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1.
J Sci Food Agric ; 100(3): 986-994, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31650545

RESUMO

BACKGROUND: Controlling the blood glucose level is an effective method to reduce type 2 diabetes and prevent diabetes-related complications. Ursolic acid is a plant extract that can reduce postprandial hyperglycemia effectively. This study aimed to explore the inhibitory effect and interaction mechanism of ursolic acid against α-amylase and α-glucosidase. RESULTS: In this study, the effect of ursolic acid on glycosidase was studied in vitro, in vivo, and in silico. The half-maximal inhibitory concentration (IC50 ) of ursolic acid on α-amylase and α-glucosidase was 0.482 ± 0.12 mg mL-1 and 0.213 ± 0.042 mg mL-1 , respectively. The results of enzymatic kinetics showed that ursolic acid inhibited α-amylase and α-glucosidase activity in a non-competitive manner. The fluorescence spectrum showed that the combination of ursolic acid and glycosidase caused the intrinsic fluorescence quenching of glycosidase. The observation of starch granules revealed that the activity of α-amylase was inhibited and the hydrolysis of starch granules was prevented in the presence of ursolic acid. Molecular docking results showed that ursolic acid bound to the inactive site of α-amylase and α-glucosidase through the formation of ursolic acid-glucosidase complex. Ursolic acid interacted with α-amylase and α-glucosidase mainly through hydrogen bonding. The postprandial hypoglycemic effect of ursolic acid in C57BL/6J mice showed that the high concentration of ursolic acid could quickly reduce postprandial blood glucose level. CONCLUSION: Ursolic acid can be considered as a natural ingredient in functional foods to control postprandial blood glucose levels and prevent diabetes by delaying the digestion of starch in foods. © 2019 Society of Chemical Industry.


Assuntos
Diabetes Mellitus Tipo 2/enzimologia , Inibidores Enzimáticos/química , Glicosídeo Hidrolases/antagonistas & inibidores , Hipoglicemiantes/química , Triterpenos/química , Animais , Glicemia/metabolismo , Simulação por Computador , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Inibidores Enzimáticos/administração & dosagem , Glicosídeo Hidrolases/química , Glicosídeo Hidrolases/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Cinética , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Período Pós-Prandial/efeitos dos fármacos , Triterpenos/administração & dosagem
2.
J Sci Food Agric ; 100(2): 509-516, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31487036

RESUMO

BACKGROUND: Emblica officinalis, known as amla in Ayurveda, has been used as a folk medicine to treat numerous pathological conditions, including diabetes. However, the novel extract of E. officinalis fruit extract (amla fruit extract, AFE, Saberry®) containing 100 g kg-1 ß-glucogallin along with hydrolyzable tannins has not yet been extensively studied for its antidiabetic potential. OBJECTIVE: The aim of this study was to investigate the antidiabetic and antioxidant activities of AFE and its stability during gastric stress as well as its thermostability. METHODS: The effect of AFE on the inhibition of pancreatic α-amylase and salivary α-amylase enzymes was studied using starch and yeast α-glucosidase enzyme using 4-nitrophenyl α-d-glucopyranoside as substrate. Further, 2,2-diphenyl-1-picrylhydrazyl radical scavenging and reactive oxygen species inhibition assay was performed against AFE. RESULTS: AFE potently inhibited the activities of α-amylase and α-glucosidase in a concentration-dependent manner with half maximal inhibitory concentration (IC50 ) values of 135.70 µg mL-1 and 106.70 µg mL-1 respectively. Furthermore, it also showed inhibition of α-glucosidase (IC50 562.9 µg mL-1 ) and dipeptidyl peptidase-4 (DPP-4; IC50 3770 µg mL-1 ) enzyme activities. AFE is a potent antioxidant showing a free radical scavenging activity (IC50 2.37 µg mL-1 ) and protecting against cellular reactive oxygen species (IC50 1.77 µg mL-1 ), and the effects elicited could be attributed to its phytoconstituents. CONCLUSION: AFE showed significant gastric acid resistance and was also found to be thermostable against wet heat. Excellent α-amylase, α-glucosidase, and DPP-4 inhibitory activities of AFE, as well as antioxidant activities, strongly recommend its use for the management of type 2 diabetes mellitus. © 2019 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.


