidores de Glicosídeo Hidrolases/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , alfa-Glucosidases/genética
19.
Fitoterapia ; 136: 104178, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31121254

RESUMO

One hitherto unknown 24-nor-13,27-cycloursane-type triterpenoid, lucumic acid A (1), one new 24-nor-ursane triterpenoid, lucumic acid B (2), along with six known triterpenoids were isolated from the ethanol extract of the leaves of Lucuma nervosa. Their structures were established on the basis of spectroscopic data interpretation. Lucumic acid A (1) is the first example of a 24-nor-triterpenoid with a 13,27-cyclopropane ring.


Assuntos
Ácido Oleanólico/análogos & derivados , Folhas de Planta/química , Pouteria/química , Triterpenos/isolamento & purificação , China , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/farmacologia , Estrutura Molecular , Ácido Oleanólico/isolamento & purificação , Ácido Oleanólico/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Triterpenos/farmacologia
20.
Fitoterapia ; 136: 104177, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31128244

RESUMO

Five new funicone derivatives, pinophilones A-E (1a/1b and 2-4), along with 18 biosynthetically related known analogues (5-22), were obtained from the culture of a mangrove sediment-derived fungus Penicillium pinophilum SCAU037. Their structures were established by analysis of 1D/2D NMR and MS data, while the absolute configurations of the new compounds were determined by ECD calculation based on time-dependent density functional theory (TD-DFT). The dihydrofuran moiety in 1a and 1b was first reported for funicone derivatives. Compound 22 exhibited antibacterial activity against Mycobacterium smegmatis and Staphylococcus aureus with IC50 of 23.5 and 2.6 µM, respectively, while 16, 18 and 22 showed significant α-glucosidase inhibitory activity with IC50 of 51.9, 78.4 and 33.8 µM, respectively.


Assuntos
Antibacterianos/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Penicillium/química , Pironas/farmacologia , Antibacterianos/isolamento & purificação , China , Sedimentos Geológicos/microbiologia , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium smegmatis/efeitos dos fármacos , Pironas/isolamento & purificação , Rhizophoraceae/microbiologia , Metabolismo Secundário , Staphylococcus aureus/efeitos dos fármacos
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