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1.
Molecules ; 26(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204232

RESUMO

Folk experiences suggest natural products in Tetradium ruticarpum can be effective inhibitors towards diabetes-related enzymes. The compounds were experimentally isolated, structurally elucidated, and tested in vitro for their inhibition effects on tyrosine phosphatase 1B (PTP1B) and α-glucosidase (3W37). Density functional theory and molecular docking techniques were utilized as computational methods to predict the stability of the ligands and simulate interaction between the studied inhibitory agents and the targeted proteins. Structural elucidation identifies two natural products: 2-heptyl-1-methylquinolin-4-one (1) and 3-[4-(4-methylhydroxy-2-butenyloxy)-phenyl]-2-propenol (2). In vitro study shows that the compounds (1 and 2) possess high potentiality for the inhibition of PTP1B (IC50 values of 24.3 ± 0.8, and 47.7 ± 1.1 µM) and α-glucosidase (IC50 values of 92.1 ± 0.8, and 167.4 ± 0.4 µM). DS values and the number of interactions obtained from docking simulation highly correlate with the experimental results yielded. Furthermore, in-depth analyses of the structure-activity relationship suggest significant contributions of amino acids Arg254 and Arg676 to the conformational distortion of PTP1B and 3W37 structures overall, thus leading to the deterioration of their enzymatic activity observed in assay-based experiments. This study encourages further investigations either to develop appropriate alternatives for diabetes treatment or to verify the role of amino acids Arg254 and Arg676.


Assuntos
Evodia/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Relação Estrutura-Atividade , alfa-Glucosidases/efeitos dos fármacos , alfa-Glucosidases/metabolismo
2.
Molecules ; 26(9)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064448

RESUMO

The 2-amino-5-(3/4-fluorostyryl)acetophenones were prepared and reacted with benzaldehyde derivatives to afford the corresponding 5-styryl-2-aminochalcone hybrids. The trans geometry of the styryl and α,ß-unsaturated carbonyl arms, and the presence of NH…O intramolecular hydrogen bond were validated using 1H-NMR and X-ray data. The 2-amino-5-styrylacetophenones and their 5-styryl-2-aminochalcone derivatives were screened in vitro for their capability to inhibit α-glucosidase and/or α-amylase activities. Their antioxidant properties were evaluated in vitro through the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and nitric oxide (NO) free radical scavenging assays. Kinetic studies of the most active derivatives from each series against α-glucosidase and/or α-amylase activities have been performed supported by molecular docking studies to determine plausible protein-ligand interactions on a molecular level. The key aspects of the pharmacokinetics of these compounds, i.e., absorption, distribution, metabolism, and excretion have also been simulated at theoretical level. The most active compounds from each series, namely, 2a and 3e, were evaluated for cytotoxicity against the normal monkey kidney cells (Vero cells) and the adenocarcinomic human epithelial (A549) cell line to establish their safety profile at least in vitro.


Assuntos
Antioxidantes/farmacologia , Carboidratos/química , Chalconas/síntese química , Chalconas/farmacologia , Simulação por Computador , Inibidores Enzimáticos/farmacologia , Receptores de Droga/química , Células A549 , Animais , Morte Celular/efeitos dos fármacos , Chalconas/química , Chalconas/farmacocinética , Chlorocebus aethiops , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Cinética , Conformação Molecular , Simulação de Acoplamento Molecular , Termodinâmica , Células Vero , alfa-Amilases/antagonistas & inibidores , alfa-Glucosidases/metabolismo
3.
Food Chem ; 361: 130144, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34082387

RESUMO

Effect of high-intensity ultrasound (HIU) compared with thermal treatments on baobab fruit pulp (BFP) quality and bioactive properties were investigated. HIU treatments, particularly at intensities of 687.5 W/cm2 for 5 min, and 344 W/cm2 for 15 min significantly (p < 0.05) increased the cloudiness index, ascorbic acid (AA) retention, total phenolic and flavonoid contents, and antioxidant capacity besides a more potent α-amylase and α-glucosidase inhibition relative to thermally treated samples. Moreover, the physicochemical parameters, colour index, and browning index were maintained with HIU besides lower 5-hydroxymethylfurfural values than thermal processing. HPLC analysis revealed that the content of most phenolic compounds was the highest in HIU treatments besides a 235-256% increase in procyanidin C1 compared with control samples. The AA retention following HIU treatments was 87.62-102.86% compared to 30.47-61.90% in thermally treated samples. Our analyses portrayed ultrasound as a feasible alternative to conventional thermal processing of BFP.