Assuntos
Antioxidantes/química , Inibidores da Dipeptidil Peptidase IV/química , Frutas/química , Inibidores de Glicosídeo Hidrolases/química , Phyllanthus emblica/química , Extratos Vegetais/química , Antioxidantes/isolamento & purificação , Diabetes Mellitus Tipo 2/enzimologia , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Extratos Vegetais/isolamento & purificação , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/química , alfa-Glucosidases/química
3.
Georgian Med News ; (294): 91-97, 2019 Sep.
Artigo em Russo | MEDLINE | ID: mdl-31687957

RESUMO

Polymorphism of N-acetyltransferase 2 (NAT2) determines the risk of certain diseases and the rate of inactivation of various xenobiotics and drugs. We investigated phenotypic polymorphism of N-acetyltransferase 2 among 141 healthy subjects and 115 patients with type 2 diabetes mellitus. An analysis of the distribution of genetic determinants, depending on the acetylation status, was carried out. The bimodal distribution of the phenotypic polymorphism of NAT 2 activity was revealed among diabetic patients and healthy individuals. There was no gender difference in NAT2 activity in both groups of subjects. Genetic analysis showed a prevalence of brown-eyed diabetic patients compared to blue-eyed persons among fast acetylators. Among diabetic patients prevailed subjects with dimples on the chin and cheeks and the enlarged ear lobe as well as the reduced proportion of patients with the ability to twist the tongue into a tube compared to healthy individuals. There was a significantly increased proportion of black-haired persons among diabetic patients compared to healthy individuals. Acetylation phenotype prediction scale developed was developed, which allows determining the acetylator status without biochemical intervention, but using anthropometric indicators.


Assuntos
Arilamina N-Acetiltransferase/genética , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Polimorfismo Genético/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
4.
J Agric Food Chem ; 67(47): 13051-13060, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31609623

RESUMO

Gymnemic acid (GA) isolated from Gymnema sylvestre (Retz.) Schult. has been shown to have antihyperglycemic activity; however, the molecular mechanisms governing these effects are unclear. In this study, GA (40 and 80 mg kg-1 day-1) was evaluated by type 2 diabetes mellitus (T2DM) rats to explore its hypoglycemic activity and underlying mechanisms of action. The results indicated that GA decreased fasting blood glucose (FBG) concentrations by 26.7% and lowered insulin concentrations by 16.1% after oral administration of GA at a dose of 80 mg kg-1 day-1 for 6 weeks in T2DM rats. Our data showed that real-time polymerase chain reaction and western blot indicated that GA upregulated the level of phosphatidylinositol-3-kinase (PI3K) and glycogen synthesis (GS) and promoted the phosphorylation of protein kinase B (Akt) while downregulated the expression of glycogen synthesis kinase-3ß (GSK-3ß) in T2DM rats. In addition, key proteins involved in adenosine monophosphate (AMP)-activated protein kinase (AMPK)-mediated gluconeogenesis [such as phosphoenolpyruvate carboxy kinase (PEPCK) and glucose-6-phosphatase (G6Pase)] were downregulated in GA-treated T2DM rats. In summary, the hypoglycemic mechanisms of GA may be related to promoting insulin signal transduction and activating PI3K/Akt- and AMPK-mediated signaling pathways in T2DM rats.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Saponinas/administração & dosagem , Triterpenos/administração & dosagem , Proteínas Quinases Ativadas por AMP/genética , Animais , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Humanos , Insulina/metabolismo , Masculino , Fosfatidilinositol 3-Quinase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
5.
Expert Opin Ther Pat ; 29(9): 689-702, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31402706

