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1.
Molecules ; 26(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34361714

RESUMO

α-glucosidase is a major enzyme that is involved in starch digestion and type 2 diabetes mellitus. In this study, the inhibition of hypericin by α-glucosidase and its mechanism were firstly investigated using enzyme kinetics analysis, real-time interaction analysis between hypericin and α-glucosidase by surface plasmon resonance (SPR), and molecular docking simulation. The results showed that hypericin was a high potential reversible and competitive α-glucosidase inhibitor, with a maximum half inhibitory concentration (IC50) of 4.66 ± 0.27 mg/L. The binding affinities of hypericin with α-glucosidase were assessed using an SPR detection system, which indicated that these were strong and fast, with balances dissociation constant (KD) values of 6.56 × 10-5 M and exhibited a slow dissociation reaction. Analysis by molecular docking further revealed that hydrophobic forces are generated by interactions between hypericin and amino acid residues Arg-315 and Tyr-316. In addition, hydrogen bonding occurred between hypericin and α-glucosidase amino acid residues Lys-156, Ser-157, Gly-160, Ser-240, His-280, Asp-242, and Asp-307. The structure and micro-environment of α-glucosidase enzymes were altered, which led to a decrease in α-glucosidase activity. This research identified that hypericin, an anthracene ketone compound, could be a novel α-glucosidase inhibitor and further applied to the development of potential anti-diabetic drugs.


Assuntos
Antracenos/química , Proteínas Fúngicas/antagonistas & inibidores , Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/química , Perileno/análogos & derivados , alfa-Glucosidases/química , Antracenos/metabolismo , Sítios de Ligação , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Inibidores de Glicosídeo Hidrolases/metabolismo , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Hipoglicemiantes/metabolismo , Cinética , Simulação de Acoplamento Molecular , Nitrofenilgalactosídeos/química , Nitrofenilgalactosídeos/metabolismo , Perileno/química , Perileno/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Saccharomyces cerevisiae/classificação , Saccharomyces cerevisiae/enzimologia , Ressonância de Plasmônio de Superfície , alfa-Glucosidases/metabolismo
2.
Nutrients ; 13(8)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34444782

RESUMO

Substrates of semicarbazide-sensitive amine oxidase (SSAO) exert insulin-like actions in adipocytes. One of them, benzylamine (Bza) exhibits antihyperglycemic properties in several rodent models of diabetes. To further study the antidiabetic potential of this naturally occurring amine, a model of severe type 2 diabetes, the obese db-/- mouse, was subjected to oral Bza administration. To this end, db-/- mice and their lean littermates were treated at 4 weeks of age by adding 0.5% Bza in drinking water for seven weeks. Body mass, fat content, blood glucose and urinary glucose output were followed while adipocyte insulin responsiveness and gene expression were checked at the end of supplementation, together with aorta nitrites. Bza supplementation delayed the appearance of hyperglycemia, abolished polydypsia and glycosuria in obese/diabetic mice without any detectable effect in lean control, except for a reduction in food intake observed in both genotypes. The improvement of glucose homeostasis was observed in db-/- mice at the expense of increased fat deposition, especially in the subcutaneous white adipose tissue (SCWAT), without sign of worsened inflammation or insulin responsiveness and with lowered circulating triglycerides and uric acid, while NO bioavailability was increased in aorta. The higher capacity of SSAO in oxidizing Bza in SCWAT, found in the obese mice, was unaltered by Bza supplementation and likely involved in the activation of glucose utilization by adipocytes. We propose that Bza oxidation in tissues, which produces hydrogen peroxide mainly in SCWAT, facilitates insulin-independent glucose utilization. Bza could be considered as a potential agent for dietary supplementation aiming at preventing diabetic complications.


