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1.
Chem Biodivers ; 16(10): e1900341, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31465610

RESUMO

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


Assuntos
Antioxidantes/farmacologia , Antagonistas Colinérgicos/farmacologia , Hipoglicemiantes/farmacologia , Fenóis/farmacologia , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Acetilcolinesterase/metabolismo , Antioxidantes/química , Antioxidantes/isolamento & purificação , Apiaceae/química , Butirilcolinesterase/metabolismo , Antagonistas Colinérgicos/química , Antagonistas Colinérgicos/isolamento & purificação , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/farmacologia , Glicosídeo Hidrolases/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Fenóis/química , Fenóis/isolamento & purificação , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Relação Estrutura-Atividade
2.
Planta Med ; 85(11-12): 1024-1033, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31261420

RESUMO

Halimium halimifolium (Hh) is a shrub used in Algerian folk medicine to treat gastrointestinal pain. An UHPLC-PDA-ESI/MSn method was developed to identify the metabolic profile of the traditionally used infusion (Hh-A) from the aerial parts. The structures of flavanols were confirmed by NMR analysis after the isolation procedure from a hydrohalcolic extract (Hh-B) that also allowed for the identification of phenolic acids, an aryl butanol glucoside, and different derivatives of quercetin, myricetin, and kaempferol. Tiliroside isomers were the chemical markers of Hh-A and Hh-B (54.33 and 36.00 mg/g, respectively). Hh-A showed a significant scavenging activity both against the radicals 1,1-diphenyl-2-picrylhydrazyl and 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (EC50 = 10.49 µg/mL and TEAC value = 1.98 mM Trolox/mg infusion) and the lipopolysaccharide-induced reactive oxygen species release in A375 and HeLa cells. Moreover, the antihyperglycemic properties, by inhibiting the α-amylase and α-glucosidase enzymes (IC50 = 0.82 mg/mL and 25.01 µg/mL, respectively), were demonstrated. To upgrade the therapeutic effect, a microencapsulation process is proposed as a strategy to optimize stability, handling, and delivery of bioactive components, avoiding the degradation and loss of the biological efficacy after oral intake. Hh-loaded microparticles were designed using cellulose acetate phthalate as the enteric coating material and spray drying as a production process. The results showed a satisfactory process yield (67.9%), encapsulation efficiency (96.7%), and micrometric characteristics of microparticles (laser-scattering, fluorescent, and scanning electron microscopy). In vitro dissolution studies (USPII-pH change method) showed that Hh-loaded microparticles are able to prevent the release and degradation of the bioactive components in the gastric tract, releasing them into the intestinal environment.


Assuntos
Cistaceae/química , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Linhagem Celular , Cistaceae/metabolismo , Suplementos Nutricionais , Composição de Medicamentos , Células HeLa , Humanos , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Espectroscopia de Ressonância Magnética , Medicina Tradicional Africana , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Plantas Medicinais/metabolismo
3.
Eur J Med Chem ; 178: 108-115, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176093

RESUMO

As dual regulators, the PTP-1B signaling pathway and α-glucosidase slow glucose release and increase the degree of insulin sensitivity, representing a promising therapeutic target for type 2 diabetes. In this study, we systematically examined the in vivo and in vitro anti-diabetic activities of natural flavonoids 1-6 from Chrysanthemum morifolium. Flavonoids 1-6 increased glucose consumption-promoting activity and the phosphorylation of GSK-3ß and Akt, and decreased PTP-1B protein level along with slightly inhibitory activity of the PTP-1B enzyme. Moreover, flavonoids 1-2 treatment induced insulin secretion in INS-1 cells. Besides, in vivo study revealed that flavonoids 2 and 5 demonstrated potent anti-hyperglycemic and anti-hyperlipidemic activity, and improved maltose and glucose tolerance. Although flavonoid 2 exhibited lower inhibitory activity against α-glucosidase in vitro, it could deglycosylated in vivo to diosmetin to function as an α-glucosidase inhibitor. Taken together, these results led to the identification of the natural flavonoids 1-6 from C. morifolium as dual regulators of α-glucosidase and the PTP-1B signaling pathway, suggesting their potential application as new oral anti-diabetic drugs or functional food ingredients.