RESUMO

Introduction: Protein tyrosine phosphatase 1B (PTP1B) inhibition has been recommended as a crucial strategy to enhance insulin sensitivity in various cells and this fact is supported by human genetic data. PTP1B inhibitors improve the sensitivity of the insulin receptor and have the ability to cure insulin resistance-related diseases. In the latter years, targeting PTP1B inhibitors is being considered an attractive target to treat T2DM and therefore libraries of PTP1B inhibitors are being suggested as potent antidiabetic drugs. Areas covered: This review provides an overview of published patents from January 2015 to December 2018. The review describes the effectiveness of potent PTP1B inhibitors as pharmaceutical agents to treat type 2 diabetes. Expert opinion: Enormous developments have been made in PTP1B drug discovery which describes progress in natural products, synthetic heterocyclic scaffolds or heterocyclic hybrid compounds. Various protocols are being followed to boost the pharmacological effects of PTP1B inhibitors. Moreover these new advancements suggest that it is possible to get small-molecule PTP1B inhibitors with the required potency and selectivity. Furthermore, future endevours via an integrated strategy of using medicinal chemistry and structural biology will hopefully result in potent and selective PTP1B inhibitors as well as safer and more effective orally available drugs.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Antígenos CD/metabolismo , Diabetes Mellitus Tipo 2/enzimologia , Desenho de Drogas , Descoberta de Drogas/métodos , Inibidores Enzimáticos/farmacologia , Humanos , Patentes como Assunto , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Receptor de Insulina/metabolismo
6.
BMC Complement Altern Med ; 19(1): 206, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391018

RESUMO

BACKGROUND: About 425 million adults had diabetes mellitus globally in 2017. Type 2 diabetes accounts for the enormous majority of diabetes cases and it is gradually growing which is predicted to increase by 48% in 2045. Imbalanced cellular carbohydrate and lipid metabolism cause an increase in postprandial blood glucose level which eventually leads to the onset and progression of type 2 diabetes mellitus. The lack of effective and safe carbohydrate hydrolyzing enzyme inhibitors contributes to the increasing prevalence. Thus, this study was targeted to assess the α-amylase inhibitory potential of isolates obtained from Aloe megalacantha Baker and Aloe monticola Reynolds, which are among the commonly used folkloric remedies for the management of diabetes mellitus. METHOD: The α-amylase inhibitory effect of Aloe megalacantha Baker and Aloe monticola Reynolds were evaluated using the 3,5-dinitro salicylic acid method. 2, 2-Diphenyl-2-picrylhydrazyl free radical scavenging property was also used to test the antioxidant effect of both plants. Results were analysed using GraphPad Prism software version 8. RESULTS: The more polar isolates (AM1 and AG1) were possessed stronger α-amylase inhibition activity than the leaves latex and the other strains (AM2 and AG2). Leaf latex of A. megalacantha, AM1, AM2, leaf latex of A. monticola, AG1, and AG2 were found to have an IC50 value of 74.76 ± 1.98, 37.83 ± 3.31, 96.75 ± 1.98, 78.10 ± 1.88, 56.95 ± 1.88 and 64.03 ± 3.60 µg/mL, respectively (P < 0.001). The leaf latexes of A. megalacantha and A. monticola showed a significant (P < 0.001) free radical hunting property with an IC50 value of 890.1 ± 1.73 and 597.5 ± 2.02 µg/mL, respectively. CONCLUSION: Hence, the outcomes of the present investigation partly justify the acclaimed use of Aloe megalacantha and Aloe monticola for the treatment of diabetes.


Assuntos
Aloe/química , Inibidores Enzimáticos/química , Extratos Vegetais/química , Antioxidantes/química , Antioxidantes/isolamento & purificação , Cromatografia em Camada Delgada , Diabetes Mellitus Tipo 2/enzimologia , Inibidores Enzimáticos/isolamento & purificação , Humanos , Cinética , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , alfa-Amilases/antagonistas & inibidores
7.
Eur J Pharmacol ; 859: 172521, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31276666

