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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 ; 328: 127076, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32480257

RESUMO

The tunillo (Stenocereus stellatus [Pfeiffer] Riccobono) is a relatively little known cactus fruit with a significant pharmacological potential. However, all currently known variants are identified visually mostly on the basis of pulp color. Differences in chemical composition and pharmacological properties also remain largely unknown. Support vector machine classifiers were applied to UV-Visible spectra of liquid samples to obtain the following, color-based categories of tunillo fruits: A1-white, A2-red, A3-purple, and A4-orange. The spectrum of A2-red could be duplicated by combining those from A3-purple and A4-orange, while UPGMA-based hierarchical clustering of psbA-trnH and matK suggested that certain differences in color might actually have a genetic basis. The pigment quantification established A2-red and A3-purple as the most suitable candidates for the extraction of betalains and complex colored matrices, respectively. A2-red also had the highest content of phenols and flavonoids and displayed a noticeable anti-hyperglycemic effect.


Assuntos
Cactaceae/química , Frutas/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Cor , Secas , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , México
3.
PLoS One ; 15(6): e0233963, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32530961

RESUMO

Eclipta alba L., also known as false daisy, is well known and commercially attractive plant with excellent hepatotoxic and antidiabetic activities. Light is considered a key modulator in plant morphogenesis and survival by regulating important physiological cascades. Current study was carried out to investigate growth and developmental aspects of E. alba under differential effect of multispectral lights. In vitro derived callus culture of E. alba was exposed to multispectral monochromatic lights under controlled aseptic conditions. Maximum dry weight was recorded in culture grown under red light (11.2 g/L) whereas negative effect was observed under exposure of yellow light on callus growth (4.87 g/L). Furthermore, red light significantly enhanced phenolics and flavonoids content (TPC: 57.8 mg/g, TFC: 11.1 mg/g) in callus cultures compared to rest of lights. HPLC analysis further confirmed highest accumulation of four major compounds i.e. coumarin (1.26 mg/g), eclalbatin (5.00 mg/g), wedelolactone (32.54 mg/g) and demethylwedelolactone (23.67 mg/g) and two minor compounds (ß-amyrin: 0.38 mg/g, luteolin: 0.39 mg/g) in red light treated culture whereas stigmasterol was found optimum (0.22 mg/g) under blue light. In vitro based biological activities including antioxidant, antidiabetic and lipase inhibitory assays showed optimum values in cultures exposed to red light, suggesting crucial role of these phytochemicals in the enhancement of the therapeutic potential of E. alba. These results clearly revealed that the use of multispectral lights in in vitro cultures could be an effective strategy for enhanced production of phytochemicals.


Assuntos
Antioxidantes/metabolismo , Eclipta/metabolismo , Eclipta/efeitos da radiação , Hipoglicemiantes/metabolismo , Compostos Fitoquímicos/metabolismo , Antioxidantes/química , Cumarínicos/metabolismo , Eclipta/crescimento & desenvolvimento , Flavonoides/metabolismo , Hipoglicemiantes/química , Luz , Fenóis/metabolismo , Compostos Fitoquímicos/química , Metabolismo Secundário/efeitos da radiação , Técnicas de Cultura de Tecidos
4.
PLoS One ; 15(6): e0235221, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584888