Assuntos
Chrysanthemum/química , Diabetes Mellitus Experimental/tratamento farmacológico , Flavonoides/uso terapêutico , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Hipoglicemiantes/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Colesterol/sangue , Cricetulus , Diabetes Mellitus Experimental/induzido quimicamente , Flavonoides/isolamento & purificação , Glucose/metabolismo , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Hipoglicemiantes/isolamento & purificação , Masculino , Camundongos , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Ratos , Estreptozocina , Triglicerídeos/sangue
4.
J Agric Food Chem ; 67(24): 6765-6772, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31180676

RESUMO

One unusual resveratrol tetramer, paeonilactiflorol (1), and 14 known compounds (2-15) were isolated from peony seeds ( Paeonia lactiflora) under the guidance of bioassay. Paeonilactiflorol (1) was determined by extensive HRESIMS, UV, IR, 1D and 2D NMR spectroscopic analyses. Most of the stilbenes showed obvious inhibition on PTP1B and α-glucosidase, superior to the monoterpene glycosides. Especially, the stilbene tetramer (1) and trimer (8) exhibited high activity inhibiting both PTP1B with IC50 values of 27.23 and 27.81 µM and α-glucosidase with IC50 values of 13.57 and 14.39 µM. Two trans-dimers (4 and 5) also showed dipeptidyl peptidase-4 (DPPIV) inhibitory activity (55.35% and 61.26%, 500 µM) in addition to PTP1B and α-glucosidase. Enzyme kinetic study indicated that the types of inhibition on PTP1B were noncompetitive for 3 and 5 and mixed for 8 and 10. Quantitative analysis suggested that the stilbene trimers 8 (23.17 ± 0.36 mg/g) and 10 (15.24 ± 0.25 mg/g) were the main contents in peony seeds and should be responsible for the antidiabetic effects. This investigation supports the therapeutic potential of peony seeds in the treatment of diabetes with stilbenes as the active constituents.


Assuntos
Inibidores da Dipeptidil Peptidase IV/química , Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/química , Paeonia/química , Extratos Vegetais/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Estilbenos/química , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Hipoglicemiantes/isolamento & purificação , Estrutura Molecular , Extratos Vegetais/isolamento & purificação , Proteína Tirosina Fosfatase não Receptora Tipo 1/química , Sementes/química , Estilbenos/isolamento & purificação , alfa-Glucosidases/química
5.
J Agric Food Chem ; 67(26): 7348-7364, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31180673

RESUMO

A chemical study on the peels of the cultivated edible mushroom Wolfiporia cocos led to the isolation and identification of 47 lanostane triterpenoids including 16 new compounds (1-16). The structures of the new compounds were determined by analysis of the NMR, MS, and electronic circular dichroism (ECD) data. Compounds 1 and 2 represent new members of the family of 4,5-secolanostane triterpenes. Compound 3 is a new aromatic lanostane triterpene with an unusual methyl rearrangement from C-10 to C-6. The absolute configurations of 1 and 8 were assigned by ECD spectra calculation. All compounds were evaluated for cytotoxicity (K562, SW480, and HepG2) and glucose-uptake-stimulating effects. Compounds 23, 25, 29, and 31 showed weak inhibition on the K562 cells with IC50 in the range of 25.7 to 68.2 µM, respectively. Compounds 21, 28, and 30 increased the glucose uptake in 3T3-L1 cells by 25%, 14%, and 50% at 5 µM, respectively. In addition, compounds 14, 23, 29, 35, and 43 showed insulin-sensitizing activity by increasing the insulin-stimulated glucose uptake at 2.5 µM in 3T3-L1 adipocytes. A preliminary structure-activity relationship analysis indicates that the 6/6/6/5 ring skeleton and the double bond between C-8 and C-9 are beneficial for the glucose-uptake-stimulating and insulin-sensitizing activities. Furthermore, the alkaline-insoluble fraction mainly containing compounds 22, 24, 28, and 31 were confirmed to have hypoglycemic and hypolipidemic activity on high-fat-diet-induced obese mice. This work confirms the potential of the peels' extracts of W. cocos as a functional food or dietary supplements.


Assuntos
Glucose/metabolismo , Extratos Vegetais/farmacologia , Triterpenos/farmacologia , Wolfiporia/química , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Camundongos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Triterpenos/química , Triterpenos/isolamento & purificação
6.
Food Chem Toxicol ; 131: 110562, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31181236