Assuntos
Benzilaminas/administração & dosagem , Benzilaminas/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Suplementos Nutricionais , Obesidade/metabolismo , Adipócitos/metabolismo , Amina Oxidase (contendo Cobre)/metabolismo , Animais , Benzilaminas/farmacologia , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Ingestão de Alimentos , Glucose/metabolismo , Humanos , Peróxido de Hidrogênio , Hiperglicemia/metabolismo , Hipoglicemiantes/metabolismo , Insulina/sangue , Masculino , Camundongos , Camundongos Knockout , Camundongos Obesos , Compostos Fitoquímicos , Receptores para Leptina/genética
3.
Molecules ; 26(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204669

RESUMO

Abelmoschus esculentus (Okra) is an important vegetable crop, widely cultivated around the world due to its high nutritional significance along with several health benefits. Different parts of okra including its mucilage have been currently studied for its role in various therapeutic applications. Therefore, we aimed to develop and characterize the okra mucilage biopolymer (OMB) for its physicochemical properties as well as to evaluate its in vitro antidiabetic activity. The characterization of OMB using Fourier-transform infrared spectroscopy (FT-IR) revealed that okra mucilage containing polysaccharides lies in the bandwidth of 3279 and 1030 cm-1, which constitutes the fingerprint region of the spectrum. In addition, physicochemical parameters such as percentage yield, percentage solubility, and swelling index were found to be 2.66%, 96.9%, and 5, respectively. A mineral analysis of newly developed biopolymers showed a substantial amount of calcium (412 mg/100 g), potassium (418 mg/100 g), phosphorus (60 mg/100 g), iron (47 mg/100 g), zinc (16 mg/100 g), and sodium (9 mg/100 g). The significant antidiabetic potential of OMB was demonstrated using α-amylase and α-glucosidase enzyme inhibitory assay. Further investigations are required to explore the newly developed biopolymer for its toxicity, efficacy, and its possible utilization in food, nutraceutical, as well as pharmaceutical industries.


Assuntos
Abelmoschus/química , Mucilagem Vegetal/química , Mucilagem Vegetal/isolamento & purificação , Abelmoschus/metabolismo , Antioxidantes/química , Biopolímeros/análise , Biopolímeros/química , Suplementos Nutricionais , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/metabolismo , Extratos Vegetais/farmacologia , Polissacarídeos/química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , alfa-Amilases/química , alfa-Glucosidases/química
4.
Molecules ; 26(14)2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34299610

RESUMO

Recently, significant advances in modern medicine and therapeutic agents have been achieved. However, the search for effective antidiabetic drugs is continuous and challenging. Over the past decades, there has been an increasing body of literature related to the effects of secondary metabolites from botanical sources on diabetes. Plants-derived metabolites including alkaloids, phenols, anthocyanins, flavonoids, stilbenoids, saponins, tannins, polysaccharides, coumarins, and terpenes can target cellular and molecular mechanisms involved in carbohydrate metabolism. In addition, they can grant protection to pancreatic beta cells from damage, repairing abnormal insulin signaling, minimizing oxidative stress and inflammation, activating AMP-activated protein kinase (AMPK), and inhibiting carbohydrate digestion and absorption. Studies have highlighted many bioactive naturally occurring plants' secondary metabolites as candidates against diabetes. This review summarizes the current knowledge compiled from the latest studies published during the past decade on the mechanism-based action of plants-derived secondary metabolites that can target various metabolic pathways in humans against diabetes. It is worth mentioning that the compiled data in this review will provide a guide for researchers in the field, to develop candidates into environment-friendly effective, yet safe antidiabetics.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Compostos Fitoquímicos/uso terapêutico , Animais , Glicemia/análise , Diabetes Mellitus/sangue , Diabetes Mellitus/metabolismo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Compostos Fitoquímicos/química , Compostos Fitoquímicos/metabolismo , Compostos Fitoquímicos/farmacologia , Plantas/química , Plantas/metabolismo , Transdução de Sinais/efeitos dos fármacos
5.
FASEB J ; 35(7): e21645, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34105824