RESUMO

Ficus krishnae stem bark and leaves are used for diabetes treatment in traditional medicines. Stem bark of F. krishnae was sequentially extracted with hexane, methanol and water, and these extracts were tested for their antihyperglyceamic activity by oral glucose tolerance test (OGTT) in overnight fasted glucose loaded normal rats. Hexane extract showed significant glucose lowering activity in OGTT, and the triterpene alcohols (cycloartenol+24-methylenecycloartanol) (CA+24-MCA) were isolated together from it by activity guided isolation and characterized by NMR and mass spectroscopy. The ratio of the chemical constituents CA and 24-MCA in (CA+24-MCA) was determined as 2.27:1.00 by chemical derivatization and gas chromatographic quantification. (CA+24-MCA) in high fat diet-streptozotocin induced type II diabetic rats showed significant antidiabetes activity at 1 mg/kg and ameliorated derailed blood glucose and other serum biochemical parameters. Cytoprotective activity of (CA+24-MCA) from glucose toxicity was evaluated in cultured RIN-5F cells by MTT assay and fluorescent microscopy. (CA+24-MCA) in in vitro studies showed enhanced cell viability in RIN-5F cells and significant protection of beta cells from glucose toxicity. Both in in vivo and in vitro studies (CA+24-MCA) showed enhancement in insulin release from the beta cells. In short term toxicity studies in mice (CA+24-MCA) did not show any conspicuous toxic symptoms. The combination of the phytosterols (CA+24-MCA) obtained through activity guided isolation of the stem bark of F. krishnae showed significant activity, and therefore is a promising candidate for new generation antidiabetes drug development.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Ficus/química , Hipoglicemiantes/uso terapêutico , Fitosteróis/química , Triterpenos/química , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Ficus/metabolismo , Teste de Tolerância a Glucose , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Conformação Molecular , Fitosteróis/isolamento & purificação , Fitosteróis/uso terapêutico , Caules de Planta/química , Caules de Planta/metabolismo , Ratos , Ratos Wistar , Triterpenos/isolamento & purificação , Triterpenos/uso terapêutico
5.
Life Sci ; 256: 117910, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32504753

RESUMO

AIMS: Insulin (Ins) covalently modified by catecholestrogens (CEs) was commonly found in diabetic patients who have developed insulin resistance. Estrogenization of insulin altered its molecular function and effect carbohydrates metabolisms in these patients. Insulin resistance is a common phenomenon in diabetes but the exact mechanism remains unknown. In this study, binding specificity and affinity of autoantibodies against estrogenized insulin (4-hydroxyestradiol-insulin; 4-OHE2-Ins) were assayed in the serum of type 1 diabetes (T1D) patients in order to explain the phenomena behind insulin resistance. MATERIALS AND METHODS: Specificity and affinity of autoantibodies from the sera of 66 T1D patients and 41 controls were analyzed by direct binding, competition ELISA and quantitative precipitin titration. Insulin was also estimated in the serum of T1D patients by ELISA. KEY FINDING: Estrogenized insulin (4-OHE2-Ins) exhibited high affinity and specificity to T1D autoantibodies in comparison to Ins (p < .05) or 4-OHE2 (p < .001). Estrogenization of insulin alters its interaction with the insulin receptor (IR). The affinity constant of 4-OHE2-Ins with the T1D autoantibodies was found to be 1.41 × 10-7 M. SIGNIFICANCE: Estrogenization of insulin by catecholestrogen makes these molecules highly antigenic and produced high-affinity autoantibodies in T1D patients. As a result, patients develop insulin resistance and presented this molecule as a potential biomarker for T1D.


Assuntos
Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Estrogênios de Catecol/química , Hipoglicemiantes/química , Insulina/química , Adulto , Autoanticorpos/metabolismo , Biomarcadores/metabolismo , Glicemia/análise , Coleta de Amostras Sanguíneas , Proposta de Concorrência , Ensaio de Imunoadsorção Enzimática , Estrogênios de Catecol/uso terapêutico , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Receptor de Insulina/imunologia , Receptor de Insulina/metabolismo , Sensibilidade e Especificidade
6.
Life Sci ; 256: 117853, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470452

RESUMO

AIMS: To investigate the diabetes-protective effect and weight-lowering potential of a novel long-acting triagonist at three metabolically related hormone receptors including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon receptors. MAIN METHODS: Triagonist were designed in an iterative manner from native GLP-1, GIP and Glucogan. Main peptide chain (termed TG peptides) and subsequently modified LTG peptides were synthesized via solid phase synthesis. In vitro receptor activity assay was performed to screen the TG peptide with most balanced potency on all three receptors. The in vitro biological activities of modified TG peptides were further investigated by albumin-binding measurement and proteolytic cleavage test. Subsequently, oral glucose tolerance test (OGTT), pharmacokinetic test and chronic study were subjected to the acute and long-term efficacy evaluation of selected fusion peptide, LTG-6. KEY FINDINGS: TG-8 exhibited equally aligned constituent efficacy and supraphysiological potency on corresponding receptor without cross-reactivity. Modified TG-8, termed LTG-6, exerted the great binding affinity for human serum albumin and the enhanced rational controlled-release of TG-8 in vitro. Further OGTT in different gene knockout mice and diabetic mice demonstrated the promising hypoglycemic and insulinotropic abilities of LTG-6. After long-term treatment for 8 weeks, LTG-6 was proved superior to co-agonists to decrease the body weight and %HbA1c, improve reverse dyslipidemia and glycemic control in the DIO models. SIGNIFICANCE: LTG-6, as a newly designed long-acting triagonist, holds potential to correct the obesity related metabolic disorders.