RESUMO

Brown seaweed Sargassum confusum (C. Agardh) has been used in traditional Chinese medicine to treat a variety of diseases. The aim of the present study was to evaluate the anti-diabetic effect of oligosaccharides from brown seaweed S. confusum (SCO). The anti-diabetic effect of SCO was evaluated in vivo using high-fat/high-sucrose fed hamsters. Molecular mechanisms of modulating gene expression of specific members of insulin signaling pathways were determined. The components of the intestinal microflora in diabetic animals were also analyzed by high-throughput 16S rRNA gene sequencing. And it was found that SCO had a sequence of sulfated anhydrogalactose and methyl sulfated galactoside units. Fasting blood glucose levels were significantly decreased after SCO administration. Histology showed that SCO could protect the cellular architecture of the liver. SCO could also significantly increase the relative abundance of Lactobacillus and Clostridium XIVa and decrease that of Allobaculum, Bacteroides and Clostridium IV. The active role of SCO in anti-diabetic effect was revealed by its regulation of insulin receptor substrate 1/phosphatidylinositol 3-kinase and c-Jun N-terminal kinase pathways. These results suggested that SCO might be used as a functional material to regulate gut microbiota in obese and diabetic individuals.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Oligossacarídeos/uso terapêutico , Sargassum/química , Animais , Bactérias/genética , Sequência de Bases , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Dieta da Carga de Carboidratos , Dieta Hiperlipídica , Hipoglicemiantes/isolamento & purificação , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Mesocricetus , Oligossacarídeos/isolamento & purificação , Substâncias Protetoras/isolamento & purificação , Substâncias Protetoras/uso terapêutico , RNA Ribossômico 16S/genética , Alga Marinha/química
7.
Curr Top Med Chem ; 19(11): 927-930, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31072292

RESUMO

BACKGROUND: Quillaja saponaria Mol. bark contains a high concentration of triterpene saponins that have been used for centuries as a cleansing, antiinflammatory and analgesic agent in Chilean folk medicine. In earlier studies, in mice, both the anti-inflammatory as well as the antinociceptive effect of the major sapogenin, quillaic acid have been demonstrated (QA). OBJECTIVE: To determine the antihyperalgesic effect of QA one and seven days after itpl administration of complete Freund's adjuvant (CFA) in male mice using the hot plate test in the presence of complete Freund's adjuvant (HP/CFA) as an acute and chronic skeletal muscle pain model. METHODS: The present study evaluated the antihyperalgesic activity of QA against acute and chronic skeletal muscle pain models in mice using the hot plate test in the presence of complete Freund's adjuvant (HP/CFA), at 24 h (acute assay) and 7 days (chronic assay) , with dexketoprofen (DEX) as the reference drug. RESULTS: In acute and chronic skeletal muscle pain assays, QA at 30 mg/kg ip elicited its maximal antihyperalgesic effects (65.0% and 53.4%) at 24 h and 7 days, respectively. The maximal effect of DEX (99.0 and 94.1 at 24 h and 7 days, respectively) was induced at 100 mg/kg. CONCLUSION: QA and DEX elicit dose-dependent antihyperalgesic effects against acute and chronic skeletal muscle pain, but QA is more potent than DEX in the early and late periods of inflammatory pain induced by CFA.


Assuntos
Músculos Abdominais/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Ácido Oleanólico/análogos & derivados , Dor/tratamento farmacológico , Quillaja/química , Animais , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Masculino , Camundongos , Camundongos Endogâmicos , Conformação Molecular , Ácido Oleanólico/química , Ácido Oleanólico/isolamento & purificação , Ácido Oleanólico/farmacologia
8.
Molecules ; 24(8)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013790

RESUMO

Rheum palmatum L. is a traditional Chinese medicine with various pharmacological properties, including anti-inflammatory, antibacterial, and detoxification effects. In this study, the mechanism of the hypoglycemic effect of purified anthraquinone-Glycoside from Rheum palmatum L. (PAGR) in streptozotocin (STZ) and high-fat diet induced type 2 diabetes mellitus (T2DM) in rats was investigated. The rats were randomly divided into normal (NC), T2DM, metformin (Met), low, middle (Mid), and high (Hig) does of PAGR groups. After six weeks of continuous administration of PAGR, the serum indices and tissue protein expression were determined, and the pathological changes in liver, kidney, and pancreas tissues were observed. The results showed that compared with the type 2 diabetes mellitus group, the fasting blood glucose (FBG), total cholesterol (TC), and triglyceride (TG) levels in the serum of rats in the PAGR treatment groups were significantly decreased, while superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) levels were noticeably increased. The expression of Fas ligand (FasL), cytochrome C (Cyt-c), and caspase-3 in pancreatic tissue was obviously decreased, and the pathological damage to the liver, kidney, and pancreas was improved. These indicate that PAGR can reduce oxidative stress in rats with diabetes mellitus by improving blood lipid metabolism and enhancing their antioxidant capacity, thereby regulating the mitochondrial apoptotic pathway to inhibitß-cell apoptosis and improve ß-cell function. Furthermore, it can regulate Fas/FasL-mediated apoptosis signaling pathway to inhibit ß-cell apoptosis, thereby lowering blood glucose levels and improving T2DM.