RESUMO

Peripheral arterial disease (PAD) is one of the major complications of diabetes due to an impairment in angiogenesis. Since there is currently no drug with satisfactory efficacy to enhance blood vessel formation, discovering therapies to improve angiogenesis is critical. An imidazolinone metabolite of the metformin-methylglyoxal scavenging reaction, (E)-1,1-dimethyl-2-(5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl) guanidine (IMZ), was recently characterized and identified in the urine of type-2 diabetic patients. Here, we report the pro-angiogenesis effect of IMZ (increased aortic sprouting, cell migration, network formation, and upregulated multiple pro-angiogenic factors) in human umbilical vein endothelial cells. Using genetic and pharmacological approaches, we showed that IMZ augmented angiogenesis by activating the endothelial nitric oxide synthase (eNOS)/hypoxia-inducible factor-1 alpha (HIF-1α) pathway. Furthermore, IMZ significantly promoted capillary density in the in vivo Matrigel plug angiogenesis model. Finally, the role of IMZ in post-ischemic angiogenesis was examined in a chronic hyperglycemia mouse model subjected to hind limb ischemia. We observed improved blood perfusion, increased capillary density, and reduced tissue necrosis in mice receiving IMZ compared to control mice. Our data demonstrate the pro-angiogenic effects of IMZ, its underlying mechanism, and provides a structural basis for the development of potential pro-angiogenic agents for the treatment of PAD.


Assuntos
Membro Posterior/fisiopatologia , Hiperglicemia/complicações , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isquemia/complicações , Metformina/metabolismo , Neovascularização Patológica/patologia , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Hipoglicemiantes/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Imidazolinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Aldeído Pirúvico/metabolismo
6.
Eur J Pharm Sci ; 164: 105915, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34146681

RESUMO

Ionic liquids (IL) technology provides a useful platform to achieve the topical delivery of therapeutic agents, because of its capability to improve skin permeability. While the majority of the researches aimed to achieve local action by topical IL delivery, systemic action of therapeutic agents by local topical application has rarely been reported. In the present work, Gliclazide (GLI), a second-generation sulfonylurea drug was transformed into an IL with tributyl(tetradecyl)phosphonium for the first time. The physicochemical properties of this IL were systematically characterized by DSC, TGA, FT-IR, NMR, and HPLC. The transdermal patch based on this IL was further prepared using DURO-TAK®87-4098. The fabricated gliclazide based ionic liquid [P6,6,6,14][GLI] transdermal patch displayed satisfactory in vitro and in vivo performance. The [P6,6,6,14][GLI] patch released 88.17% of the loaded drug within a 3-day period in the in vitro dissolution test, confirming its sustained release property. Meanwhile, GLI effectively permeated through the artificial skin from [P6,6,6,14][GLI] transdermal patch in the in vitro skin permeation test, with the permeation rate and lag time of 16.571 ± 0.328 µg/cm2/h and 3.027 ± 0.154 h respectively. The [P6,6,6,14][GLI] transdermal patch showed favorable PK profile in rat as compared with GLI oral suspension. The relative bioavailability of GLI reached 92.06% of GLI oral suspension, while the Cmax was significantly reduced. Most importantly, [P6,6,6,14][GLI] transdermal patch demonstrated superior hypoglycemic effect to the oral suspension both in the fasted and fed condition, confirming the feasibility of systemic action by local topical delivery of IL. In addition, the [P6,6,6,14][GLI] transdermal patch caused no skin irritation based on histopathological analysis.


Assuntos
Gliclazida , Líquidos Iônicos , Administração Cutânea , Animais , Preparações de Ação Retardada/metabolismo , Gliclazida/metabolismo , Hipoglicemiantes/metabolismo , Ratos , Pele/metabolismo , Absorção Cutânea , Espectroscopia de Infravermelho com Transformada de Fourier , Adesivo Transdérmico
7.
Eur J Med Chem ; 223: 113665, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34192642

RESUMO

New types of antidiabetic agents are continually needed with diabetes becoming the epidemic in the world. Indole alkaloids play an important role in natural products owing to their variable structures and versatile biological activities like anticonvulsant, anti-inflammatory, antidiabetic, antimicrobial, and anticancer activities, which are a promising source of novel antidiabetic drugs discovery. The synthesized indole derivatives possess similar properties to natural indole alkaloids. In the last two decades, more and more indole derivatives have been designed and synthesized for searching their bioactivities. This present review describes comprehensive structures of indole compounds with the potential antidiabetic activity including natural indole alkaloids and the synthetic indole derivatives based on the structure classification, summarizes their approaches isolated from natural sources or by synthetic methods, and discusses the antidiabetic effects and the mechanisms of action. Furthermore, this review also provides briefly synthetic procedures of some important indole derivatives.