Assuntos
Diabetes Mellitus Experimental/prevenção & controle , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos/farmacologia , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores de Glucagon/agonistas , Animais , Peso Corporal/efeitos dos fármacos , Teste de Tolerância a Glucose , Células HEK293 , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Doenças Metabólicas/etiologia , Doenças Metabólicas/prevenção & controle , Camundongos , Camundongos Knockout , Obesidade/complicações , Obesidade/tratamento farmacológico , Peptídeos/química , Ratos , Ratos Sprague-Dawley , Trombina/química
7.
Zhongguo Zhong Yao Za Zhi ; 45(6): 1368-1373, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32281350

RESUMO

Eight compounds,(R)-2-[5-(methoxycarbonyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]acetic acid(1),(3S,4R)-3,4-dihydro-3,4-epoxy-5-hydroxynaphthalen-1(2H)-one(2),(-)-mitorubrinol(3),(-)-mitorubrin(4),(±)-asperlone A(5), terreusinone(6), verrucisidinol(7) and cerebroside C(8) were isolated from the endophytic fungus Talaromyces purpurogenus by using various column chromatographic techniques. Their structures were identified by NMR, MS, CD and optical rotation. Compounds 1 and 2 were new compounds. Their anti-diabetic activities in vitro were evaluated, and compound 1 showed moderate inhibitory activity toward XOD at 10 µmol·L~(-1) with the inhibition rate of 69.9%.


Assuntos
Talaromyces/química , Tylophora/microbiologia , Endófitos/química , Hipoglicemiantes/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Metabolismo Secundário , Xantina Oxidase/antagonistas & inibidores
8.
Arch Biochem Biophys ; 686: 108364, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32315653

RESUMO

Fucoxanthin (Fx), a major carotenoid found in brown seaweed, is known to show a unique and wide variety of biological activities. Upon absorption, Fx is metabolized to fucoxanthinol and amarouciaxanthin, and these metabolites mainly accumulate in visceral white adipose tissue (WAT). As seen in other carotenoids, Fx can quench singlet oxygen and scavenge a wide range of free radicals. The antioxidant activity is related to the neuroprotective, photoprotective, and hepatoprotective effects of Fx. Fx is also reported to show anti-cancer activity through the regulation of several biomolecules and signaling pathways that are involved in either cell cycle arrest, apoptosis, or metastasis suppression. Among the biological activities of Fx, anti-obesity is the most well-studied and most promising effect. This effect is primarily based on the upregulation of thermogenesis by uncoupling protein 1 expression and the increase in the metabolic rate induced by mitochondrial activation. In addition, Fx shows anti-diabetic effects by improving insulin resistance and promoting glucose utilization in skeletal muscle.


Assuntos
Suplementos Nutricionais/análise , Alga Marinha/química , Xantofilas/química , Xantofilas/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/metabolismo , Antioxidantes/química , Antioxidantes/metabolismo , Descoberta de Drogas , Radicais Livres/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Resistência à Insulina , Fígado/metabolismo , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Depuradores/metabolismo , Oxigênio Singlete/metabolismo , Proteína Desacopladora 1/química , Proteína Desacopladora 1/metabolismo , Xantofilas/efeitos adversos , beta Caroteno/análogos & derivados , beta Caroteno/química
9.
Life Sci ; 253: 117651, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32304764