Assuntos
Antraquinonas , Antioxidantes , Diabetes Mellitus Experimental/tratamento farmacológico , Glucosídeos , Hipoglicemiantes , Rheum/química , Animais , Antraquinonas/química , Antraquinonas/isolamento & purificação , Antraquinonas/farmacologia , Antioxidantes/química , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2 , Glucosídeos/química , Glucosídeos/isolamento & purificação , Glucosídeos/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo
9.
Nutrients ; 11(4)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939853

RESUMO

Type 2 diabetes is a complex, heterogeneous, and polygenic disease. Currently, available drugs for treating type 2 diabetes predominantly include sulfonylureas, α-glucosidase inhibitors, and biguanides. However, long-term treatment with these therapeutic drugs is often accompanied by undesirable side effects, which have driven interest in the development of more effective and safer antidiabetic agents. To address the urgent need for new chemical solutions, we focused on the analysis of structurally novel and/or biologically new metabolites produced by insect-associated microbes as they have recently been recognized as a rich source of natural products. Comparative LC/MS-based analysis of Actinomadura sp. RB99, isolated from a fungus-growing termite, led to the identification of the type II polyketide synthase-derived fridamycin A. The structure of fridamycin A was confirmed by ¹H NMR data and LC/MS analysis. The natural microbial product, fridamycin A, was examined for its antidiabetic properties in 3T3-L1 adipocytes, which demonstrated that fridamycin A induced glucose uptake in 3T3-L1 cells by activating the AMP-activated protein kinase (AMPK) signaling pathway but did not affect adipocyte differentiation, suggesting that the glucose uptake took place through activation of the AMPK signaling pathway without inducing adipogenesis. Our results suggest that fridamycin A has potential to induce fewer side effects such as weight gain compared to rosiglitazone, a commonly used antidiabetic drug, and that fridamycin A could be a novel potential therapeutic candidate for the management of type 2 diabetes.


Assuntos
Adipócitos/efeitos dos fármacos , Antraquinonas/farmacologia , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Células 3T3-L1 , Adipócitos/fisiologia , Adipogenia/efeitos dos fármacos , Animais , Antraquinonas/química , Antraquinonas/isolamento & purificação , Transporte Biológico/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Camundongos , Estrutura Molecular
10.
J Agric Food Chem ; 67(18): 5278-5288, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-30964673

RESUMO

Diabetes and its complications are one of the most concerned metabolic diseases worldwide and threaten human health severely. Hypoglycemic and hypolipidemic effects of glucomannan extracted from konjac on high-fat diet and streptozocin-induced type 2 diabetic rats were evaluated in this study. Administration of konjac glucomannan significantly decreased the levels of fasting blood glucose, serum insulin, glucagon-like peptide 1, and glycated serum protein. The concentrations of serum lipids, including total cholesterol, triacylglycerols, low-density lipoprotein cholesterol, and non-esterified fatty acid, were notably reduced by konjac glucomannan treatment. In addition, antioxidant capacity, pancreatic injury, and adipose cell hypertrophy were ameliorated by konjac glucomannan administration in type 2 diabetic rats. Besides, ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry-based lipidomics analysis was used to explore the improvement of lipid metabolic by konjac glucomannan treatment. The disturbance of glycerolipid (diacylglycerol, monoacylglycerol, and triacylglycerol), fatty acyl (acylcarnitine and hydroxyl fatty acid), sphingolipid (ceramide and sphingomyelin), and glycerophospholipid (phosphatidylcholine) metabolism were attenuated by the glucomannan treatment. This study provided new insights for investigating the anti-diabetic effects of konjac glucomannan and suggests that konjac glucomannan may be a promising nutraceutical for treating type 2 diabetes.


Assuntos
Amorphophallus/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipolipemiantes/administração & dosagem , Mananas/administração & dosagem , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos não Esterificados/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Hipolipemiantes/química , Hipolipemiantes/isolamento & purificação , Insulina/sangue , Masculino , Mananas/química , Mananas/isolamento & purificação , Ratos , Ratos Wistar
11.
Carbohydr Polym ; 215: 307-315, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30981359