RESUMO

Dipeptidyl peptidase-4 (DPP-4) inhibitors prevent the degradation of glucagon-like peptide-1 (GLP-1) and improve glycemic control. The GLP-1 insulinotropic effect involves a pathway through vagus nerve GLP-1 receptors in the gut, in addition to a direct effect on the pancreas. Therefore, this study verified whether DPP-4 inhibition in the gut contributed to the improvement of glycemic control. Anagliptin, a DPP-4 inhibitor, was administered orally or subcutaneously (with or without passing through the gastrointestinal tract, respectively) to mice. The association between blood glucose suppression following oral glucose challenge and DPP-4 inhibition in the small intestine and plasma was assessed. Oral administration of anagliptin (0.03-0.3 mg/kg) in normal mice significantly suppressed blood glucose, which was associated with an increase in insulin secretion at a dose of ≥0.1 mg/kg (P < 0.05). Subcutaneous administration of anagliptin (0.01-0.1 mg/kg) produced similar results. However, plasma DPP-4 inhibition following oral administration was weaker than that following subcutaneous administration; blood glucose suppression was significantly correlated with small intestinal DPP-4 inhibition (r = 0.949, P < 0.01), but not with plasma DPP-4 inhibition. Additionally, similar results were observed in a type 2 diabetes model (r = 0.975, P < 0.001). Thus, these results demonstrated that an improvement in glycemic control was dependent upon small intestinal DPP-4 inhibition. As these effects were accompanied by the elevation of intact GLP-1 in the portal, this suggests that improvement in glucose tolerance after anagliptin treatment might be related to an increase in GLP-1 receptor signaling in the small intestine and portal vein.


Assuntos
Inibidores da Dipeptidil Peptidase IV/farmacologia , Incretinas/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/enzimologia , Animais , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/metabolismo , Teste de Tolerância a Glucose , Incretinas/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pirimidinas/farmacologia
8.
J Sci Food Agric ; 99(14): 6380-6391, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31283026

RESUMO

BACKGROUND: Prickly pears are potential candidates for the development of low-cost functional foods because they grow with low water requirements in arid regions of the world. They are sources of betalains and phenolic compounds, which have been reported to contribute to human health. The study of the biological activity of different varieties and of their isolated bioactive constitutes is fundamental in the design of functional foods. In this context, our objective is the assessment of the ability of Spanish and Mexican prickly-pear cultivars to inhibit enzymes related to type 2 diabetes and the inflammatory response, and the contribution of their bioactive compounds to their nutra-pharmaceutical potential. RESULTS: Prickly pear peels presented the highest antioxidant activity due to their high isorhamnetin glycoside content. Isorhamnetin glycosides showed significantly higher antioxidant and anti-inflammatory activity than aglycone, particularly isorhamnetin glucosyl-rhamnosyl-pentoside (IG2), which also reported antihyperglycemic activity. Morada, Vigor, and Sanguinos whole fruits exhibited moderate α-amylase inhibition and higher α-glucosidase inhibition, which is ideal for lowering glucose absorption in hyperglycemia management. Sanguinos peels presented the highest anti-inflammatory activity because of their high indicaxanthin content and isorhamnetin glycoside profile. CONCLUSIONS: In the design of prickly pear functional foods, technological processing should prioritize the retention or concentration of these bioactive compounds to preserve (or increase) their natural antioxidant, antihyperglycemic and anti-inflammatory activity. Peels of red and orange varieties should be further evaluated for antioxidant and anti-inflammatory purposes while whole fruits of red and purple varieties could be considered possible candidates for hyperglycemia management. © 2019 Society of Chemical Industry.


Assuntos
Anti-Inflamatórios/química , Diabetes Mellitus Tipo 2/enzimologia , Inibidores Enzimáticos/química , Hipoglicemiantes/química , Extratos Vegetais/química , Pyrus/química , Antioxidantes/química , Betalaínas/química , Diabetes Mellitus Tipo 2/metabolismo , Frutas/química , Inibidores de Glicosídeo Hidrolases/química , Humanos , Cinética , Fenóis/química , Pyrus/classificação , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/química , alfa-Amilases/metabolismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
9.
Biomed Res Int ; 2019: 5613514, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355267