Assuntos
Adansonia/química , Inibidores Enzimáticos/farmacologia , Frutas/química , Ultrassom/métodos , alfa-Amilases/antagonistas & inibidores , Antioxidantes/análise , Antioxidantes/química , Ácido Ascórbico/análise , Biflavonoides/análise , Catequina/análise , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/química , Flavonoides/análise , Inibidores de Glicosídeo Hidrolases/análise , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Fenóis/análise , Proantocianidinas/análise , alfa-Glucosidases/metabolismo
4.
Food Res Int ; 143: 110262, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33992363

RESUMO

Buckwheat was processed by solid-state fermentation (SSF) with the probiotic fungal strain Eurotium cristatum YL-1. The effects of SSF on the phytochemical content, as well as the antioxidant and α-glucosidase inhibitory activities, on buckwheat were revealed. Metabolite differences between non-fermented buckwheat (BW) and E. cristatum fermented buckwheat (FBW) were investigated by LC-MS/MS-based untargeted metabolomics. Results showed that 103 and 68 metabolites remarkably differed between BW and FBW in positive and negative ionization modes, respectively. Most phenolic compounds and alkaloids were significantly up-regulated during SSF. Hydrolytic enzymes (i.e., ß-glucosidase, α-amylase, protease, and cellulase) were produced by the filamentous fungus E. cristatum during SSF. In vitro spectrophotometric assays demonstrated that the total phenolics content, ferric reducing antioxidant power, reducing power, scavenging activities of DPPH radical and ABTS+, and α-glucosidase inhibitory activity of buckwheat were considerably enhanced after processing by SSF with E. cristatum. Additionally, solvents with different polarities significantly influenced the antioxidant and α-glucosidase inhibitory activities of buckwheat extracts. Our study indicated that processing by SSF with E. cristatum can greatly improve the phytochemical components of buckwheat and consequently contribute to its antioxidant and α-glucosidase inhibitory activities. SSF with E. cristatum is an innovative method for enhancing the health-promoting components and bioactivities of buckwheat.


Assuntos
Eurotium , Fagopyrum , Antioxidantes , Aspergillus , Cromatografia Líquida , Fermentação , Espectrometria de Massas em Tandem , alfa-Glucosidases/metabolismo
5.
Biomed Res Int ; 2021: 6652777, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33987444

RESUMO

Background: The leaves of Hagenia abyssinica have been used in the management of diabetes mellitus in Ethiopian folk medicine. Thus, this study is aimed at investigating the in vitro α-amylase and α-glucosidase inhibitory and antioxidant activities of the crude extract and solvent fractions of H. abyssinica leaves. Methods: The in vitro α-amylase and α-glucosidase inhibitory and antioxidant activities of the plant extract were assessed using 3,5-dinitrosalicylic acid (DNSA), p-nitro-phenyl-a-D glucopyranoside (p-NPG), and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays, respectively. Each value of percent inhibition of α-amylase, α-glucosidase, and DPPH scavenging effect was presented as means ± SEM (n = 3). Results: The α-amylase inhibitory activity of the crude extract and solvent fractions was found to be concentration-dependent. The strongest activity was exhibited by the crude extract at the highest concentration with a percentage inhibition of 74.52% (IC50, 14.52 µg/ml) followed by water fraction 68.24% (IC50, 16.31 µg/ml), ethyl acetate fraction 61.57% (IC50, 18.73 µg/ml), and chloroform fraction 56.87% (IC50, 21.57 µg/ml) of H. abyssinica leaves. In the α-glucosidase inhibition assay, the maximum activity was exhibited by the aqueous fraction 62.54% (IC50, 11.67 µg/ml) followed by ethyl acetate fraction 54.97% (IC50, 15.89 µg/ml), crude extract 46.79% (IC50, >16.5 µg/ml), and chloroform fraction 36.44% (IC50, >16.5 µg/ml). In the antioxidant assay, the crude extract exhibited the highest antioxidant activity 86.36% (IC50, 10.25 µg/ml) followed by water fraction 78.59% (IC50, 13.86 µg/ml), ethyl acetate fraction 71.58% (IC50, 16.34 µg/ml), and chloroform fraction 63.65% (IC50, 18.83 µg/ml). Conclusion: This study has revealed that H. abyssinica leaves possess noticeable in vitro α-amylase and α-glucosidase inhibitory and antioxidant activities.


