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1.
Food Chem ; 333: 127478, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32663752

RESUMO

Moringa oleifera Lam. (M. oleifera) leaves have long been consumed as both nutritive vegetable and popular folk medicine for hyperglycemia and hyperlipidemia in Kenya communities. In the current study, in vitro inhibition by M. oleifera leaf extract (MOLE, 90% (v/v) ethanol) of α-glucosidase and pancreatic lipase was demonstrated, followed by determination of the effects of MOLE on both glucose consumption and lipid levels (TC, TG, HDL-C and LDL-C) in 3T3-L1 cells. Potential ligands in MOLE were fast screened using affinity ultrafiltration LC-MS, and 14 and 10 components displayed certain binding affinity to α-glucosidase and pancreatic lipase, respectively. Docking studies revealed the binding energies and hydrogen bonds between potential ligands and enzymes. This study suggests that M. oleifera leaves may be a promising natural source for the prevention and treatment of hyperglycemia and hyperlipidemia as well as a functional food or other product for health care in the near future.


Assuntos
Moringa oleifera/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Células 3T3-L1 , Animais , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Lipase/antagonistas & inibidores , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos
2.
Food Chem ; 329: 127168, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32512395

RESUMO

A polyphenols-rich extract was obtained from polyvinylpolypyrrolidone (PVPP) winery residue, and its neuroprotective effects and ability to modulate the kinetics of type 2 diabetes-relevant enzymes were characterized. The PVPP-white wine extract is a mixture of polyphenols (840.08 ± 161.25 µg/mg, dry weight) dominated by proanthocyanidins and hydroxycinnamic acids, affording strong antioxidant activity, as detected by the protection of membrane lipids against oxidation and superoxide radical anion scavenging activity. Regarding type 2 diabetes framework, the extract inhibits α-glucosidase (Ki = 166.9 µg/mL) and aldose reductase (Ki = 127.5 µg/mL) through non-competitive mechanisms. Despite the modest ability to inhibit rat brain acetylcholinesterase, it protects neuronal SH-SY5Y cells against oxidative damage promoted by glutamate, decreasing reactive oxygen species generation and preserving cell redox state. Thus, PVPP-white wine extract has potential to support the development of functional foods and/or nutraceuticals aiming neuroprotection and glucose homeostasis regulation, with high relevance in Alzheimers disease and type 2 diabetes interlink.


Assuntos
Diabetes Mellitus Tipo 2/enzimologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Povidona/análogos & derivados , Vinho , Acetilcolinesterase , Aldeído Redutase/metabolismo , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular , Proteínas Ligadas por GPI/antagonistas & inibidores , Ácido Glutâmico/toxicidade , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/prevenção & controle , Oxirredução , Extratos Vegetais/química , Polifenóis/análise , Polifenóis/farmacologia , Povidona/química , Proantocianidinas/química , Proantocianidinas/farmacologia , Ratos , Vinho/análise
3.
Biochem Soc Trans ; 48(3): 1287-1295, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: covidwho-592506

RESUMO

The ongoing COVID-19 pandemic, caused by SARS-CoV-2, has pushed the health systems of many countries to breaking point and precipitated social distancing measures that have crippled economic activities across the globe. A return to normality is unlikely until effective therapeutics and a vaccine are available. The immediacy of this problem suggests that drug strategies should focus on repurposing approved drugs or late-stage clinical candidates, as these have the shortest path to use in the clinic. Here, we review and discuss the role of host cell N-glycosylation pathways to virus replication and the drugs available to disrupt these pathways. In particular, we make a case for evaluation of the well-tolerated drugs miglitol, celgosivir and especially miglustat for the treatment of COVID-19.