RESUMO

AIMS: To investigate the combination of dimerization and PEGylation to enhance the receptor activation and in vivo stability of Oxyntomodulin (OXM). MAIN METHODS: All LDM peptides were produced by using standard method of solid phase synthesis. The in vitro effects of LDM peptides were assessed by glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GcgR) binding test and Proteolytic stability test. Subsequently, saline, Liraglutide and three doses of LDM-3 treated groups were subjected to the evaluation of aute and long-term efficacy. KEY FINDINGS: Five long-acting OXM conjugates, termed LDM-1 to LDM-5, were designed using cysteine (Cys)-specific modification reaction including the activated PEG, bisMal-NH2, and OXM-Cys, and all prepared with high purity. LDM-3 exhibited greater GLP-1R and GcgR activation and ameliorative serum stability. In addition, LDM-3 was identified with enhanced insulinotropic and glycemic abilities in the gene knockout mice. The prolonged glucose-lowering effects of the LDM-3 were proved by hypoglycemic duration test and multiple oral glucose tolerance tests (OGTTs) in the diet-induced obesity (DIO) mice. Furthermore, the pharmacokinetic tests in Sprague Dawley (SD) rat and cynomolgus monkey exhibited the lifespans of LDM-3 at 90 nmol·kg-1 were 101.5 h and 119.4 h, respectively. Nevertheless, consecutive 8-week administration of LDM-3 improved the cumulative body weight gain, food intake, % HbA1c, glucose tolerance and the pancreatic of the obese mice. SIGNIFICANCE: LDM-3, as a dual GLP-1R and GcgR agonist, holds potential to be developed as a promising therapeutic candidate for both diabetes and obesity.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hipoglicemiantes/química , Oxintomodulina/química , Receptores de Glucagon/metabolismo , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus/metabolismo , Dimerização , Glucagon/metabolismo , Teste de Tolerância a Glucose , Hipoglicemiantes/farmacocinética , Macaca fascicularis , Masculino , Camundongos , Camundongos Knockout , Camundongos Obesos , Obesidade/metabolismo , Oxintomodulina/farmacocinética , Polietilenoglicóis/química , Ratos Sprague-Dawley , Técnicas de Síntese em Fase Sólida , Perda de Peso/efeitos dos fármacos
10.
Bol. latinoam. Caribe plantas med. aromát ; 19(2): 188-206, mar. 2020. ilus, tab
Artigo em Inglês | LILACS | ID: biblio-1104201

RESUMO

The present study aimed to screen the Rhazya stricta Decne root for its antihyperglycemic and antioxidants potential through invitro assays along with phytochemical and elemental analyses. The crude extract was prepared through maceration and fractionated using solvent-solvent extraction technique. The spectroscopic studies indicated the presence of various phytochemical classes in the extract and its fractions. The antioxidant assays showed notable results along with a good concentration of phenolic and flavonoid contents. Enzyme inhibition assays demonstrated glucose-lowering effects by inhibiting the enzyme activity which could reduce post-prandial blood glucose level. The Dipeptidyl peptidase-IV (DPP-IV) inhibition assay results showed the novel DPP-IV inhibition activity of the plant extract and all fractions showed noteworthy enzyme inhibition and antihyperglycemic activity. Conclusively, the Rhazya stricta root extract displayed its antioxidant and antihyperglycemic potential due to the presence of various classes of phytochemicals and micro-nutrients.


El presente estudio tuvo como objetivo examinar la raíz de Rhazya stricta Decne por su potencial antihiperglicémico y antioxidante a través de ensayos in vitro junto con análisis fitoquímicos y elementales. El extracto crudo se preparó por maceración y se fraccionó usando una técnica de extracción solvente-solvente. Los estudios espectroscópicos indicaron la presencia de varias clases fitoquímicas en el extracto y sus fracciones. Los ensayos antioxidantes mostraron resultados notables junto con una importante concentración de contenido fenólico y flavonoide. Los ensayos de inhibición enzimática demostraron efectos reductores de la glucosa al inhibir la actividad enzimática que podría reducir el nivel de glucosa posprandial en sangre. Los resultados del ensayo de inhibición de Dipeptidyl peptidase-IV (DPP-IV) mostraron la nueva actividad de inhibición de DPP-IV del extracto de la planta y todas las fracciones mostraron una notable inhibición enzimática y actividad antihiperglicémica. En conclusión, el extracto de raíz de Rhazya stricta Decne mostró su potencial antioxidante y antihiperglicémico debido a la presencia de varias clases de fitoquímicos y micronutrientes.