Assuntos
Hipoglicemiantes/química , Indóis/química , Carbolinas/química , Carbolinas/metabolismo , Carbolinas/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/metabolismo , Hipoglicemiantes/uso terapêutico , Indóis/metabolismo , Indóis/uso terapêutico , PPAR alfa/química , PPAR alfa/metabolismo , PPAR gama/química , PPAR gama/metabolismo , Terpenos/química , Terpenos/metabolismo , Terpenos/uso terapêutico
8.
Eur J Med Chem ; 223: 113630, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34175538

RESUMO

In search of dually active PPAR-modulators/aldose reductase (ALR2) inhibitors, 16 benzylidene thiazolidinedione derivatives, previously reported as partial PPARγ agonists, together with additional 18 structural congeners, were studied for aldose reductase inhibitory activity. While no compounds had dual property, our efforts led to the identification of promising inhibitors of ALR2. Eight compounds (11, 15-16, 20-24, 30) from the library of 33 compounds were identified as potent and selective inhibitors of ALR2. Compound 21 was the most effective and selective inhibitor with an IC50 value of 0.95 ± 0.11 and 13.52 ± 0.81 µM against ALR2 and aldehyde reductase (ALR1) enzymes, respectively. Molecular docking and dynamics studies were performed to understand inhibitor-enzyme interactions at the molecular level that determine the potency and selectivity. Compound 21 was further subjected to in silico and in vitro studies to evaluate the pharmacokinetic profile. Being less acidic (pKa = 9.8), the compound might have a superior plasma membrane permeability and reach the cytosolic ALR2. This fact together with excellent drug-likeness criteria points to improved bioavailability compared to the clinically used compound Epalrestat. The designed compounds represent a novel group of non-carboxylate inhibitors of aldose reductase with an improved physicochemical profile.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Tiazolidinedionas/farmacologia , Aldeído Redutase/química , Aldeído Redutase/metabolismo , Animais , Células CACO-2 , Domínio Catalítico , Cães , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Células Madin Darby de Rim Canino , Masculino , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Ratos Wistar , Relação Estrutura-Atividade , Tiazolidinedionas/síntese química , Tiazolidinedionas/metabolismo , Tiazolidinedionas/farmacocinética
9.
Artigo em Inglês | MEDLINE | ID: mdl-34052752

RESUMO

Detailed metabolic profiling of needles of five Pinus species was investigated using complementary HPLC-MS/MS techniques together with supervised and unsupervised chemometric tools. This resulted in putative identification of 44 compounds belonging to flavonoids, phenolics, lignans, diterpenes and fatty acids. Unsupervised principal component analysis showed that differences were maintained across the metabolites characteristic of each Pinus species, are mainly related to di-O-p-coumaroyltrifolin, p-coumaroyl quinic acid derivative, arachidonic acid, hydroxypalmitic acid, isopimaric acid and its derivative. A supervised Partial Least Squares regression analysis was performed to correlate HPLC-MS/MS profiles with the variation observed in the in vitro anticholinesterase, antiaging and anti-diabetic potential. All investigated Pinus extracts exerted their antiaging activity via increasing telomerase and TERT levels in normal human melanocytes cells compared to the control (untreated cells). Profound inhibition activities of acetylcholinesterase and dipeptidyl peptidase-4 were also observed with P. pinea and P. canariensis extracts having comparable antidiabetic activities to sitagliptin as a standard antidiabetic drug. Our findings suggested that pine needles are a good source of phenolics and diterpenoids that have possible health promoting activities in management and alleviation of diabetic conditions and Alzheimer disease.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Metaboloma/fisiologia , Pinus , Espectrometria de Massas em Tandem/métodos , Inibidores da Colinesterase/análise , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Diterpenos/análise , Diterpenos/química , Diterpenos/metabolismo , Flavonoides/análise , Flavonoides/química , Flavonoides/metabolismo , Hipoglicemiantes/análise , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Metabolômica , Pinus/química , Pinus/metabolismo , Extratos Vegetais/química , Substâncias Protetoras/análise , Substâncias Protetoras/química , Substâncias Protetoras/metabolismo , Extração em Fase Sólida/métodos
10.
J Med Chem ; 64(8): 4312-4332, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33843223