Assuntos
Antivirais/farmacologia , Betacoronavirus/química , Infecções por Coronavirus/metabolismo , Reposicionamento de Medicamentos/métodos , Inibidores de Glicosídeo Hidrolases/farmacologia , Pneumonia Viral/metabolismo , Antivirais/uso terapêutico , Calnexina/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Glicosilação/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Humanos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Dobramento de Proteína/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Replicação Viral/efeitos dos fármacos , alfa-Glucosidases/metabolismo
4.
Biochem Soc Trans ; 48(3): 1287-1295, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32510142

RESUMO

The ongoing COVID-19 pandemic, caused by SARS-CoV-2, has pushed the health systems of many countries to breaking point and precipitated social distancing measures that have crippled economic activities across the globe. A return to normality is unlikely until effective therapeutics and a vaccine are available. The immediacy of this problem suggests that drug strategies should focus on repurposing approved drugs or late-stage clinical candidates, as these have the shortest path to use in the clinic. Here, we review and discuss the role of host cell N-glycosylation pathways to virus replication and the drugs available to disrupt these pathways. In particular, we make a case for evaluation of the well-tolerated drugs miglitol, celgosivir and especially miglustat for the treatment of COVID-19.


Assuntos
Antivirais/farmacologia , Betacoronavirus/química , Infecções por Coronavirus/metabolismo , Reposicionamento de Medicamentos/métodos , Inibidores de Glicosídeo Hidrolases/farmacologia , Pneumonia Viral/metabolismo , Antivirais/uso terapêutico , Calnexina/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Glicosilação/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Humanos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Dobramento de Proteína/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Replicação Viral/efeitos dos fármacos , alfa-Glucosidases/metabolismo
5.
Zhongguo Zhong Yao Za Zhi ; 45(5): 1180-1187, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32237463

RESUMO

Based on the idea of plant metabolomics, ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS/MS) was used to compare the chemical composition between 6 batches of fruit vinegar brewed from Choerospondias axillaris fruit peel and 6 batches of apple vinegar purchased from 3 companies. Antioxidant and α-glucosidase inhibition activities were also tested in vitro. A total of 43 compounds were identified by reference substance, liquid chromatography-mass spectrometry(LC-MS/MS) fragmentation information or literature data. A total of 40 compounds were identified in the C. axillaris fruit peel vinegar. A total of 16 compounds were identified in apple vinegar. There were 13 common ingredients including organic acids and esters such as citric acid, 2-isopropyl malic acid, and triethyl citrate. The results of partial leastsquares-discriminant analysis(PLS-DA) indicated that they had 33 significantly different compounds such as proanthocyanidin oligomer, quercetin-3-O-rhamnoside and heptadecanoic acid. The proanthocyanidins and flavonoid glycosides in C. axillaris peel vinegar were more abundant than apple vinegar, so it had better health function than ordinary fruit vinegar. The results showed that C. axillaris fruit peel vinegar had stronger antioxidant and α-glucosidase inhibition activities in vitro. The vinegar brewed from waste C. axillaris fruit peel had more chemical ingredients than the apple vinegar. C. axillaris fruit peel vinegar had better biological activity and health function, so it had good development prospect. This study provided the scientific evidence for exploiting the C. axillaris fruit peel into high value-added products. It also provided ideas for the comprehensive development and utilization of similar Chinese medicine waste.


Assuntos
Ácido Acético/farmacologia , Anacardiaceae/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Malus/química , Antioxidantes , Cromatografia Líquida de Alta Pressão , Frutas/química , Extratos Vegetais , Espectrometria de Massas em Tandem , alfa-Glucosidases
6.
Food Chem ; 324: 126847, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32344340

RESUMO

This study aimed to investigate the inhibitory effect of chestnut inner skin extract (CISE) on the activity of postprandial blood sugar-related enzymes. In total, 12 flavonoids were identified by HPLC-TOF-MS. CISE showed strong and weak inhibition on α-amylase and α-glucosidase, with the IC50 of 27.2 and 2.3 µg/mL, respectively. The inhibition modes of CISE against α-amylase and α-glucosidase were mixed-type and non-competitive type, respectively. Epicatechin gallate noncompetitively inhibited α-amylase, α-glucosidase and dipeptidyl peptidase IV (DPP-IV). Analysis by ultraviolet-visible spectroscopy, fluorescence spectroscopy and circular dichroism suggested that flavonoids altered the hydrophobicity and microenvironment of these enzymes. CISE decreased the starch bioavailability by reducing the enzymatic hydrolysis rate and increasing the fraction of undigested starch. The extract reduced the rapidly digestible starch and increased the resistant starch after incorporation into A-, B- or C- crystallinity starch. Thus, the chestnut inner skin is a useful resource for regulating postprandial blood sugar level.