Assuntos
Extratos Vegetais/farmacologia , Apocynaceae/química , Hipoglicemiantes/farmacologia , Antioxidantes/farmacologia , Fenóis/análise , Espectrofotometria Ultravioleta , Flavonoides/análise , Glicemia/efeitos dos fármacos , Técnicas In Vitro , Extratos Vegetais/química , Espectroscopia de Infravermelho com Transformada de Fourier , Raízes de Plantas/química , Dipeptidil Peptidases e Tripeptidil Peptidases/antagonistas & inibidores , Compostos Fitoquímicos , Hipoglicemiantes/química , Antioxidantes/química
11.
J Food Sci ; 85(4): 1060-1069, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32147838

RESUMO

Inonotus obliquus is a traditional mushroom well known for its therapeutic value. In this study, various solvent fractions of I. obliquus were preliminarily screened for their antioxidant, α-amylase and α-glucosidase inhibition properties. To improve the drug delivery, the active fraction (ethyl acetate fraction) of I. obliquus was synthesized into fungisome (ethyl acetate phophotidyl choline complex, EAPC) and its physical parameters were assessed using Fourier transform infrared spectroscopy (FTIR), High performance liquid chromatography (HPLC), Scanning electron microscope (SEM), and ς potential analysis. Then normal human hepatic L02 cells was used to evaluate the cytotoxicity of EAPC. The results showed that EA fraction possesses significant free radical scavenging, α-amylase and α-glucosidase inhibition properties. FTIR, SEM, and HPLC analysis confirmed the fungisome formation. The particle size of EAPC was 102.80 ± 0.42 nm and the ς potential was -54.30 ± 0.61 mV. The percentage of drug entrapment efficiency was 97.13% and the drug release rates of EAPC in simulated gastric fluid and simulated intestinal fluid were 75.04 ± 0.29% and 93.03 ± 0.36%, respectively. EAPC was nontoxic to L02 cells, however it could selectively fight against the H2 O2 induced oxidative damage in L02 cells. This is the first study to provide scientific information to utilize the active fraction of I. obliquus as fungisome. PRACTICAL APPLICATIONS: Inonotus obliquus (IO) is a traditional medicinal fungus. The extracts of IO have obvious antioxidant and hypoglycemic activities. Ethyl acetate (EA) fraction of IO was encapsulated in liposomes to form EAPC. EAPC has a sustained-release effect. It has nontoxic to L02 cells and could protect L02 cells from oxidative damage caused by hydrogen peroxide. This study could provide new ideas for the treatment of diabetes.


Assuntos
Agaricales/química , Antioxidantes/farmacologia , Basidiomycota/química , Inibidores Enzimáticos/farmacologia , Peróxido de Hidrogênio/toxicidade , Extratos Vegetais/farmacologia , alfa-Amilases/antagonistas & inibidores , Antioxidantes/química , Antioxidantes/isolamento & purificação , Linhagem Celular , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , alfa-Amilases/química , alfa-Glucosidases/química
12.
Z Naturforsch C J Biosci ; 75(3-4): 103-112, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32187019

RESUMO

The current study aimed to evaluate the in vivo hypoglycemic potential of Myristica fragrans seed extract co-administered with glimepiride in Swiss albino mice. Computational tools were used to further verify the in vivo findings and to help compare this combination to the glimepiride-pioglitazone combination in terms of the binding affinity of the ligands to their respective target protein receptors and the relative stability of the drug-protein complexes. The effect of the combined therapy was observed both in alloxan- and glucose-induced hyperglycemic Swiss albino mice. The mean fasting blood glucose level of the test groups was measured and statistically evaluated using Student's t test. The combined therapy significantly reduced the blood glucose level in a time-dependent manner compared to glimepiride alone. The binding affinity of glimepiride was found to be -7.6 kcal/mol with sulfonylurea receptor 1 in molecular docking. Conversely, macelignan-peroxisome proliferator-activated receptor (PPAR) α and macelignan-PPAR γ complexes were stabilized with -9.2 and -8.3 kcal/mol, respectively. Molecular dynamic simulation revealed that macelignan-PPAR α and γ complexes were more stable than pioglitazone complexes. The combination shows promise in animal and computer models and requires further trials to provide evidence of its activity in humans.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Lignanas/administração & dosagem , Myristica/química , Compostos de Sulfonilureia/administração & dosagem , Aloxano/efeitos adversos , Animais , Diabetes Mellitus Tipo 2/induzido quimicamente , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Glucose/efeitos adversos , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Lignanas/química , Lignanas/farmacologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , PPAR alfa/metabolismo , PPAR gama/metabolismo , Pioglitazona/administração & dosagem , Pioglitazona/farmacologia , Extratos Vegetais/química , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacologia , Fatores de Tempo
13.
Diabetes Res Clin Pract ; 162: 108090, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32088311