Assuntos
Antioxidantes/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Extratos Vegetais , Rosaceae/química , alfa-Amilases/antagonistas & inibidores , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Solventes/química , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo
6.
J Biosci Bioeng ; 132(1): 9-17, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33934979

RESUMO

Rice is a source of bioactive compounds related to human health and has been used for both consumption and traditional medicine. The authors investigated the synergistic and additive effect of rice extract (RE) combined with five aromatic compounds against three enzymes: α-glucosidase, α-amylase and tyrosinase. RE was purified by thin-layer chromatography (TLC) and preparative TLC (PTLC) with different solvent systems. RE had higher α-glucosidase and α-amylase inhibitory activity than the five aromatic compounds, while the five aromatic compounds had higher tyrosinase inhibitory activity than RE. The combination of RE/acarbose produced synergic inhibition of α-glucosidase and α-amylase, whereas RE showed additive inhibition of both enzymes when combined with aromatic compounds. The five aromatic compounds showed additive inhibition of tyrosinase when combined with RE. The combination of 2-methoxy-4-vinylphenol/vanillin/guaiacol produced synergistic inhibition of α-amylase while showing antagonism of α-glucosidase and tyrosinase. Interestingly, the RE produced additive inhibition of α-glucosidase, α-amylase and tyrosinase when combined with the 2-methoxy-4-vinylphenol/vanillin/guaiacol combination. RE had rich bioactive compounds related to α-glucosidase, α-amylase and tyrosinase inhibitory activity. Volatile compounds, including 2-methoxy-4-vinylphenol, vanillin and guaiacol, enhanced the inhibitory activity of RE against α-glucosidase, α-amylase and tyrosinase activities.


Assuntos
Inibidores de Glicosídeo Hidrolases/farmacologia , Hidrocarbonetos Aromáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Oryza/química , Extratos Vegetais/farmacologia , alfa-Amilases/antagonistas & inibidores , alfa-Glucosidases/metabolismo , Interações Medicamentosas , Humanos
7.
Artigo em Inglês | MEDLINE | ID: mdl-33992880

RESUMO

The lack of direct connection between traditional herbal medicines and multiple biological targets is a bottleneck in herbal research and quality evaluation. To solve this problem, a strategy for the discovery of active ingredients from function-similar herbal medicines based on multiple biological targets was proposed in this article. The technical route includes chromatographic separation, mass spectrometry analysis, enzymatic activity detection, pharmacophore analysis and molecular docking. Five citrus herbs of Citri Reticulatae Pericarpium (CRP), Citri Exocarpium Rubrum (CER), Citri Grandis Exocarpium (CGE), Aurantii Fructus Immaturus (AFI) and Aurantii Fructus (AF) were used as the research objects. A total of 136 chemical components were identified from above five herbs based on LC-Q-TOF-MS/MS and database matching. The extracts of the five herbs showed obvious inhibitory effects on α-glucosidase and acetylcholinesterase in a concentration-dependent manner. Interestingly, the different types of components in the herbs exhibited selectivity for different targets: flavanone glycosides are effective on α-glucosidase but ineffective on acetylcholinesterase; polymethoxyflavonoids are effective on acetylcholinesterase but ineffective on α-glucosidase. Furthermore, we found for the first time that the components in citrus herbs exhibit opposite structure-activity relationships on the above two targets. For example, the methoxy group can enhance the activity of compounds on acetylcholinesterase but weaken the activity of compounds on α-glucosidase. The selective action is a supplement to the "multi-components, multi-targets" system of herbal medicines. Pharmacophore analysis and molecular docking were applied to explore the interaction between active ingredients and biological targets from the perspective of ligands and receptors, respectively. By combining the above multiple technologies, a strong connection among herbal medicines, chemical components and multiple biological targets was established. This work not only helps to understand the similar function of citrus herbs for the treatment of diabetes and Alzheimer's disease, but also provides selective lead compounds for the development of related drugs. This strategy is also helpful to improve the quality evaluation of citrus herbs from the perspective of biological activity.


Assuntos
Bioensaio/métodos , Inibidores da Colinesterase , Cromatografia Líquida/métodos , Citrus/química , Inibidores de Glicosídeo Hidrolases , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Flavonoides , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Relação Estrutura-Atividade , Espectrometria de Massas em Tandem , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
8.
Molecules ; 26(7)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808152

RESUMO

Numerous scientific studies have confirmed the beneficial therapeutic effects of phenolic acids. Among them gentisic acid (GA), a phenolic acid extensively found in many fruit and vegetables has been associated with an enormous confirmed health benefit. The present study aims to evaluate the antidiabetic potential of gentisic acid and highlight its mechanisms of action following in silico and in vitro approaches. The in silico study was intended to predict the interaction of GA with eight different receptors highly involved in the management and complications of diabetes (dipeptidyl-peptidase 4 (DPP4), protein tyrosine phosphatase 1B (PTP1B), free fatty acid receptor 1 (FFAR1), aldose reductase (AldR), glycogen phosphorylase (GP), α-amylase, peroxisome proliferator-activated receptor gamma (PPAR-γ) and α-glucosidase), while the in vitro study studied the potential inhibitory effect of GA against α-amylase and α-glucosidase. The results indicate that GA interacted moderately with most of the receptors and had a moderate inhibitory activity during the in vitro tests. The study therefore encourages further in vivo studies to confirm the given results.