Assuntos
Inibidores da Dipeptidil Peptidase IV/farmacologia , Fagaceae/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Extratos Vegetais/farmacologia , Disponibilidade Biológica , Catequina/análogos & derivados , Catequina/farmacologia , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/química , Flavonoides/análise , Inibidores de Glicosídeo Hidrolases/química , Nozes/química , Extratos Vegetais/química , Amido/farmacocinética , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/química , alfa-Glucosidases/química
7.
BMC Complement Med Ther ; 20(1): 129, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345272

RESUMO

BACKGROUND: Evolvulus alsinoides (Linn.) Linn. (Convolvulaceae) is a therapeutic herb alleviating brain patterns associated with three categories of regulatory principles of the body, mind, and behaviour. In the current research, enzyme inhibition and cytotoxic potentials of E. alsinoides (L.) L. leaf extract has been studied validating its potential application. METHODS: The plant phenolics in the leaf extracts obtained via cold-maceration with solvents viz.: n-hexane, chloroform, ethyl acetate, methanol, and water were quantitatively analyzed. The antioxidant potency was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and Ferric Reducing Ability of Plasma (FRAP) assays at five concentrations (100-500 µg). The enzyme inhibition potential was performed with α-amylase, α-glucosidase, and acetylcholinesterase at seven concentrations (25-500 µg). The experiments were done in triplicates and statistically validated using Minitab-17 and SPSS 22. RESULTS: Water extract contain 45.08 ± 0.02 mg GAE/g, 49.30 ± 0.07 mg GAE/g, 211.21 ± 0.02 mg QE/g tannins, phenolics, flavonoids respectively. Its antioxidant activity was supported by IC50 52.43 ± 0.2 µg/mL (DPPH assay) and 41.58 ± 0.03 (FRAP assay). Methanolic extract inhibits α-amylase with IC50 1.33 ± 0.05 µg/mL. Water extract inhibits α-glucosidase and acetylcholinesterase with IC50 3.58 ± 0.02 µg/mL and 4.46 ± 0.03 µg/mL. Cytotoxicity studies with SH-SY5Y cell-line substantiate the inhibition potential of water extract with IC50 103.0035 µg/mL. DISCUSSION AND CONCLUSIONS: The extracts with potent antioxidant and enzyme-inhibiting activity were determined. The findings of the research are the first report about the inhibition effects of Evolvulus alsinoides (Linn.) Linn extracts against α-amylase, α-glucosidase and acetylcholinesterase. The extracts shall be examined in future studies to evaluate its pharmaceutical potential.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Diabetes Mellitus/tratamento farmacológico , Inibidores de Glicosídeo Hidrolases/farmacologia , Extratos Vegetais/farmacologia , alfa-Amilases/antagonistas & inibidores , Acetilcolinesterase , Doença de Alzheimer/enzimologia , Linhagem Celular Tumoral , Convolvulaceae/química , Diabetes Mellitus/enzimologia , Humanos , Índia , Medicina Ayurvédica , Extratos Vegetais/química , Folhas de Planta/química , alfa-Glucosidases
8.
BMC Complement Med Ther ; 20(1): 72, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32143602