RESUMO

A purified polysaccharide, designated as MFP-2A, was isolated from Mallotus furetianus (Bail) Muell Arg. The primary structure characteristics were determined by HPGPC, HPLC, FT-IR, methylation analysis, NMR, SEM and AFM. The results showed that MFP-2A was a homogeneous heteropolysaccharide with an average molecular weight of 25.96 KDa. The monosaccharide composition was consisted of mannose, galactose, arabinose, galacturonic acid and glucose with a molar ratio of 3.05:2.84:1.84:0.86:1.41. In addition, methylation and NMR analysis revealed that the main glycosidic bonds of MFP-2A were comprised of 1,4,6-linked-ß-d-Galp, 1,3,6-linked-ß-d-Manp, 1,5-linked-α-l-Araf, 1-linked-α-l-Araf, 1,4-linked-α-d-GalAp and 1,4-linked-α-d-Glcp residues. Moreover, MFP-2A also exhibited significant free radical scavenging ability and α-glucosidase inhibitory activities in vitro. Overall, these results demonstrated that MFP-2A from Mallotus furetianus (Bail) Muell Arg could serve as a potential anti-diabetic and functional food.


Assuntos
Antioxidantes/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/farmacologia , Mallotus (Planta)/química , Polissacarídeos/farmacologia , Antioxidantes/química , Antioxidantes/isolamento & purificação , Configuração de Carboidratos , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , alfa-Glucosidases/metabolismo
12.
J Ethnopharmacol ; 236: 220-230, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30849506

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Korean red ginseng (KRG) has been traditionally used to treat diabetes. Ginsenosides are considered as the major bioactive components mediating anti-diabetic effects of KRG. However, considering that ginsenosides account for only about 3-4% of ginsengs, other fractions of KRG may also carry potential anti-diabetic effects. There is no study reporting the differentiated effects of ginsenosides (Spn) and non-saponin fractions (NSpn) of KRG on glycemic control. AIM OF THE STUDY: We investigated the effects of KRG, Spn, and NSpn on the indications of glycemic control and sought to elucidate physiological factors contributing their effects. MATERIALS AND METHODS: Human T2DM mimicking Nagoya-Shibata-Yasuda (NSY/hos) mice were given KRG, Spn, or NSpn admixed in rodent diet at 200 mg/kg/day for 24 weeks. Glycemic and obesity indications, blood lipid profile, systematic and local oxidative stress markers in metabolically important organs, and systematic inflammatory markers were assessed. Molecular assessments associated with glycemic control in liver and skeletal muscle were further performed. RESULTS: KRG attenuated deterioration in glucose homeostasis as evidenced by significantly lower fasting blood glucose from 22nd week and AUC during GTT at the end of the experiment compare to control. Spn enhanced insulin secretion in response to glucose stimulation and reduced protein level of glycogen phosphorylase in liver. On the other hand, NSpn ameliorated oxidative stress and inflammation. Some beneficial effects of Spn and NSpn were reflected in KRG treated mice. KRG also attenuated the accumulation of malondialdehyde in skeletal muscle and, accordingly, enhanced insulin responsiveness compare to control. CONCLUSION: Anti-diabetic properties of KRG are not solely determined by the contents of ginsenosides but the harmonic functions of its different fractions.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Panax/química , Extratos Vegetais/farmacologia , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Ginsenosídeos/isolamento & purificação , Ginsenosídeos/farmacologia , Humanos , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/uso terapêutico , Masculino , Medicina Tradicional Chinesa/métodos , Camundongos , Camundongos Endogâmicos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Resultado do Tratamento
13.
J Ethnopharmacol ; 236: 196-204, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30844488