RESUMO

Objective: The present study aimed to compare levels of matrix metalloproteinase-9 (MMP-9) and myeloperoxidase (MPO) in gingival crevicular fluid (GCF) from subjects with controlled and noncontrolled Type 2 Diabetes Mellitus (T2D), with and without stage 2 grade B periodontitis (POD2B) versus healthy (H) subjects. Methods: The levels of both enzymes, from 80 GCF samples collected with PerioPaper strips, were analyzed by a Multiplex/Luminex assay. Five groups were formed, all current patients at the Institutional Dentistry Service, and distributed as follows: two groups of diabetics (one controlled and one poorly controlled); two groups with the previous conditions and diagnosed with POD2B; and one H group. Results: The highest concentration of MMP-9 corresponded to the H group, while the lowest corresponded to the T2D controlled group. Regarding MPO levels, the highest levels were associated with the T2D controlled with POD2B group and the lowest with the T2D controlled group. Conclusions: No apparent relationship between the elevation of MMP-9 and MPO levels was observed among subjects with T2D, with and without POD2B, compared to H subjects.


Assuntos
Diabetes Mellitus Tipo 2/enzimologia , Líquido do Sulco Gengival/enzimologia , Metaloproteinase 9 da Matriz/metabolismo , Periodontite/enzimologia , Peroxidase/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
10.
Wounds ; 31(5): E39-E41, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31184591

RESUMO

OBJECTIVE: The aim of this study is to evaluate how treatment with total contact cast (TCC) affects the balance of proteases in diabetic foot ulcers (DFUs) as they heal. MATERIALS AND METHODS: This was a prospective observational study of 22 eligible patients with neuropathic plantar DFUs in a hospital-based wound care center. All patients treated with TCC had adequate arterial circulation (ankle-brachial index > 0.75), no sign of infection, and all DFUs were grade 1A according to the University of Texas Diabetic Wound Classification System. Patients had weekly follow-up visits for wound evaluation and reapplication of the TCC. Wound tissues were obtained at baseline (week 0 prior to initial treatment), week 3, week 6, and week 12. Tissue homogenates were analyzed for matrix metalloprotease (MMP) 2, MMP-9, tissue inhibitor matrix metalloproteinase (TIMP) 1, and TIMP-2. Wound measurements were obtained at weekly follow-up visits, and healing rates were calculated by photodigital planimetry. RESULTS: Treatment with TCC for 3 weeks resulted in a 20% decrease in MMP-2 (P = .031) and 44% decrease in MMP-9 (P = .018). By week 6, MMP-2 and MMP-9 levels were reduced by 37% and 55%, respectively. Tissue inhibitor matrix metalloproteinase 1 increased by 42% (P = .033) and TIMP-2 by 44% (P = .04) after 6 weeks of therapy with TCC. CONCLUSIONS: This significant and rapid drop of both MMP-2 and MMP-9 strongly suggests a decline of the inflammatory phase and initiation of the proliferation phase.


Assuntos
Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 2/enzimologia , Pé Diabético/enzimologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Moldes Cirúrgicos , Diabetes Mellitus Tipo 1/cirurgia , Diabetes Mellitus Tipo 2/cirurgia , Pé Diabético/cirurgia , Regulação para Baixo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Cicatrização/fisiologia , Adulto Jovem
11.
Mol Cell Biochem ; 459(1-2): 171-182, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31154588

RESUMO

Alzheimer's disease (AD) and type 2 diabetes (T2D) share the common hallmark of insulin resistance. It is conjectured that receptor tyrosine kinases (RTKs) play definitive roles in the process. To decipher the signaling overlap behind this phenotypic resemblance, the activity status of RTKs is probed in post-mortem AD and T2D tissues and cell models. Activities of only about one-third changed in a similar fashion, whereas about half of them showed opposite outcomes when exposed to contrasting signals akin to AD and T2D. Interestingly, irrespective of disease type, RTKs with enhanced and compromised activities clustered distinctly, indicating separate levels of regulations. Similar regulatory mechanisms within an activity cluster could be inferred, which have potential to impact future therapeutic developments.