RESUMO

BACKGROUND: Flavonoids from plant medicines are supposed to be viable alternatives for the treatment of type 2 diabetes (T2D) as less toxicity and side effects. Radix scutellariae (RS) is a widely used traditional medicine in Asia. It has shown great potential in the research of T2D. However, the pharmacological actions remain obscured due to the complex chemical nature of plant medicines. METHODS: In the present study, a systematic method combining ultrafiltration UPLC-TripleTOF-MS/MS and network pharmacology was developed to screen α-glucosidase inhibitors from flavonoids of RS, and explore the underlying mechanism for the treatment of T2D. RESULTS: The n-butanol part of ethanol extract from RS showed a strong α-glucosidase inhibition activity (90.55%, IC50 0.551 mg/mL) against positive control acarbose (90.59%, IC50 1.079 mg/mL). A total of 32 kinds of flavonoids were identified from the extract, and their ESI-MS/MS behaviors were elucidated. Thirteen compounds were screened as α-glucosidase inhibitors, including viscidulin III, 2',3,5,6',7-pentahydroxyflavanone, and so on. A compound-target-pathway (CTP) network was constructed by integrating these α-glucosidase inhibitors, target proteins, and related pathways. This network exhibited an uneven distribution and approximate scale-free property. Chrysin (k = 87), 5,8,2'-trihydroxy-7-methoxyflavone (k = 21) and wogonin (k = 20) were selected as the main active constituents with much higher degree values. A protein-protein interaction (PPI) weighted network was built for target proteins of these α-glucosidase inhibitors and drug targets of T2D. PPARG (Cd = 0.165, Cb = 0.232, Cc = 0.401), ACACB (Cd = 0.155, Cb = 0.184, Cc = 0.318), NFKB1 (Cd = 0.233, Cb = 0.161, Cc = 0.431), and PGH2 (Cd = 0.194, Cb = 0.157, Cc = 0.427) exhibited as key targets with the highest scores of centrality indices. Furthermore, a core subnetwork was extracted from the CTP and PPI weighted network. Type II diabetes mellitus (hsa04930) and PPAR signaling pathway (hsa03320) were confirmed as the critical pathways. CONCLUSIONS: These results improved current understanding of natural flavonoids on the treatment of T2D. The combination of ultrafiltration UPLC-TripleTOF-MS/MS and network pharmacology provides a novel strategy for the research of plant medicines and complex diseases.


Assuntos
Flavonoides/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Extratos Vegetais/farmacologia , Scutellaria baicalensis/química , China , Cromatografia Líquida de Alta Pressão , Flavonoides/química , Inibidores de Glicosídeo Hidrolases/química , Espectrometria de Massas , Extratos Vegetais/química , Ultrafiltração
9.
BMC Res Notes ; 13(1): 56, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019574

RESUMO

OBJECTIVE: Andrographis paniculata, widely used as an antidiabetic in Indonesian traditional medicines (jamu), contains chemical compounds whose concentration is related to its therapeutic effects. The concentration of solvents used for extraction will also affect the number of compounds extracted. Therefore, a quality control method is needed to ensure consistency in quantifying these compounds in A. paniculata to improve its therapeutic application. High-performance liquid chromatography fingerprint analysis combined with chemometrics was used to evaluate extracts from different solvent extraction treatments. The content of andrographolide, the main bioactive compound in A. paniculata, and the level of α-glucosidase inhibition activity, an indicator of its antidiabetic activity, were also determined. RESULTS: Fingerprint chromatograms of A. paniculata extracts from different treatments exhibited a similar pattern with several peaks in common, only differing in area and intensity value. The A. paniculata extracts were classified using HPLC fingerprint and principal component analysis to allow grouping according to their respective solvent extraction treatments. The highest andrographolide content and α-glucosidase inhibition activity occurred in the 50% ethanol extract and the lowest in the water extract. HPLC fingerprint analysis could be used for identifying A. paniculata extracts based on solvent extraction, thus improving quality control for their therapeutic application.


Assuntos
Andrographis/química , Cromatografia Líquida de Alta Pressão/métodos , Extratos Vegetais/classificação , Solventes/química , Diterpenos/análise , Inibidores de Glicosídeo Hidrolases/farmacologia , Análise de Componente Principal
10.
Phytochemistry ; 171: 112232, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31911266

RESUMO

Corni Fructus, also known as the fruit of Cornus officinalis Sieb. et Zucc., has long been used as a traditional Chinese medicine and is widely consumed as a nutritional food in the form of function drink and wine. Recently, Corni Fructus has attracted considerable interest because of its anti-diabetic effects. A systematic phytochemical investigation of Corni Fructus was performed to find anti-diabetic components, which led to the isolation of 10 unreported iridoid glycosides, cornusdiglycosides A-J (1-8, 9a/9b and 10a/10b). Their chemical structures were determined through spectroscopic analysis (ultraviolet [UV], infrared [IR], high-resolution electrospray ionisation mass spectroscopy [HRESIMS], one-dimensional [1D] and two-dimensional [2D] nuclear magnetic resonance [NMR]). Such morroniside-type diglycosides were first reported from natural sources, and all isolates were evaluated for α-glucosidase inhibitory activity. The results showed that all compounds (1-10) exhibited α-glucosidase (from Saccharomyces cerevisiae) inhibitory activities with IC50 values ranging from 78.9 ± 4.09 to 162.2 ± 9.17 µM, whereas acarbose, the positive control, displayed α-glucosidase inhibitory activity with IC50 value of 118.9 ± 7.89 µM.