RESUMO

The G-protein coupled receptors (GPCRs) activated by free fatty acids (FFAs) have emerged as new and exciting drug targets, due to their plausible translation from pharmacology to medicines. This perspective aims to report recent research about GPR120/FFAR4 and its involvement in several diseases, including cancer, inflammatory conditions, and central nervous system disorders. The focus is to highlight the importance of GPR120 in Type 2 diabetes mellitus (T2DM). GPR120 agonists, useful in T2DM drug discovery, have been widely explored from a structure-activity relationship point of view. Since the identification of the first reported synthetic agonist TUG-891, the research has paved the way for the development of TUG-based molecules as well as new and different chemical entities. These molecules might represent the starting point for the future discovery of GPR120 agonists as antidiabetic drugs.


Assuntos
Descoberta de Drogas , Hipoglicemiantes/química , Fenilpropionatos/química , Receptores Acoplados a Proteínas G/agonistas , Adipogenia , Animais , Ácidos Carboxílicos/química , Ácidos Carboxílicos/metabolismo , Ácidos Carboxílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/uso terapêutico , Ligantes , Camundongos , Fenilpropionatos/metabolismo , Fenilpropionatos/uso terapêutico , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico
11.
J Med Chem ; 64(9): 5863-5873, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33886333

RESUMO

Although multivalent glycosidase inhibitors have shown enhanced glycosidase inhibition activities, further applications and research directions need to be developed in the future. In this paper, two positional isomeric perylene bisimide derivatives (PBI-4DNJ-1 and PBI-4DNJ-2) with 1-deoxynojirimycin conjugated were synthesized. Furthermore, PBI-4DNJ-1 and PBI-4DNJ-2 showed positional isomeric effects on the optical properties, self-assembly behaviors, glycosidase inhibition activities, and hypoglycemic effects. Importantly, PBI-4DNJ-1 exhibited potent hypoglycemic effects in mice with 41.33 ± 2.84 and 37.45 ± 3.94% decreases in blood glucose at 15 and 30 min, respectively. The molecular docking results showed that the active fragment of PBI-4DNJ-1 has the highest binding energy (9.649 kcal/mol) and the highest total hydrogen bond energy (62.83 kJ/mol), which were related to the positional isomeric effect on the hypoglycemic effect in mice. This work introduced a new means to develop antihyperglycemic agents in the field of multivalent glycomimetics.


Assuntos
Glucosamina/análogos & derivados , Glicosídeo Hidrolases/metabolismo , Hipoglicemiantes/química , Imidas/química , Perileno/análogos & derivados , Administração Oral , Animais , Sítios de Ligação , Glicemia/análise , Glucosamina/química , Glicosídeo Hidrolases/antagonistas & inibidores , Ligação de Hidrogênio , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/metabolismo , Isomerismo , Cinética , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Perileno/química , Ligação Proteica , Termodinâmica
12.
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
13.
J Med Chem ; 64(8): 4947-4959, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33825469