Assuntos
Frutas/química , Gentisatos/metabolismo , Inibidores de Glicosídeo Hidrolases/metabolismo , Hipoglicemiantes/metabolismo , alfa-Amilases , alfa-Glucosidases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo
9.
Int J Biol Macromol ; 182: 482-491, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33838190

RESUMO

Maltase can catalyze the hydrolysis of α-1,4-glucosidic linkages and release α-d-glucoses that are used as a source of energy by insects. Maltase has been extensively studied in Lepidoptera and Diptera, while the characterization and evolutionary history of maltase are largely unknown in Hymenoptera. Here, we undertook a bioinformatics study and identified 105 maltase genes in 12 fig wasp species. Together with the maltase genes of Nasonia vitripennis and Apis mellifera, phylogenetic analysis showed that all the maltase genes were clustered into three clades. Clade I and III included maltase genes from all the fig wasp species, while clade II contained the maltase genes from non-pollinating fig wasps (NPFWs) only. Interestingly, the maltase genes located in clade II were intronless. Fig pollinators and NPFWs had lineage-specific gene expansion in clade I and II respectively, which were mainly derived from tandem duplications. The three clades displayed distinct gene structures. Furthermore, maltase showed significant functional divergence among the three clades and the critical amino acid sites were detected. These sites could be responsible for the ligand-binding preference and hydrolytic specificity. Overall, our results demonstrated that maltase might contribute to the discrepancy of life histories and feeding regimes between fig pollinators and NPFWs.


Assuntos
Evolução Molecular , Duplicação Gênica , Proteínas de Insetos/genética , alfa-Glucosidases/genética , Animais , Sítios de Ligação , Proteínas de Insetos/metabolismo , Traços de História de Vida , Domínios Proteicos , Vespas/classificação , Vespas/enzimologia , Vespas/genética , alfa-Glucosidases/metabolismo
10.
Molecules ; 26(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802826

RESUMO

Opuntia dillenii Ker Gawl. is one of the medicinal plants used for the prevention and treatment of diabetes mellitus (DM) in Morocco. This study aims to investigate the antihyperglycemic effect of Opuntia dillenii seed oil (ODSO), its mechanism of action, and any hypoglycemic risk and toxic effects. The antihyperglycemic effect was assessed using the OGTT test in normal and streptozotocin (STZ)-diabetic rats. The mechanisms of action were explored by studying the effect of ODSO on the intestinal absorption of d-glucose using the intestinal in situ single-pass perfusion technique. An Ussing chamber was used to explore the effects of ODSO on intestinal sodium-glucose cotransporter 1 (SGLT1). Additionally, ODSO's effect on carbohydrate degrading enzymes, pancreatic α-amylase, and intestinal α-glucosidase was evaluated in vitro and in vivo using STZ-diabetic rats. The acute toxicity test on mice was performed, along with a single-dose hypoglycemic effect test. The results showed that ODSO significantly attenuated the postprandial hyperglycemia in normal and STZ-diabetic rats. Indeed, ODSO significantly decreased the intestinal d-glucose absorption in situ. The ex vivo test (Ussing chamber) showed that the ODSO significantly blocks the SGLT1 (IC50 = 60.24 µg/mL). Moreover, ODSO indu\ced a significant inhibition of intestinal α-glucosidase (IC50 = 278 ± 0.01 µg/mL) and pancreatic α-amylase (IC50 = 0.81 ± 0.09 mg/mL) in vitro. A significant decrease of postprandial hyperglycemia was observed in sucrose/starch-loaded normal and STZ-diabetic ODSO-treated rats. On the other hand, ODSO had no risk of hypoglycemia on the basal glucose levels in normal rats. Therefore, no toxic effect was observed in ODSO-treated mice up to 7 mL/kg. The results of this study suggest that ODSO could be suitable as an antidiabetic functional food.