Assuntos
Cornus/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Glicosídeos/farmacologia , Glucosídeos Iridoides/farmacologia , Compostos Fitoquímicos/farmacologia , alfa-Glucosidases/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Glicosídeos/química , Glicosídeos/isolamento & purificação , Humanos , Glucosídeos Iridoides/química , Glucosídeos Iridoides/isolamento & purificação , Conformação Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação
11.
J Enzyme Inhib Med Chem ; 35(1): 565-573, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31969031

RESUMO

Embelin is a naturally occurring para-benzoquinone isolated from Embelia ribes (Burm. f.) of the Myrsinaceae family. It was first discovered to have potent inhibitory activity (IC50 = 4.2 µM) against α-glucosidase in this study. Then, four series of novel embelin derivatives were designed, prepared and evaluated in α-glucosidase inhibition assays. The results show that most of the embelin derivatives synthesised are effective α-glucosidase inhibitors, with IC50 values at the micromolar level, especially 10d, 12d, and 15d, the IC50 values of which are 1.8, 3.3, and 3.6 µM, respectively. Structure-activity relationship (SAR) studies suggest that hydroxyl groups in the 2/5-position of para-benzoquinone are very important, and long-chain substituents in the 3-position are highly preferred. Moreover, the inhibition mechanism and kinetics studies reveal that all of 10d, 12d, 15d, and embelin are reversible and mixed-type inhibitors. Furthermore, docking experiments were carried out to study the interactions between 10d and 15d with α-glucosidase.


Assuntos
Benzoquinonas/farmacologia , Desenho de Fármacos , Inibidores de Glicosídeo Hidrolases/farmacologia , alfa-Glucosidases/metabolismo , Benzoquinonas/síntese química , Benzoquinonas/química , Relação Dose-Resposta a Droga , Embelia/química , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
12.
Carbohydr Polym ; 230: 115586, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31887942

RESUMO

α-Glycosidase is an essential target for the management of postprandial serum glucose in diabetic patients. Therefore, the interest has been growing in the screening of α-glycosidase inhibitor from natural resource. In the present study, the structure and α-glycosidase inhibitory activity of a polysaccharide (named as ACPP-1) from Aconitum coreanum were investigated. Based on the results from high performance gel permeation chromatography, GC-MS and 1D/2D nuclear magnetic resonance spectroscopy, ACPP-1 was a highly-linear polysaccharide with a molecular weight of 34.0 kD and containing over 90 % of glucose. It was composed of (1→4)-α-d-Glcp and α-Araf. ACPP-1 exhibited a dose-dependent inhibitory eff ;ect against α-glycosidase activity in vitro and the IC50 value was ∼0.8 mg/mL. In oral starch tolerance test, treatment with ACPP-1 (800 mg/kg) significantly improved the starch tolerance in mice. Taken together, this study provided a potential intervention and management for postprandial hyperglycemia by the polysaccharide fraction from A. coreanum.


Assuntos
Aconitum/química , Inibidores de Glicosídeo Hidrolases/química , Polissacarídeos/química , alfa-Glucosidases/química , Animais , Cromatografia em Gel , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Camundongos , Peso Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Polissacarídeos/ultraestrutura , alfa-Glucosidases/farmacologia , alfa-Glucosidases/ultraestrutura
13.
J Trace Elem Med Biol ; 58: 126448, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31901726