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Hopea ponga (Dennst.) Mabb. Is used in traditional herbal formulations for diabetes complications. The aim of this study is to evaluate the antidiabetic effect of extracts and compounds from H. ponga. MATERIALS AND METHODS: Silica gel column chromatography was performed to identify various chemical components of the plant extract. Different extracts of H. ponga and isolated compounds were screened for their antidiabetic effect by modulation of digestive enzymes and protein glycation. The effect of glucose uptake by the compounds and the pathways through which the compounds mediate the glucose uptake potential were confirmed by fluorescent microscopy, flow cytometry and western blot analysis. RESULTS: Acetone and ethanol extracts of the stem bark of Hopea ponga (Dennst.) Mabb. Afforded six resveratrol oligomers namely, E-resveratrol (1), (-)-ε-viniferin (2), (-)-α-viniferin (3), trihydroxyphenanthrene glucoside (THPG) (4), vaticaphenol A (5), (-)-hopeaphenol (6), along with four phytosterols. The structures were determined on the basis of spectroscopic analyses including nuclear magnetic resonance (NMR) spectroscopy and high resolution mass spectrometry (HRMS) data. Compounds 1-5 and 7-10 were tested for their α-glucosidase, α-amylase and glycation inhibitiory activities. All the resveratrol oligomers (1-5) showed prominent α-glucosidase inhibition with IC50 values, 12.56 ±â€¯1.00, 23.98 ±â€¯1.11, 7.17 ±â€¯1.10, 31.74 ±â€¯0.42 and 16.95 ±â€¯0.39 µM, respectively. Molecular docking studies also supported the observed α-glucosidase inhibition. Compound 3 displayed IC50 values of 4.85 ±â€¯0.06 and 27.10 ±â€¯0.04 µM in α-amylase and glycation inhibitory assays activity. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay revealed that the compounds 3 and 4 were found to be less toxic at a concentration of 100 µM (<10%) and 25 µM (<20%), respectively. The effect of glucose uptake performed by 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG) in L6 myoblast were measured by fluorescent microscopy and flow cytometry. The compounds 3 and 4 showed 2-NBDG uptake of 49.6% and 38.8% respectively. By examining the molecular pathway through which the compounds elicit their glucose uptake potential, it was observed that both the compounds mainly act via AMPK pathway. CONCLUSION: This is the first report on the isolation of compounds from H. ponga. Altogether, the results of this study reveal the antidiabetic effects of H. ponga extracts and isolated compounds promoting traditional use of this plant in the treatment of diabetes.


Assuntos
Dipterocarpaceae/química , Hipoglicemiantes/farmacologia , Extratos Vegetais/farmacologia , Resveratrol/farmacologia , Acetona/química , Animais , Linhagem Celular , Diabetes Mellitus/tratamento farmacológico , Ensaios Enzimáticos , Etanol/química , Glicosilação/efeitos dos fármacos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Concentração Inibidora 50 , Medicina Tradicional/métodos , Simulação de Acoplamento Molecular , Estrutura Molecular , Mioblastos , Casca de Planta/química , Extratos Vegetais/química , Caules de Planta/química , Ratos , Resveratrol/química , Resveratrol/isolamento & purificação , Testes de Toxicidade , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/química , alfa-Amilases/metabolismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
14.
Mar Drugs ; 17(3)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875760

RESUMO

The marine alga, Symphyocladia latiuscula (Harvey) Yamada, is a good source of bromophenols with numerous biological activities. This study aims to characterize the anti-diabetic potential of 2,3,6-tribromo-4,5-dihydroxybenzyl derivatives isolated from S. latiuscula via their inhibition of tyrosine phosphatase 1B (PTP1B) and α-glucosidase. Additionally, this study uses in silico modeling and glucose uptake potential analysis in insulin-resistant (IR) HepG2 cells to reveal the mechanism of anti-diabetic activity. This bioassay-guided isolation led to the discovery of three potent bromophenols that act against PTP1B and α-glucosidase: 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol (1), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (2), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether) (3). All compounds inhibited the target enzymes by 50% at concentrations below 10 µM. The activity of 1 and 2 was comparable to ursolic acid (IC50; 8.66 ± 0.82 µM); however, 3 was more potent (IC50; 5.29 ± 0.08 µM) against PTP1B. Interestingly, the activity of 1⁻3 against α-glucosidase was 30⁻110 times higher than acarbose (IC50; 212.66 ± 0.35 µM). Again, 3 was the most potent α-glucosidase inhibitor (IC50; 1.92 ± 0.02 µM). Similarly, 1⁻3 showed concentration-dependent glucose uptake in insulin-resistant HepG2 cells and downregulated PTP1B expression. Enzyme kinetics revealed different modes of inhibition. In silico molecular docking simulations demonstrated the importance of the 7⁻OH group for H-bond formation and bromine/phenyl ring number for halogen-bond interactions. These results suggest that bromophenols from S. latiuscula, especially highly brominated 3, are inhibitors of PTP1B and α-glucosidase, enhance insulin sensitivity and glucose uptake, and may represent a novel class of anti-diabetic drugs.


Assuntos
Compostos de Benzil/farmacologia , Diabetes Mellitus/tratamento farmacológico , Éteres/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Rodófitas/química , alfa-Glucosidases/metabolismo , Compostos de Benzil/química , Compostos de Benzil/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Éteres/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/farmacologia , Células Hep G2 , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Resistência à Insulina , Simulação de Acoplamento Molecular
15.
Life Sci ; 223: 194-201, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30898648