Assuntos
Diabetes Mellitus Experimental/dietoterapia , Frutas/química , Hiperglicemia/dietoterapia , Hipoglicemiantes/farmacologia , Opuntia/química , Extratos Vegetais/farmacologia , Sementes/química , Animais , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/metabolismo , Hiperglicemia/enzimologia , Hiperglicemia/metabolismo , Concentração Inibidora 50 , Cinética , Camundongos , Marrocos , alfa-Amilases Pancreáticas/metabolismo , Extratos Vegetais/toxicidade , Plantas Medicinais/química , Ratos , Ratos Wistar , Transportador 1 de Glucose-Sódio/metabolismo , alfa-Glucosidases/metabolismo
11.
Molecules ; 26(7)2021 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-33916551

RESUMO

Vaccinium dunalianum Wight, usually processed as a traditional folk tea beverage, is widely distributed in the southwest of China. The present study aimed to investigate the antioxidant, α-glucosidase and pancreatic lipase inhibitory activities of V.dunalianum extract and isolate the bioactive components. In this study, the crude extract (CE) from the buds of V. dunalianum was prepared by the ultrasound-assisted extraction method in 70% methanol and then purified with macroporous resin D101 to obtain the purified extract (PM). Five fractions (Fr. A-E) were further obtained by MPLC column (RP-C18). Bioactivity assays revealed that Fr. B with 40% methanol and Fr. D with 80% methanol had better antioxidant with 0.48 ± 0.03 and 0.62 ± 0.01 nM Trolox equivalent (TE)/mg extract for DPPH, 0.87 ± 0.02 and 1.58 ± 0.02 nM TE/mg extract for FRAP, 14.42 ± 0.41 and 19.25 ± 0.23 nM TE/mg extract for ABTS, and enzyme inhibitory effects with IC50 values of 95.21 ± 2.21 and 74.55 ± 3.85 for α-glucosidase, and 142.53 ± 11.45 and 128.76 ± 13.85 µg/mL for pancreatic lipase. Multivariate analysis indicated that the TPC and TFC were positively related to the antioxidant activities. Further phytochemical purification led to the isolation of ten compounds (1-10). 6-O-Caffeoylarbutin (7) showed significant inhibitory effects on α-glucosidase and pancreatic lipase enzymes with values of 38.38 ± 1.84 and 97.56 ± 7.53 µg/mL, and had the highest antioxidant capacity compared to the other compounds.


Assuntos
Antioxidantes/isolamento & purificação , Arbutina/análogos & derivados , Ácidos Cafeicos/isolamento & purificação , Flavonoides/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Lipase/química , Vaccinium/química , alfa-Glucosidases/química , Antioxidantes/química , Arbutina/química , Arbutina/isolamento & purificação , Benzotiazóis/antagonistas & inibidores , Benzotiazóis/química , Compostos de Bifenilo/química , Ácidos Cafeicos/química , Flavonoides/química , Inibidores de Glicosídeo Hidrolases/química , Lipase/antagonistas & inibidores , Lipase/metabolismo , Extração Líquido-Líquido/métodos , Metanol/química , Picratos/química , Extratos Vegetais/química , Folhas de Planta/química , Solventes/química , Sonicação , Ácidos Sulfônicos/antagonistas & inibidores , Ácidos Sulfônicos/química , alfa-Glucosidases/metabolismo
12.
Food Chem ; 356: 129682, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-33812196

RESUMO

Passion fruit peel, a potential source of bioactive compounds, has been used as food stabilizing agent. However, the phenolic composition and bioactivity of passion fruit peel have rarely been reported. The effects of simulated gastrointestinal digestion on the bioactive components, bioactivity and bioaccessibility of passion fruit peel ethanol extracts (PFPE) were investigated using high performance liquid chromatography-tandem mass spectrometry analysis (quasi-targeted metabolomics). Phenols (178) were identified, of which 25 inhibited alpha-glucosidase activity. The stabilities of PFPE phenols were significantly affected by pH changes and digestive enzymes during simulated digestion. The 1,1-diphenyl-2-picrylhydrazyl free radical scavenging capacity and ferric ion reducing antioxidant power were decreased by 32% and 30%, respectively, while 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulphonate) free radical scavenging capacity increased by 17%. Alpha-glucosidase inhibition decreased with decreased PFPE phenolic content. Therefore, passion fruit peel could be considered a source of natural antioxidants and alpha-glucosidase inhibitors.