Assuntos
Doença de Alzheimer/enzimologia , Encéfalo/enzimologia , Diabetes Mellitus Tipo 2/enzimologia , Resistência à Insulina , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais , Doença de Alzheimer/patologia , Encéfalo/patologia , Diabetes Mellitus Tipo 2/patologia , Células Hep G2 , Humanos
12.
Diabetes Metab Syndr ; 13(3): 2021-2024, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31235130

RESUMO

AIM: This study evaluated the activity of xanthine oxidase in Nigerians with type 2 diabetic mellitus as well as its relationship with lipid peroxidation, inflammatory bio markers and glycemic control indices. METHODS: Two hundred and thirty seven (237) subjects, comprising of one hundred and fifty seven (157) DM subjects and eighty (80) aged matched controls participated in this study. Blood samples were collected from the participants for the estimations of xanthine oxidase activity, uric acid, malon diadehyde (MDA), erythrocyte sedimentation rate (ESR), high sensitive c - reactive protein (hs CRP), glucose, fructosamine and glycosylated hemoglobin by standard methods. RESULTS: The results of this study showed a significantly increased activity of xanthine oxidase in DM (0.044 ±â€¯0.05µ/mg) compared with apparently healthy controls (0.028 ±â€¯0.00 µ/mg). The mean plasma levels of MDA (42.40 ±â€¯2.50µmol/l) and uric acid (7.22 ±â€¯0.20 mg/dl) in DM were significantly higher (p ≤ 0.05) than healthy non DM group. The mean levels of hs CRP in DM (4.09 ±â€¯0.91µg/ml) was significantly higher than controls (1.30 ±â€¯0.50µg/ml, p = 0.009). While no association of xanthine oxidase was observed with glycemic control indices and hs CRP, a negative association of xanthine oxidase was observed with MDA (r = -0.514, p = 0.000). CONCLUSION: Increased activity of xanthine oxidase in DM was associated with increased lipid peroxidation and could be a salient entity towards the onset on complications.


Assuntos
Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/epidemiologia , Peroxidação de Lipídeos , Estresse Oxidativo , Xantina Oxidase/metabolismo , Adulto , Idoso , Glicemia/análise , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Feminino , Seguimentos , Frutosamina/metabolismo , Hemoglobina A Glicada/análise , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Nigéria/epidemiologia , Prognóstico , Ácido Úrico/metabolismo
13.
Biomed Res Int ; 2019: 5747436, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214617

RESUMO

The metabolic syndrome is defined by impaired carbohydrate metabolism and lipid disorders and often accompanied by hypertension, all of which will lead to obesity and insulin resistance. Glucocorticoids play a regulatory role in the metabolism of proteins, lipids, and carbohydrates. There is growing evidence for a role of glucocorticoids in the development of the metabolic syndrome. The most important factor that regulates the access of endogenous glucocorticoids to receptors after release of glucocorticoids and their diffusion into the cytoplasm of target cells is the steroid metabolism involving a microsomal enzyme, 11ß-hydroxysteroid dehydrogenase (11ß-HSD). The changes in intracellular glucocorticoid metabolism in the pathogenesis of obesity indicate the participation of modulation by 11ß-HSD1, which may represent a new therapeutic target for the treatment of diseases such as type 2 diabetes, visceral obesity, or atherosclerosis. The aim of our study was to determine the fast and effective method to assess inhibition activity of compounds in relation with 11ß-hydroxysteroid dehydrogenase. The material for this study was human liver and kidney microsomes. In this study we used ELISA technique using 96-well microplates coated with antibodies which were specific for analyzed enzymes. The method can quickly and efficiently measure the inhibition of both 11ß-HSD1 and 11ß-HSD2. This method can be used to search for and determine inhibitors of this enzyme. Cortisone and cortisol were used as the substrates for corresponding enzyme assays. Furthermore, 3-N-allyl-2-thiouracil derivatives were used by us for comparison purposes in developing the method, although, due to their structure, those derivatives have not previously been considered as potential inhibitors of 11ß-HSD1. 3-N-Allyl-2-thiouracil derivatives are a group worth considering, because by modifying their structure (e.g., by introducing other substituents into the pyrimidine ring) it will be possible to obtain an increase in the activity of compounds in this regard. In conclusion, this study shows an efficient and fast method of determining inhibition activity of compounds in relation with 11ß-hydroxysteroid dehydrogenase.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Inibidores Enzimáticos , Microssomos/enzimologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , Aterosclerose/tratamento farmacológico , Aterosclerose/enzimologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/enzimologia , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Obesidade Abdominal/tratamento farmacológico , Obesidade Abdominal/enzimologia
14.
BMC Complement Altern Med ; 19(1): 136, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31215434