RESUMO

BACKGROUND: Increasing resistance to available drugs and their associated side-effects have drawn wide attention towards designing alternative therapeutic strategies for control of hyperglycemia and oxidative stress. The roles of the sizes and shapes of the nanomaterials used in the treatment and management of Type 2 Diabetes Mellitus (T2DM) in preventing chronic hyperglycaemia and oxidative stress are investigated. We report specifically on the effects of doping silver (Ag) into the ZnO nanorods (ZnO:Ag NR's) as a rational drug designing strategy. METHODS: Inhibition of porcine pancreatic α-amylase, murine pancreatic amylase, α-glucosidase, murine intestinal glucosidase and amyloglucosidase are checked for evaluation of antidiabetic potential. In addition, the radical scavenging activities of ZnO:Ag NR's against nitric oxide, DDPH and superoxide radicals are evaluated. RESULTS: Quantitative radical scavenging and metabolic enzyme inhibition activities of ZnO:Ag NR's at a concentration of 100 µg/mL were found to depend on the amount of Ag doped in up to a threshold level (3-4 %). Circular dichroism analysis revealed that the interaction of the NR's with the enzymes altered their secondary conformation. This alteration is the underlying mechanism for the potent enzyme inhibition. CONCLUSIONS: Enhanced inhibition of enzymes and scavenging of free radicals primarily responsible for reactive oxygen species (ROS) mediated damage, provide a strong scientific rationale for considering ZnO:Ag NR's as a candidate nanomedicine for controlling postprandial hyperglycaemia and the associated oxidative stress.


Assuntos
Antioxidantes/farmacologia , Hipoglicemiantes/farmacologia , Nanotubos/química , Prata/farmacologia , Óxido de Zinco/farmacologia , Amilases/antagonistas & inibidores , Amilases/metabolismo , Animais , Compostos de Bifenilo/química , Inibidores Enzimáticos/farmacologia , Depuradores de Radicais Livres/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Intestinos/enzimologia , Camundongos , Nanotubos/ultraestrutura , Óxido Nítrico/metabolismo , Pâncreas/enzimologia , Picratos/química , Superóxidos/metabolismo , Suínos , alfa-Glucosidases/metabolismo
14.
Eur J Med Chem ; 188: 112034, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31927314

RESUMO

A new library of pyrido-pyrrolidine hybrid compounds were designed, developed and screened for their antidiabetic property with α-glucosidase. The design is based on preliminary screening of key fragments identified from literature reported α-glucosidase inhibitors and antidiabetic compounds. The most active fragments were stitched to provide a pyrido-pyrrolidine hybrid molecule as a new motif. A library of these compounds were synthesized and screened against a series of α-glycosidases. Subsequently, compound 3k was the most efficacious analog with IC50 of 0.56 µM. Photoluminescence study and circular dichroism experiments indicated that compound 3k modulates the primary and secondary structure of the enzyme. It successfully brings down the fasting blood glucose level for streptozotocin (STZ, 70 mg/kg, Intraperitoneal) induced type I diabetic male Sprague-Dawley rats (250-320 g). At lower concentration, compound 3k slightly stimulates proliferation of BRIN-BD11 (α-glucose responsive beta cells from rat pancreas islets that secretes insulin) cells.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Descoberta de Drogas , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/farmacologia , Pirrolidinas/farmacologia , alfa-Glucosidases/metabolismo , Animais , Sítios de Ligação/efeitos dos fármacos , Proteínas Sanguíneas/química , Proteínas Sanguíneas/metabolismo , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/metabolismo , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/sangue , Inibidores de Glicosídeo Hidrolases/química , Humanos , Hipoglicemiantes/sangue , Hipoglicemiantes/química , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirrolidinas/sangue , Pirrolidinas/química , Ratos , Ratos Sprague-Dawley , Solubilidade , Estreptozocina , Relação Estrutura-Atividade , Termodinâmica
15.
Biosci Biotechnol Biochem ; 84(3): 598-605, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31724491

RESUMO

Red kidney beans (Phaseolus vulgaris L.) contain bioactive compounds that are known to exhibit antidiabetic effects via inhibition of α-glucosidase. However, information on the nonpolar components that exhibit antidiabetic activity is limited. Here, we report the isolation and structure determination of components with α-glucosidase inhibitory activity, which were obtained from the hexane extract of red kidney beans. Triacylglycerols (TAGs) were identified as the major components exhibiting inhibitory activity against α-glucosidase. The chemical structure of TAGs was determined by a combination of GC-MS and UPLC-MS/MS. The primary TAGs identified were LnLnLn (trilinolenin) and LnLLn (1,3-dilinolenoyl-2-linoleoyl glycerol). The major fatty acids present in these TAGs were α-linolenic acid (ω-3) and linoleic acid (ω-6). These TAGs were also found to inhibit the α-glucosidase activity in a similar fashion as acarbose. These results suggest that TAGs have potency as antidiabetics and support the potential suitability of red kidney beans for diabetes treatment.