Assuntos
Cromatografia Líquida de Alta Pressão , Passiflora/química , Fenóis/análise , Extratos Vegetais/química , Espectrometria de Massas em Tandem , Digestão , Etanol/química , Sequestradores de Radicais Livres/química , Frutas/química , Frutas/metabolismo , Passiflora/metabolismo , Fenóis/química , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
13.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807278

RESUMO

Pompe disease is an autosomal recessive disorder caused by a deficiency in the enzyme acid alpha-glucosidase. The late-onset form of Pompe disease (LOPD) is characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles. In LOPD, the levels of GAA enzyme activity and the severity of the clinical pictures may be highly variable among individuals, even in those who harbour the same combination of GAA mutations. The result is an unpredictable genotype-phenotype correlation. The purpose of this study was to identify the genetic factors responsible for the progression, severity and drug response in LOPD. We report here on a detailed clinical, morphological and genetic study, including a whole exome sequencing (WES) analysis of 11 adult LOPD siblings belonging to two Italian families carrying compound heterozygous GAA mutations. We disclosed a heterogeneous pattern of myopathic impairment, associated, among others, with cardiac defects, intracranial vessels abnormality, osteoporosis, vitamin D deficiency, obesity and adverse response to enzyme replacement therapy (ERT). We identified deleterious variants in the genes involved in autophagy, immunity and bone metabolism, which contributed to the severity of the clinical symptoms observed in the LOPD patients. This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.


Assuntos
Autofagia/genética , Doença de Depósito de Glicogênio Tipo II/genética , alfa-Glucosidases/genética , Adulto , Idoso , Autofagia/fisiologia , Terapia de Reposição de Enzimas/métodos , Família , Feminino , Variação Genética/genética , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Mutação , Linhagem , Músculos Respiratórios , Irmãos , alfa-Glucosidases/metabolismo
14.
Molecules ; 26(6)2021 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-33799441

RESUMO

Medicago lupulina is an ancient edible plant from the Fabaceae family. In this work, two eco-friendly methods for extraction of bioactive phenolics from M. lupulina were developed using mixtures of water with two non-toxic, skin- and environmentally-friendly polyol solvents: glycerol and polypropylene glycol. Ultrasound-assisted extractions were optimized using a Box-Behnken design. The independent variables were the concentration of organic solvent in water (X1), extraction temperature (X2) and time (X3), while the response was phenolic content. The optimum conditions for extraction of polyphenols were (X1, X2, X3): (45%, 70 °C, 60 min) and (10%, 80 °C, 60 min) for glycerol and polypropylene glycol extraction, respectively. The extracts prepared at optimum conditions were rich in phenolic compounds, mainly derivatives of apigenin, kaempferol, luteolin, quercetin, caffeic and ferulic acid, as well as coumestrol. Their cosmeceutical and antidiabetic activity was tested. Both extracts demonstrated notable antioxidant, anti-lipoxygenase and anti-α-amylase activity. In addition to those activities, the glycerol extract efficiently inhibited protein coagulation, elastase and α-glucosidase activity. Glycerol present in the extract displayed enzyme-inhibiting activity in several assays and supported the action of the bioactive constituents. Thus, the optimized glycerol extract is a desirable candidate for direct incorporation in antidiabetic food supplements and cosmeceutical products.


Assuntos
Antioxidantes/química , Cosmecêuticos/química , Inibidores de Glicosídeo Hidrolases/química , Medicago/química , Fenóis/química , alfa-Amilases/antagonistas & inibidores , alfa-Glucosidases/metabolismo , Antioxidantes/farmacologia , Cosmecêuticos/farmacologia , Glicerol/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Fenóis/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polímeros/química , Polifenóis/química , Propilenoglicóis/química , Solventes/química
15.
Food Chem ; 353: 129374, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-33740505

RESUMO

Camel milk proteins are an important substrate for bioactive peptides generation. This study investigates in-vitro antidiabetic effect (via inhibition of α-amylase (AA), α-glucosidase (AG) and dipeptidyl peptidase IV (DPP-IV)) of bovine (BC) and camel casein (CC) hydrolysates. Further, effect of simulated gastrointestinal digestion (SGID) on inhibitory potential of generated hydrolysates was also explored. Both BC and CC hydrolysates displayed potent inhibitory properties against AA (IC50 value- 0.58 & 0.59 mg/mL), AG (IC50 value- 1.04 & 0.59 mg/mL) and DPP-IV (IC50 value- 0.62 & 0.66 mg/mL), respectively. Among different peptides identified in BC and CC hydrolysates, it was observed that FLWPEYGAL was predicted to be most potent inhibitory peptide against AA. While LPTGWLM, MFE and GPAHCLL as most active inhibitor of AG and HLPGRG, QNVLPLH and PLMLP were predicted to be active against DPP-IV. Overall, BC and CC hydrolysates can be proposed to be used in different food formulations as functional antidiabetic agents.