RESUMO

AIMS: To determine the time elapsed from when a patient ≥ 65 years old is diagnosed with type 2 diabetes mellitus (T2DM) and begins antidiabetic treatment until a change in treatment is required as well as the factors associated with the change. METHODS: A retrospective study was conducted on patients 65 years or older with a first-time diagnosis of T2DM, and these patients were followed for 60 months until an addition or change was made to their antidiabetic drug regimen. Kaplan-Meier survival analysis was performed to determine the time elapsed until such a modification occurred. RESULTS: We identified 13,573 patients with a mean age of 76.8 ± 7.7 years; 59.3% were women. A total of 9144 (67.4%) patients began treatment with a single antidiabetic drug, 4146 (30.5%) began with two, and 282 (2.1%) began with three, especially metformin (n = 10858, 80.0%), sulfonylureas (n = 4525, 33.3%), and insulins (n = 2334, 17.2%). A total of 52.4% (n = 7106) of the patients underwent treatment modification (addition, 39.3% and change, 13.1%). Only 11.2% (n = 600) of the additions corresponded to new antidiabetic drugs (GLP-1 receptor agonists, SGLT2 inhibitors, DPP4 inhibitors). The mean time to modification was 39.1 ± 23.4 months, and the modification occurred earlier in those who started with various antidiabetic agents (33.2 vs. 42.6 months; p < 0.001), men (38.3 vs. 40.4 months; p < 0.001), and those who took glibenclamide vs. metformin (31.9 vs. 44.6 months, p < 0.001). CONCLUSIONS: Most elderly adults who were diagnosed with T2DM after 65 years of age were treated with the appropriate medications. Therapy was modified for more than half of the patients, The addition of new antidiabetic drugs was infrequent.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/classificação , Hipoglicemiantes/uso terapêutico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/diagnóstico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Quimioterapia Combinada , Feminino , Glibureto/uso terapêutico , Humanos , Hipoglicemiantes/química , Insulina/uso terapêutico , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Taxa de Sobrevida , Fatores de Tempo
14.
J Med Chem ; 63(6): 2958-2973, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32077280

RESUMO

Autoimmune deficiency and destruction in either ß-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting ß-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. In vitro, GNF2133 is able to proliferate both rodent and human ß-cells. In vivo, GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).


Assuntos
Compostos Aza/química , Compostos Aza/farmacologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Indóis/química , Indóis/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Compostos Aza/farmacocinética , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus Tipo 1/metabolismo , Humanos , Hipoglicemiantes/farmacocinética , Indóis/farmacocinética , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Simulação de Acoplamento Molecular , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar
15.
Food Chem ; 317: 126411, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32087517

RESUMO

Widely used throughout the world as traditional medicine for treating a variety of diseases ranging from cancer to microbial infections, members of the Tradescantia genus show promise as sources of desirable bioactive compounds. The bioactivity of several noteworthy species has been well-documented in scientific literature, but with nearly seventy-five species, there remains much to explore in this genus. This review aims to discuss all the bioactivity-related studies of Tradescantia plants and the compounds discovered, including their anticancer, antimicrobial, antioxidant, and antidiabetic activities. Gaps in knowledge will also be identified for future research opportunities.


Assuntos
Plantas Medicinais/química , Tradescantia/química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Medicina Tradicional
16.
Food Funct ; 11(2): 1560-1571, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32003379

RESUMO

Previously, we have reported the opposite effects of compounds isolated from Lagerstroemia speciosa leaves on a glucose transport (GLUT4) assay. Ellagitannins from L. speciosa activated GLUT4, while ellagic acid derivatives showed an inhibitory effect. As part of our continuing research on anti-diabetic nutritional supplements, we herein compared the anti-diabetic effects of several extracts (LE1-8) from leaves of L. speciosa using different manufacturing processes based on the contents of ellagitannins and ellagic acid derivatives. Their anti-diabetic effects were evaluated through glucose uptake and adipocyte differentiation in 3T3-L1 cells in vitro as well as alloxan induced diabetic mice in vivo. These extracts were given to mice by gavage at doses of 0.25, 1.0, and 4.0 g per kg body weight once a day for 21 consecutive days. Results showed that LE1 (1.0 g kg-1), LE3 (1.0 or 4.0 g kg-1), LE4 (1.0 or 4.0 g kg-1), LE5 (0.25 or 1.0 or 4.0 g kg-1) and LE7 (1.0 or 4.0 g kg-1) showed significant anti-diabetic effects in alloxan-induced diabetic mice as indicated by the decreased levels of fasting blood glucose, body weight, serum biomarkers, tissue weight and body fat, and increased final insulin levels. LE8 (1.0 g kg-1) showed a moderate anti-diabetic effect as illustrated by the reduced fasting blood glucose level while LE2 and LE6 showed slight effects in alloxan-induced diabetic mice. The potential correlation of the content of ellagitannins, ellagic acid derivatives, and corosolic acid with the anti-diabetic activity was discussed.