Assuntos
Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Hexanos/química , Phaseolus/química , Triglicerídeos/isolamento & purificação , Cromatografia Líquida/métodos , Diabetes Mellitus/tratamento farmacológico , Ácidos Graxos/análise , Cromatografia Gasosa-Espectrometria de Massas , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Estrutura Molecular , Espectrometria de Massas em Tandem , Triglicerídeos/química
16.
Phytochemistry ; 170: 112192, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31726325

RESUMO

Chemical fractionation of the ethanolic extract of Eclipta prostrata yielded a series of unreported terpenoid constituents, including a rare 6/6/6/6-fused tetracyclic triterpenoid, a pentacyclic triterpenoid, two pentacyclic triterpenoid saponins, a diterpenoid and a sesquiterpenoid. Structures were assigned to these compounds on the basis of comprehensive spectroscopic analyses, with the absolute configurations of the tetracyclic triterpenoid, the diterpenoid and the sesquiterpenoid being determined via explanation of electronic circular dichroism data. Screening of these isolates in an array of bioassays revealed antibacterial, cytotoxic and α-glucosidase inhibitory activities for selective compounds. Of particular interest, the tetracyclic triterpenoid showed very strong inhibition against α-glucosidase with an IC50 of 0.82 ±â€¯0.18 µM, being 103-fold as active as the positive control acarbose.


Assuntos
Antibacterianos/farmacologia , Eclipta/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Neoplasias/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Terpenos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Bacillus subtilis/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Células HeLa , Humanos , Testes de Sensibilidade Microbiana , Neoplasias/patologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Staphylococcus aureus/efeitos dos fármacos , Terpenos/química , Terpenos/isolamento & purificação , alfa-Glucosidases/metabolismo
17.
Prep Biochem Biotechnol ; 50(2): 123-132, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31702433

RESUMO

The chemo-profiling of ethanolic extract of faba beans seeds was performed and explored as an α-glucosidase inhibitor. The inhibition of α-glucosidase is one of the alternatives approach to control postprandial hyperglycemia by, resulting in the delay of the carbohydrate digestion of absorbable monosaccharides. Ethanolic seed extract showed phenolic compounds, flavonoid such as gallic acid (m/z [M- H] = 169.0124,C7H6O5) ellagic acid derivatives epigallocatechin (m/z [M- H = 305.0644,C15H14O7),catechin (m/z [M- H] = 289.0656,C15H14O6), epigallocatechin gallate (m/z [M- H] = 457.0578,C22H18O11) and epicatechin monogallate (m/z [M- H] = 441.081, C22H18O10). The extract was found to exert inhibitory activity (88.28 ± 2.67%) (IC50 value of 2.30 ± 0.032 mg/mL) with a mixed mode of inhibition (Km, apparent = 0.54 ± 0.020 mM and Vmax, apparent 0.136 ± 0.04 mM/min). Molecular docking studies of gallic acid and catechin on α-glucosidase proposed productive binding modes having binding energy (-6.58 kcal/mol and -7.25 kcal/mol) with an effective number of hydrogen bonds and binding energy. Tyr63, Arg197, Asp198, Glu 233, Asn324, Asp 326 of α-glucosidase participated in binding events with gallic acid and catechin. Molecular dynamics simulation studies were performed for both complexes i.e. gal:α-glucosidase and cat:α-glucosidase along with apo state of α-glucosidase, which revealed stable systems during the simulation. These findings of the present study may give an insight into the further development of the novel antidiabetic drug from the seeds of faba beans.