Assuntos
Caseínas/metabolismo , Digestão/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Sequência de Aminoácidos , Animais , Camelus , Caseínas/química , Bovinos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Proteínas do Leite/química , Peptídeos/química , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo
16.
Biomed Pharmacother ; 137: 111357, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33724918

RESUMO

3,4-Diaminopyridine (3,4-DAP) and its phosphate form, 3,4-DAPP have been used efficiently in the past years to treat muscular weakness in myasthenic syndromes with neuromuscular junctions (NMJs) impairment. Pompe disease (PD), an autosomal recessive metabolic disorder due to a defect of the lysosomal enzyme α-glucosidase (GAA), presents some secondary symptoms that are related to neuromuscular transmission dysfunction, resulting in endurance and strength failure. In order to evaluate whether 3,4-DAPP could have a beneficial effect on this pathology, we took advantage of a transient zebrafish PD model that we previously generated and characterized. We investigated presynaptic and postsynaptic structures, NMJs at the electron microscopy level, and zebrafish behavior, before and after treatment with 3,4-DAPP. After drug administration, we observed an increase in the number of acetylcholine receptors an increment in the percentage of NMJs with normal structure and amelioration in embryo behavior, with recovery of typical movements that were lost in the embryo PD model. Our results revealed early NMJ impairment in Pompe zebrafish model with improvement after administration of 3,4-DAPP, suggesting its potential use as symptomatic drug in patients with Pompe disease.


Assuntos
Amifampridina/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Junção Neuromuscular/efeitos dos fármacos , Animais , Comportamento Animal , Embrião não Mamífero , Atividade Motora/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Junção Neuromuscular/ultraestrutura , Receptores Colinérgicos/efeitos dos fármacos , Peixe-Zebra , alfa-Glucosidases/metabolismo
17.
Food Chem ; 353: 129448, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-33711702

RESUMO

Vanillin is a natural phenolic compound mainly used as flavors in food industry. In this work, a new functionality of vanillin as the α-glucosidase inhibitor was studied based on the inhibition kinetic mechanism. The inhibitory effect (IC50) of vanillin against α-glucosidase was 28.34 ± 0.89 mg/mL, which belongs to mixed inhibition mechanism and its process was spontaneous. Vanillin could bind to α-glucosidase by hydrophobic interactions and hydrogen bonds with -8.42 kcal/mol intermolecular energy to form the steric hindrance. The average binding distances was calculated as 2.20 nm according to energy transfer theory. In addition, the protein secondary structure and denaturation temperature (decreasing about 10 °C) were changed significantly after vanillin binding to α-glucosidase, resulting in an inhibitory effect. The findings of this research provide insights for the development of vanillin as potential inhibitor for α-glucosidase in special dietary foods.


Assuntos
Benzaldeídos/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo , Benzaldeídos/química , Benzaldeídos/metabolismo , Domínio Catalítico , Dicroísmo Circular , Transferência de Energia , Transferência Ressonante de Energia de Fluorescência , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/metabolismo , Ligação de Hidrogênio , Cinética , Simulação de Acoplamento Molecular , Desnaturação Proteica , Estrutura Secundária de Proteína , Temperatura
18.
J Chromatogr A ; 1642: 462041, 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33721816

RESUMO

Cortex Lycii, as a kind of traditional Chinese medicines, have shown prospects in the prevention of diabetes and its complications. However, there is comparatively little information regarding the characterization of potentially hypoglycemic compounds derived from Cortex Lycii. In this study, we performed a global non-selective investigation of α-glucosidase inhibitors in Cortex Lycii based on a bioactivity-labeling high-resolution mass spectrometry-metabolomics method. Samples of Cortex Lycii were collected from different Chinese provinces and their ethyl acetate extracts were analyzed using an in vitro α-glucosidase inhibition assay for bioactivity-labeling. The ethyl acetate extracts were also subjected to liquid chromatography-mass spectrometry analysis and multivariate data analysis was subsequently conducted to identify correlations between the bioactivity measured from the enzyme-involved test and the profiles obtained based on high-resolution mass spectrometry. The variables contributing significantly to the separation of the more-active from the less-active samples were considered to indicate the potential target ions of active compounds. MS/MS fragment patterns and nuclear magnetic resonance analyses were used to identify the potential target ions. The developed platform mentioned above facilitated rapid identification of four α-glucosidase inhibitors, namely, N-p-trans-coumaroyltyramine (1), N-trans-caffeoyl-tyramine (2), (9R,10E,12Z)-9-hydroxy-10,12-octadecadienoic acid (3a), and (9S,10E,12Z)-9-hydroxy-10,12-octadecadienoic acid (3b) from Cortex Lycii. The α-glucosidase inhibitory activities of compounds 3a and 3b with IC50 values of 1.0413±0.0551 and 1.0423±0.0049 mM, respectively, are reported here for the first time. Enzyme kinetics revealed that both 3a and 3b were non-competitive inhibitors of α-glucosidase, with Ki values of 2.20 and 2.24 mM, respectively. In short, the presented work identified compounds 3a and 3b as potential α-glucosidase inhibitors with higher inhibitory activity and a different mode of inhibition compared to the standard α-glucosidase inhibitor, acarbose. The integrated approach adopted in this study can be extended as a normalized procedure to rapidly identify active compounds, even from complex extracts, and can readily be adapted for the study of other natural products.