RESUMO

Hapten-specific endogenous antibodies are naturally occurring antibodies present in human blood. Herein, we investigated a new strategy in which small-molecule haptens were utilized as naturally occurring antibody binders for peptide half-life extension. The glucagon-like peptide 1 receptor agonist exendin 4 was site-specifically functionalized with the dinitrophenyl (DNP) hapten at the C-terminus via sortase A-mediated ligation. The resulting Ex4-DNP conjugates retained GLP-1 receptor activation potency in vitro and had a similar in vivo acute glucose-lowering effect comparable to that of native Ex4. Pharmacokinetic studies and hypoglycemic duration tests demonstrated that the Ex4-DNP conjugates displayed significantly elongated half-lives and improved long-acting antidiabetic activity in the presence of endogenous anti-DNP antibodies. In chronic treatment studies, once-daily administration of optimal conjugate 7 demonstrated more beneficial effects without prominent toxicity compared with Ex4. This strategy provides a new approach and represents an alternative to the well-established peptide-Fc fusion strategy to improve the peptide half-life and the therapeutic efficacy.


Assuntos
Anticorpos/sangue , Exenatida/química , Haptenos/química , Hipoglicemiantes/síntese química , Sequência de Aminoácidos , Animais , Anticorpos/imunologia , Complexo Antígeno-Anticorpo/química , Complexo Antígeno-Anticorpo/metabolismo , Glicemia/análise , Diabetes Mellitus Experimental/tratamento farmacológico , Dinitrobenzenos/química , Dinitrobenzenos/imunologia , Desenho de Fármacos , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Teste de Tolerância a Glucose , Meia-Vida , Haptenos/imunologia , Hipoglicemiantes/metabolismo , Hipoglicemiantes/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL
14.
PLoS One ; 16(3): e0247619, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33661961

RESUMO

Thiazolidinediones are very important and used as a drug for the treatment of type 2 diabetes. Here, we report a convenient approach to synthesis 3-m-tolyl-5-arylidene-2,4-thiazolidinediones (TZDs) derivatives 7a-e in two steps with moderate to good yield using morpholine as a catalyst. All the structures were confirmed by their spectral IR, 1H NMR and 13C NMR data. The anti-diabatic activity of all synthesized molecules is evaluated by docking with peroxisome proliferator-activated receptor-γ (PPARγ). Preliminary flexible docking studies reveals that our compounds 7a, 7d and 7e showed better binding affinity with the protein and could be a potential candidate for the treatment of type 2 diabetes in near future.


Assuntos
Hipoglicemiantes/química , Morfolinas/química , Tiazolidinedionas/química , Tiazolidinas/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13/métodos , Catálise , Hipoglicemiantes/síntese química , Hipoglicemiantes/metabolismo , Modelos Químicos , Simulação de Acoplamento Molecular , Estrutura Molecular , PPAR gama/química , PPAR gama/metabolismo , Ligação Proteica , Espectroscopia de Prótons por Ressonância Magnética/métodos , Espectrofotometria Infravermelho/métodos , Relação Estrutura-Atividade , Tiazolidinedionas/síntese química , Tiazolidinedionas/metabolismo
15.
J Med Chem ; 64(7): 4130-4149, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33769827

RESUMO

G-protein-coupled receptor 40 (GPR40) is considered as an attractive drug target for treating type 2 diabetes, owing to its role in the free fatty acid-mediated increase in glucose-stimulated insulin secretion (GSIS) from pancreatic ß-cells. To identify a new chemotype of GPR40 agonist, a series of 2-aryl-substituted indole-5-propanoic acid derivatives were designed and synthesized. We identified two GPR40 agonist lead compounds-4k (3-[2-(4-fluoro-2-methylphenyl)-1H-indol-5-yl]propanoic acid) and 4o (3-[2-(2,5-dimethylphenyl)-1H-indol-5-yl]propanoic acid), having GSIS and glucagon-like peptide 1 secretory effects. Unlike previously reported GPR40 partial agonists that only activate the Gq pathway, 4k and 4o activated both the Gq and Gs signaling pathways and were characterized as GPR40 full agonists. In in vivo efficacy studies, 4o significantly improved glycemic control in both C57BL/6J and db/db mice and increased plasma-active GLP-1 in C57BL/6J mice. Thus, 4o represents a promising lead for further development as a novel GPR40 full agonist against type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Indóis/uso terapêutico , Propionatos/uso terapêutico , Receptores Acoplados a Proteínas G/agonistas , Animais , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipoglicemiantes/síntese química , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacocinética , Indóis/síntese química , Indóis/metabolismo , Indóis/farmacocinética , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Propionatos/síntese química , Propionatos/metabolismo , Propionatos/farmacocinética , Ligação Proteica , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-Atividade
16.
Food Chem ; 355: 129496, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33780793