RESUMO

AIMS: Diabetic nephropathy (DN) is the most common complication of diabetes mellitus. Endoplasmic reticulum (ER) plays an important role in the development and progression of DN. Arctigenin (ATG), a lignan extract from Fructus Arctii, exhibits anti-inflammatory, anticarcinogenic, anti-oxidative stress and immunomodulatory properties. The present research aimed to investigate whether ATG could protect against diabetes-related renal injury and inhibit ER stress in db/db mice. MAIN METHODS: Male db/db mice were randomly divided into two groups: DN group and ATG treatment group (DN + ATG). db/m mice were defined as the normal control group (NC). ATG was dissolved in 0.5% carboxymethyl cellulose sodium salt solution and administered orally at a dose of 80 mg/kg to mice in the DN + ATG group once daily for 8 consecutive weeks. HK2 cells were used to determine the effects of ATG on ER stress and cell apoptosis in vitro. KEY FINDINGS: ATG administration significantly reduced blood glucose, urine albumin excretion, and urine albumin to creatinine ratio, and attenuated renal pathological injury when compared with untreated db/db mice. These changes were accompanied by decreased expression of both ER stress-related markers and caspase 12 level in the kidneys of db/db mice. In vitro, high glucose activated ER stress signal transduction pathway and induced cell apoptosis in HK2 cells, which were blocked by ATG. SIGNIFICANCE: Our results suggest that ATG exerts renoprotective effects on diabetes-related renal injury in db/db mice and cytoprotective effects on high glucose induced cell apoptosis and inhibits ER stress.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Furanos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Lignanas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Arctium/química , Técnicas de Cultura de Células , Linhagem Celular , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Furanos/isolamento & purificação , Humanos , Hipoglicemiantes/isolamento & purificação , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Lignanas/isolamento & purificação , Masculino , Camundongos Endogâmicos C57BL
16.
Fitoterapia ; 134: 270-289, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30840917

RESUMO

Diabetes mellitus (DM), a chronic metabolic disease, severely affects patients' life and intensively increases risks of developing other diseases. It is estimated that 0.4 billion individuals worldwide are subjected to diabetes, especially type 2 diabetes mellitus. At present, although various synthetic drugs for diabetes such as Alogliptin and Rosiglitazone, etc. have been used to manage diabetes, some of them showed severe side effects. Given that the pathogenesis of type 2 diabetes mellitus, natural occurring drugs are beneficial alternatives for diabetes therapy with low adverse effects or toxicity. Recently, more and more plant-derived extracts or compounds were evaluated to have anti-diabetic activities. Their anti-diabetic mechanisms involve certain key targets like α-glucosidase, α-amylase, DPP-4, PPAR γ, PTP1B, and GLUT4, etc. Here, we summarize the newly found anti-diabetic (type 2 diabetes mellitus) natural compounds and extracts from 2011-2017, and give the identification of their molecular targets. This review could provide references for the research of natural agents curing type 2 diabetes mellitus (T2DM).


Assuntos
Produtos Biológicos/isolamento & purificação , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Hipoglicemiantes/isolamento & purificação , Produtos Biológicos/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Estrutura Molecular , Terapia de Alvo Molecular
17.
Pak J Pharm Sci ; 32(1): 69-74, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30772792

RESUMO

Mulberry (M. alba L.) has prominent use in traditional Chinese medicine since ancient times but its therapeutic properties have not been sufficiently explored in India. Present study was designed to isolate and identify the polyphenolic constituents present in mulberry leaf (M. latifolia) using HPLC and to evaluate its antihyperglycemic and antihyperlipedemic properties in streptozotocin (STZ) induced diabetic wistar rat models. HPLC analysis identified chlorogenic acid (103mg/100gm), caffeic acid (4.3mg/100gm), coumaric acid (11.61mg/kg), rutin (53mg/100gm) and quercetin (46.19mg/100gm) as the major constituents of crude polyphenolic extracts in M. latifolia. STZ induced diabetic rats administered with mulberry leaf extract at doses 250 and 500mg/kg after 4 weeks of treatment significantly improved their glycemic control (p<0.001). Body weight increased significantly (p<0.001) after administration of BC259 extract at a dose of 500mg/kg. Results also showed that there was a significant decrease in serum urea (p<0.001) and creatinine level (p<0.01). Significant decline was observed in the levels of serum triglycerides (p<0.01), total cholesterol (p<0.001), LDL-cholesterol (p<0.01) and VLDL-cholesterol (p<0.01), while the serum HDL-cholesterol (p<0.01) significantly increased. Results revealed that the leaf extract of M. latifolia (var.BC259) causes significant antidiabetic and antihypercholesterolemic activity. Evidence of identified bioactive polyphenolic compounds present in M. latifolia leaf extract strengthens its antidiabetic property.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Morus , Extratos Vegetais/farmacologia , Folhas de Planta , Polifenóis/farmacologia , Animais , Anticolesterolemiantes/isolamento & purificação , Anticolesterolemiantes/farmacologia , Biomarcadores/sangue , Glicemia/metabolismo , Colesterol/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/diagnóstico , Hipoglicemiantes/isolamento & purificação , Masculino , Morus/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Polifenóis/isolamento & purificação , Ratos Wistar , Estreptozocina , Triglicerídeos/sangue , Ganho de Peso/efeitos dos fármacos
18.
Biomed Pharmacother ; 112: 108598, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30784908