Assuntos
Medicamentos de Ervas Chinesas/química , Inibidores de Glicosídeo Hidrolases/análise , Espectrometria de Massas , Metabolômica , Cromatografia Líquida de Alta Pressão , Inibidores de Glicosídeo Hidrolases/química , Concentração Inibidora 50 , Íons , Cinética , Espectroscopia de Ressonância Magnética , Análise Multivariada , Extratos Vegetais/química , Análise de Componente Principal , Reprodutibilidade dos Testes , alfa-Glucosidases/metabolismo
19.
Molecules ; 26(4)2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33672038

RESUMO

Our previous study found that desmethylxanthohumol (1) inhibited α-glucosidase in vitro. Recently, further investigations revealed that dehydrocyclodesmethylxanthohumol (2) and its dimer analogue rottlerone (3) exhibited more potent α-glucosidase inhibitory activity than 1. The aim of this study was to synthesize a series of rottlerone analogues and evaluate their α-glucosidase and DPP-4 dual inhibitory activity. The results showed that compounds 4d and 5d irreversibly and potently inhibited α-glucosidase (IC50 = 0.22 and 0.12 µM) and moderately inhibited DPP-4 (IC50 = 23.59 and 26.19 µM), respectively. In addition, compounds 4d and 5d significantly promoted glucose consumption, with the activity of 5d at 0.2 µM being comparable to that of metformin at a concentration of 1 mM.


Assuntos
Inibidores da Dipeptidil Peptidase IV/farmacologia , Flavonoides/síntese química , Flavonoides/farmacologia , Glucose/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Propiofenonas/síntese química , Propiofenonas/farmacologia , Dipeptidil Peptidase 4/metabolismo , Flavonoides/química , Células Hep G2 , Humanos , Cinética , Propiofenonas/química , alfa-Glucosidases/metabolismo
20.
Molecules ; 26(4)2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669312

RESUMO

Diabetes mellitus is a chronic disease and one of the fastest-growing health challenges of the last decades. Studies have shown that chronic low-grade inflammation and activation of the innate immune system are intimately involved in type 2 diabetes pathogenesis. Momordica charantia L. fruits are used in traditional medicine to manage diabetes. Herein, we report the purification of a new 23-O-ß-d-allopyranosyl-5ß,19-epoxycucurbitane-6,24-diene triterpene (charantoside XV, 6) along with 25ξ-isopropenylchole-5(6)-ene-3-O-ß-d-glucopyranoside (1), karaviloside VI (2), karaviloside VIII (3), momordicoside L (4), momordicoside A (5) and kuguaglycoside C (7) from an Indian cultivar of Momordica charantia. At 50 µM compounds, 2-6 differentially affected the expression of pro-inflammatory markers IL-6, TNF-α, and iNOS, and mitochondrial marker COX-2. Compounds tested for the inhibition of α-amylase and α-glucosidase enzymes at 0.87 mM and 1.33 mM, respectively. Compounds showed similar α-amylase inhibitory activity than acarbose (0.13 mM) of control (68.0-76.6%). Karaviloside VIII (56.5%) was the most active compound in the α-glucosidase assay, followed by karaviloside VI (40.3%), while momordicoside L (23.7%), A (33.5%), and charantoside XV (23.9%) were the least active compounds. To better understand the mode of binding of cucurbitane-triterpenes to these enzymes, in silico docking of the isolated compounds was evaluated with α-amylase and α-glucosidase.


Assuntos
Anti-Inflamatórios/farmacologia , Simulação por Computador , Frutas/química , Glicosídeos/química , Glicosídeos/farmacologia , Hipoglicemiantes/farmacologia , Momordica charantia/química , Triterpenos/química , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/química , Bioensaio , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Glicosídeos/isolamento & purificação , Hipoglicemiantes/química , Ligantes , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Células RAW 264.7 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Triterpenos/isolamento & purificação , alfa-Amilases/química , alfa-Amilases/metabolismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
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