Assuntos
Catequina/metabolismo , Ácido Gálico/metabolismo , Extratos Vegetais/farmacologia , Polifenóis/metabolismo , Vicia faba/metabolismo , alfa-Glucosidases/metabolismo , Cromatografia Líquida de Alta Pressão , Inibidores de Glicosídeo Hidrolases/farmacologia , Simulação de Acoplamento Molecular , Sementes/química , Espectrometria de Massas por Ionização por Electrospray , Vicia faba/embriologia
18.
Eur J Med Chem ; 186: 111831, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31740052

RESUMO

Heparanase is regarded as a promising target for anticancer drugs and Ronepastat is one of the most promising heparanase inhibitors insert in clinical study for Multiple Myeloma Therapy. To improve its pharmacokinetic/pharmacodynamic profile, as well to have an antidote able to neutralize its activity in case of over dosages or intolerance, a new class of its derivatives was obtained inserting non-carbohydrate moieties of different length between the polysaccharide chain and biotin or its derivatives. In vitro these novel derivatives maintain the anti-heparanase activity without induced toxicity. The newly synthesized compounds retained the ability to attenuate the growth of CAG myeloma tumors in mice with potency similar, or in one case even higher than that of the reference compound Roneparstat as well as inhibited metastatic dissemination (lung colonization) of murine B16-F10 melanoma cells in vivo.


Assuntos
Antineoplásicos/farmacologia , Biotina/química , Glucuronidase/antagonistas & inibidores , Glicóis/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Heparina/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glucuronidase/metabolismo , Glicóis/síntese química , Glicóis/química , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Imagem Óptica , Relação Estrutura-Atividade
19.
Crit Rev Food Sci Nutr ; 60(4): 695-708, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30638035

RESUMO

The objective of this review is to summarize knowledge on the inhibitory effects (IEs) of flavonoids on α-amylase (αA) and α-glucosidase (αG) relevant to the search of substitutes of acarbose (Aca). Flavonoids reported to be more effective at inhibiting αG than Aca have been summarized. The concept of "relative coefficient to Aca (RCAca)" has been proposed to integrate data from various reports. Correlations between hydrogen bond donors (H-donors), hydrogen bond acceptors (H-acceptors), partition coefficient values (XLog P3), and RCAca are discussed. Two kinds of binding modes between flavonoids and enzymes have been observed: (i) flavonoids directly bind to amino acid residues (AARs) in the active sites of enzymes and exclude the binding of substrate; (ii) flavonoids interact with AARs near the active site and close the channel to the active center. Some groups are correlated with stronger IEs: (i) substitutions of caffeoyl, galloyl, and prenyl groups in flavonoids enhance IEs; (ii) steric hindrance attenuates IEs, and linear molecules tend to be stronger inhibitors of porcine pancreatic αA (PPA). Whilst many achievements have been made, our understanding of the combined effects of different flavonoids, and flavonoids and Aca, remain ambiguous, and the effects of food matrices and stomach digestion on IEs of flavonoids are poorly understood. This review provides a comprehensive understanding on the use of flavonoids as αA and αG inhibitors for controlling diabetes.


Assuntos
Flavonoides/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , alfa-Amilases/antagonistas & inibidores , alfa-Glucosidases/metabolismo , Acarbose/farmacologia , Animais , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/enzimologia , Humanos
20.
Nat Prod Res ; 34(3): 369-377, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30600701

RESUMO

The crude polysaccharide extracted from Cordyceps militaris was chemically modified to obtain carboxymethylated derivatives (CM-CPS) and acetylated derivatives (AC-CPS). The physicochemical characterizations were comparatively investigated by chemical methods, high-performance gel permeation chromatography, FT-IR spectra, NMR analysis, Congo red test, scanning electron microscopy, atomic force microscopy and differential scanning calorimetry. Then α-glucosidase inhibitory activities were conducted to determine the structure-bioactivity relationship. Results indicated that carboxymethylation and acetylation modification of polysaccharide were successful with the carboxymethyl substitutions might being C-6, C-2 and acetyl substitutions at C-3, C-6 inferred from NMR analysis. In addition, the tertiary structure, ultrastructure, melting properties were also different from native polysaccharide. Besides, α-glucosidase inhibitory activities of derivatives exhibited differently with CM-CPS to be the lowest. Therefore, it was concluded that change of structure in polysaccharide had certain effect on bioactivity with degree of substitution and substituents position being the influence factors.


Assuntos
Cordyceps/química , Polissacarídeos/química , alfa-Glucosidases/efeitos dos fármacos , Acetilação , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/farmacologia , Metilação , Polissacarídeos/isolamento & purificação , Espectroscopia de Infravermelho com Transformada de Fourier
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