RESUMO

Anisomeles malabarica (AM) is an aromatic plant traditionally used for the treatment of diabetes mellitus in India. Following bioassay guided fractionation, we recently identified an active fraction of AM (AMAF, with potential mix of active principles) that showed significant antihyperglycemic and antihyperlipidemic activities. In addition, AMAF treatment improved insulin levels. However, the biochemical mechanism/s through which AMAF demonstrates the antidiabetic effects is largely unknown. Based on its beneficial effects we investigated the biochemical mechanism of the anti-diabetic activity of A.malabarica active fraction (AMAF) in streptozotocin (STZ) induced diabetic rats. Streptozotocin induced diabetic rats were treated with AMAF (50 mg AMAF/kg/day) for 30 days and alterations in the body weights, glycogen and protein content of tissues, functional markers of hepatic and renal tissues, carbohydrate metabolic enzymes and their genes expression were evaluated. Lipid peroxides levels and activities of antioxidant enzymes of hepatic and renal tissues were also measured. The AMAF treatment resulted in increase in body weights, hepatic and renal protein and tissue glycogen levels in diabetic treated rats compared to diabetic rats. In addition, the treatment improved activities of carbohydrate metabolic enzymes, antioxidant enzymes and, liver and renal functional markers in the AMAF treated diabetic rats. Gene expressions of key carbohydrate metabolic enzymes/factors glucokinase, glucose transporter protein (GLUT-2) and phosphoenolpyruvate carboxykinase (PEPCK) were also normalized up on AMAF treatment in diabetic rats. Our studies indicate that the isolated active fraction of AM (AMAF) from the leaves of A.malabarica positively regulated the glucose homeostasis and oxidative stress through carbohydrate metabolism and antioxidant enzyme activities respectively in hepatic and renal tissues.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Lamiaceae , Extratos Vegetais/uso terapêutico , Animais , Fenômenos Biomecânicos/efeitos dos fármacos , Fenômenos Biomecânicos/fisiologia , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Avaliação Pré-Clínica de Medicamentos/métodos , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Estreptozocina/toxicidade
20.
Int J Mol Sci ; 20(3)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717198

RESUMO

We previously demonstrated that an aspalathin-enriched green rooibos extract (GRE) reversed palmitate-induced insulin resistance in C2C12 skeletal muscle and 3T3-L1 fat cells by modulating key effectors of insulin signalling such as phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) and AMP-activated protein kinase (AMPK). However, the effect of GRE on hepatic insulin resistance is unknown. The effects of GRE on lipid-induced hepatic insulin resistance using palmitate-exposed C3A liver cells and obese insulin resistant (OBIR) rats were explored. GRE attenuated the palmitate-induced impairment of glucose and lipid metabolism in treated C3A cells and improved insulin sensitivity in OBIR rats. Mechanistically, GRE treatment significantly increased PI3K/AKT and AMPK phosphorylation while concurrently enhancing glucose transporter 2 expression. These findings were further supported by marked stimulation of genes involved in glucose metabolism, such as insulin receptor (Insr) and insulin receptor substrate 1 and 2 (Irs1 and Irs2), as well as those involved in lipid metabolism, including Forkhead box protein O1 (FOXO1) and carnitine palmitoyl transferase 1 (CPT1) following GRE treatment. GRE showed a strong potential to ameliorate hepatic insulin resistance by improving insulin sensitivity through the regulation of PI3K/AKT, FOXO1 and AMPK-mediated pathways.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Chalconas/farmacologia , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Resistência à Insulina , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Células 3T3 , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Aspalathus/química , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Linhagem Celular , Chalconas/isolamento & purificação , Dieta Hiperlipídica/efeitos adversos , Açúcares da Dieta/efeitos adversos , Regulação da Expressão Gênica , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hiperglicemia/etiologia , Hiperglicemia/genética , Hiperglicemia/metabolismo , Hipoglicemiantes/isolamento & purificação , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Camundongos , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Ácido Palmítico/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Extratos Vegetais/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Transdução de Sinais
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