RESUMO

Metabolite profiles of green beans (the caged and the wild) Luwak (civet) coffees were evaluated by NMR techniques combined with chemometrics. The bioactivities of the green coffee beans were examined with antioxidant tests and an alpha-glucosidase inhibitory assay. Both are invitro tests related to the antidiabetic properties. Our results showed the civet coffees possessed unique metabolomes and were different from the regular arabica coffee. Both civet coffees were characterized by higher concentrations of alanine, citrate, lactate, malate, and trigonelline. Lactate and lipids were found as the most important compounds discriminating the caged civet coffee from the wild civet coffee. Bioactivity assays exhibited the antidiabetic activities of the civet coffees were better than the activity of the regular coffee. These results suggested that the civet coffees are promising functional foods reducing the diabetes risk. It is the first report evaluating metabolite profiles of both civet coffees using 1H NMR-based metabolomics.


Assuntos
Coffea/metabolismo , Hipoglicemiantes/metabolismo , Metabolômica , Animais , Espectroscopia de Ressonância Magnética
17.
Biochem Pharmacol ; 189: 114453, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33545119

RESUMO

A novel PMet-P(cdmPEG2K) polymeric micellar carrier was developed for tumor-targeted co-delivery of DOX and nucleic acids (NA), based on polymetformin and a structure designed to lose the PEG shell in response to the acidic extracellular tumor environment. NA/DOX co-loaded micelleplexes exhibited enhanced inhibition of cell proliferation compared to DOX-loaded micelles, and displayed a higher level of cytotoxicity at an acidic pH (6.8) which mimicks the tumor microenvironment. The PMet-P(cdmPEG2K) micelles achieved significantly improved transfection with either a reporter plasmid or Cy3-siRNA, and enhanced DOX intracellular uptake in 4T1.2 cells at pH 6.8. Importantly, PMet-P(cdmPEG2K) micelles showed excellent pEGFP (EGFP expression plasmid) transfection in an aggressive murine breast cancer (4T1.2) model. By using a plasmid encoding IL-12 (pIL-12), we investigated the combined effect of chemotherapy and gene therapy. PMet-P(cdmPEG2K) micelles co-loaded with DOX and pIL-12 were more effective at inhibiting tumor growth compared to micelles loaded with DOX or pIL-12 alone. In addition, this micellar system was effective in co-delivery of siRNA and DOX into tumor cells. Our results suggest that PMet-P(cdmPEG2K) has the potential for chemo and nucleic acid combined cancer therapy.


Assuntos
Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Micelas , Ácidos Nucleicos/administração & dosagem , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Doxorrubicina/química , Doxorrubicina/metabolismo , Feminino , Concentração de Íons de Hidrogênio , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Metformina/química , Metformina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ácidos Nucleicos/química , Ácidos Nucleicos/metabolismo
18.
Eur J Med Chem ; 215: 113269, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33588177

RESUMO

Diabetic nephropathy (DN) is resulted from activations of polyol pathway and oxidative stress by abnormal metabolism of glucose, and no specific medication is available. We designed a novel class of benzoxazolone derivatives, and a number of individuals were found to have significant antioxidant activity and inhibition of aldose reductase of the key enzyme in the polyol pathway. The outstanding compound (E)-2-(7-(4-hydroxy-3-methoxystyryl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid was identified to reduce urinary proteins in diabetic mice suggesting an alleviation in the diabetic nephropathy, and this was confirmed by kidney hematoxylin-eosin staining. Further investigations showed blood glucose normalization, declined in the polyol pathway and lipid peroxides, and raised glutathione and superoxide dismutase activity. Thus, we suggest a therapeutic function of the compound for DN which could be attributed to the combination of hypoglycemic, aldose reductase inhibition and antioxidant.