Assuntos
Ácido Elágico , Taninos Hidrolisáveis , Hipoglicemiantes , Lagerstroemia/química , Extratos Vegetais , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Ácido Elágico/química , Ácido Elágico/farmacocinética , Ácido Elágico/farmacologia , Taninos Hidrolisáveis/química , Taninos Hidrolisáveis/farmacocinética , Taninos Hidrolisáveis/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Extratos Vegetais/química , Extratos Vegetais/farmacocinética , Extratos Vegetais/farmacologia , Folhas de Planta/química
17.
Biochim Biophys Acta Gen Subj ; 1864(5): 129543, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32007578

RESUMO

BACKGROUND: PYY (1-36) peptides from phylogenetically ancient fish, such as sea lamprey, have previously been shown to function as specific neuropeptide Y1 receptor (NPYR1) agonists. Although, sea lamprey PYY (1-36) is N-terminally stable, we reveal in this study that the peptide is subject to endopeptidase mediated C-terminal dipeptide degradation. In an attempt to prevent this, (d-Arg35)-sea lamprey PYY (1-36) was developed. METHODS: In vitro bioassays assessed enzymatic stability, insulinostatic activity as well as beta-cell anti-apoptotic actions of (d-Arg35)-sea lamprey PYY (1-36). Follow-up studies examined the impact of twice daily administration of sea lamprey PYY (1-36) or (d-Arg35)-sea lamprey PYY (1-36) in multiple low dose STZ-induced diabetic mice. RESULTS: (d-Arg35)-sea lamprey PYY (1-36) was fully resistant to plasma enzymatic degradation. The peptide possessed similar significant insulinostatic, as well as positive anti-apoptotic biological actions, as the parent peptide. Sea lamprey PYY (1-36) and (d-Arg35)-sea lamprey PYY (1-36) delayed diabetes progression in STZ mice. Both treatment interventions induced a significant decrease in body weight, food and fluid intake as well as glucose and glucagon concentrations. In addition, glucose tolerance, plasma and pancreatic insulin were partially normalised. (d-Arg35)-sea lamprey PYY (1-36) was significantly more effective than sea lamprey PYY (1-36) in terms of enhancing glucose-stimulate insulin release. Both treatments improved pancreatic islet morphology, linked to decreased apoptosis of beta-cells. CONCLUSION: We present (d-Arg35)-sea lamprey PYY (1-36) as the first-in-class N- and C-terminally stable PYY (1-36) peptide analogue. GENERAL SIGNIFICANCE: Enzymatically stable, long-acting PYY (1-36) peptides highlight the therapeutic benefits of sustained activation of NPYR1's in diabetes.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Peptídeos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Receptores de Neuropeptídeo Y/agonistas , Animais , Linhagem Celular , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/prevenção & controle , Proteínas de Peixes/química , Proteínas de Peixes/uso terapêutico , Hipoglicemiantes/química , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Peptídeos/química , Petromyzon , Substâncias Protetoras/química , Receptores de Neuropeptídeo Y/metabolismo
18.
J Enzyme Inhib Med Chem ; 35(1): 524-538, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31939313

RESUMO

A series of nitrogen heterocycles containing α-ethoxyphenylpropionic acid derivatives were designed as dual PPARα/γ agonist ligands for the treatment of type 2 diabetes (T2D) and its complications. 6-Benzoyl-benzothiazol-2-one was the most tolerant of the tested heterocycles in which incorporation of O-methyl oxime ether and trifluoroethoxy group followed by enantiomeric resolution led to the (S)-stereoisomer 44 b displaying the best in vitro pharmacological profile. Compound 44 b acted as a very potent full PPARγ agonist and a weak partial agonist on the PPARα receptor subtype. Compound 44 b showed high efficacy in an ob/ob mice model with significant decreases in serum triglyceride, glucose and insulin levels but mostly with limited body-weight gain and could be considered as a selective PPARγ modulator (SPPARγM).