Assuntos
Antioxidantes/uso terapêutico , Benzoxazóis/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Aldeído Redutase/antagonistas & inibidores , Aldeído Redutase/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/metabolismo , Benzoxazóis/síntese química , Benzoxazóis/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Células HEK293 , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade
19.
Life Sci ; 271: 119182, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33577851

RESUMO

Glitazones are synthetic derivatives of thiazolidinedione, and are designated as oral anti-diabetic agents, primarily acting on peroxisome proliferator-activated receptor-gamma (PPAR-γ) receptors and driving some crucial metabolic pathways linked to glucose and lipid metabolism at transcriptional level. Despite presenting adverse effects, including weight gain, fluid retention, prostate hyperplasia, hyperinsulinemia, and myocardial infarction, they are still preferred in clinical settings due to their utmost efficacy and selectivity. However, these complications kept glitazones restrained for long-term usage. The present review briefly highlights some important synthetic derivatives of thiazolidine2,4-dione and emphasizes the influence of various structural manipulations on their bio-efficacy.


Assuntos
Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Tiazolidinedionas/química , Tiazolidinedionas/metabolismo , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Glucose/antagonistas & inibidores , Glucose/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Resistência à Insulina/fisiologia , PPAR gama/metabolismo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Tiazolidinedionas/uso terapêutico
20.
J Sci Food Agric ; 101(10): 4193-4200, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-33420740

RESUMO

BACKGROUND: Postprandial hyperglycemia and decreased insulin secretion are relevant to risk factors in the development of type 2 diabetes and its complications. Plant foods with antidiabetic properties could be an affordable alternative in the prevention and treatment of this disease. In the present study, the antihyperglycemic and hypoglycemic activity of Bixa orellana, Psidium guajava L., Cucurbita moschata, Raphanus sativus L. and Brassica oleracea var. capitata - Mayan plant foods - were evaluated at doses of 5 and 10 mg kg-1 . Antihyperglycemic activity was measured in healthy Wistar rats and those with obesity induced by high-sucrose diet (group HSD) (20%). The hypoglycemic activity was measure in healthy CD1 mice. RESULTS: Fasting glucose, Lee index and the body weight of HSD rats increased significantly (P ≤ 0.05) after 12 weeks of induction compared to healthy rats. In healthy rats, P. guajava and Bixa orellana (10 mg kg-1 ) demonstrated higher and statistically different (P ≤ 0.05) antihyperglycemic activity compared to control acarbose (0.5 mg kg-1 ). In the HSD rat group, all Mayan plant foods (10 mg kg-1 ) demonstrated antihyperglycemic activity statistically equal (P ≤ 0.05) to control acarbose. However, Brassica oleracea and R. sativus registered the highest antihyperglycemic activity. Bixa orellana and P. guajava (5 mg kg-1 ) showed similar hypoglycemic activity (P ≤ 0.05) to glibenclamide (0.5 mg kg-1 ) but was not significant (P ≤ 0.05) compared to insulin (5 UI kg-1 ). CONCLUSION: The present study provides valuable evidence on the possible health benefits of Mayan plant foods. These foods could contribute to the development of therapeutic diet strategies for the prevention and treatment of diabetes. © 2021 Society of Chemical Industry.


Assuntos
Bixaceae/metabolismo , Brassica/metabolismo , Cucurbita/metabolismo , Diabetes Mellitus Tipo 2/dietoterapia , Hipoglicemiantes/metabolismo , Obesidade/dietoterapia , Psidium/metabolismo , Raphanus/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Insulina/metabolismo , Masculino , México , Obesidade/metabolismo , Ratos , Ratos Wistar
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