Assuntos
Benzotiazóis/farmacologia , Hipoglicemiantes/farmacologia , PPAR alfa/agonistas , PPAR gama/agonistas , Fenilpropionatos/farmacologia , Animais , Benzotiazóis/síntese química , Benzotiazóis/química , Células COS , Chlorocebus aethiops , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Ligantes , Masculino , Camundongos , Camundongos Obesos , Simulação de Acoplamento Molecular , Estrutura Molecular , PPAR alfa/genética , PPAR gama/genética , Fenilpropionatos/síntese química , Fenilpropionatos/química , Relação Estrutura-Atividade
19.
Food Chem ; 313: 126099, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31927321

RESUMO

Diabetes mellitus is a metabolic disorder characterized by hyperglycemia, which can be counteracted by inhibition of α-glucosidase and α-amylase, both involved in the carbohydrate metabolism. Fourteen C-glucosidic ellagitannins and three galloylated glucoses were studied as potential α-glucosidase and α-amylase inhibitors. Most of the compounds were found to be moderate inhibitors of α-amylase, but potent inhibitors of α-glucosidase, showing low-micromolar IC50 values, far lower than that of the antidiabetic drug acarbose. This selectivity can be an advantage for their possible application as functional food ingredients with anti-diabetic properties because strong α-amylase inhibition generally causes undesired side effects. The best inhibitors were selected for further studies. Intrinsic fluorescence measurements confirmed their high affinity towards α-glucosidase, highlighting a static quenching mechanism. Circular dichroism measurements and kinetics of inhibition indicated that the most active C-glucosidic ellagitannin roburin D (RobD) is a competitive inhibitor, whereas α-pentagalloylglucose (α-PGG) acts as a mixed-type inhibitor.


Assuntos
Taninos Hidrolisáveis/química , Hipoglicemiantes/química , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo , Dicroísmo Circular , Glucosídeos/química , Taninos Hidrolisáveis/metabolismo , Hipoglicemiantes/metabolismo , Concentração Inibidora 50 , Cinética , Espectrometria de Fluorescência , alfa-Amilases/antagonistas & inibidores , alfa-Glucosidases/química
20.
PLoS One ; 15(1): e0227105, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31914140

RESUMO

BACKGROUND: Diabetes mellitus is one of the most common todays public health problems. According to a survey by the World Health Organization, this metabolic disorder has reached global epidemic proportions, with a worldwide prevalence of 8.5% in the adult population. OBJECTIVES: The present study aimed to investigate the hypoglycemic effect of aqueous extract of Mangifera indica (EAMI) leaves in streptozotocin-induced diabetic rats. METHODS: Sixty male rats were divided into 2 groups: Normoglycemic and Diabetic. Each group was subdivided into negative control, glibenclamide 3 or 10 mg/kg, EAMI 125, 250, 500, and 1000 mg/kg. Intraperitoneal injection of streptozotocin 100 mg/kg was used to DM induction. The hypoglycemic response was assessed acutely after two and four weeks of treatment. After a 6-hour fasting period, the fasting blood glucose of animals was verified, and 2.5 g/kg glucose solution was orally administered. The insulin tolerance test and plasma insulin levels assessment were performed in the morning after fasting of 12 to 14 hours. RESULTS AND CONCLUSION: The chemical analysis of EAMI showed high levels of phenolic compounds. There was no significant difference in fasting blood glucose between normoglycemic and diabetic groups, and that EAMI did not have an acute effect on diabetes. After two and four weeks of treatment, the extract significantly reduced blood glucose levels, exceeding glibenclamide effects. EAMI was effective in maintaining the long-term hypoglycemic effect, as well as, significantly increased the sensitivity of diabetic animals to insulin and the plasma insulin level.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Extratos Vegetais/uso terapêutico , Animais , Glicemia/análise , Diabetes Mellitus Experimental/sangue , Hipoglicemiantes/química , Insulina/sangue , Masculino , Mangifera/química , Extratos Vegetais/química , Ratos Wistar
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