RESUMO

BACKGROUND: Tomato fruit (Lycopersicon esculentum Mill.) has been suggested to be useful for the prevention of diabetes. Esculeoside A is the main saponin compounds in tomatoes. This study investigated the hypoglycemic effects and the underlying mechanism of esculeoside A in C57BLKS/Leprdb (db/db) mice. METHODS: Wild-type C57BLKS (db/dm) mice were used in the db/dm mouse group and db/db mice were randomly divided into 2 groups: untreated and treated db/db mouse groups. Esculeoside A (100 mg/kg) was administered by gavage for 56 days to the treated db/db mouse group. Distilled water was administered to the db/dm mouse group and the untreated db/db mouse group. The blood and liver biochemical parameters and the expression of liver insulin signaling-related proteins were examined. RESULTS: The results showed that esculeoside A reduced the fasting blood glucose (FBG) levels and improved the glucose tolerance. Further investigation revealed that hepatic protein expressions of total AMP-activated protein kinase (T-AMPK), phosphorylated AMP-activated protein kinase (p-AMPK), insulin receptor substrate-1 (IRS-1), and glucokinase (GCK) were significantly upregulated after esculeoside A treatment. In contrast, the hepatic protein expression of phosphoenolpyruvate carboxykinase (PEPCK) was significantly downregulated by esculeoside A treatment. CONCLUSION: These findings suggested that esculeoside A has a potential of alleviating the metabolic abnormalities in db/db mice via regulation of AMPK/IRS-1 pathway. Our findings supported a possible application of esculeoside A as a functional supplement for diabetes treatment.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Proteínas Substratos do Receptor de Insulina/genética , Sapogeninas/administração & dosagem , Proteínas Quinases Ativadas por AMP/genética , Animais , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Glucoquinase/genética , Glucoquinase/metabolismo , Humanos , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Regulação para Cima
15.
Expert Opin Ther Pat ; 29(7): 535-553, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31203700

RESUMO

INTRODUCTION: Dipeptidyl peptidase 4 (DPP-4) belongs to the family of serine proteases and is involved in the degradation of GLP-1 and GIP hormones, which enhance the production and release of insulin. Targeting DPP-4 inhibitors is increasingly being considered as promising paradigms to treat type 2 diabetes mellitus and therefore DPP-4 inhibitors are being considered as promising antidiabetic drugs. AREAS COVERE: This review provides an overview of published patents describing natural and synthetic DPP-4 inhibitors from January 2015 to December 2018. EXPERT OPINION: A fair number of new synthetic and natural DPP-4 inhibitors have been reported in the last four years which describe the progress in the development of various heterocyclic scaffolds or heterocyclic hybrid compounds. As a result of this, many marketed DPP-4 inhibitors that have been approved by the appropriate governing bodies during the past decade, have been introduced as inhibitors. Molecular hybridization is an emerging idea in medicinal chemistry and therefore hybrid compounds of DPP-4 inhibitors with other DPP-4 inhibitors or with antidiabetic drugs should be formulated for a comprehensive evaluation. More detailed pharmacovigilance of DPP-4 inhibitors is required because this will address the pancreas-related adverse events as well as their impact on cardiovascular outcomes via long-term studies.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Animais , Diabetes Mellitus Tipo 2/enzimologia , Dipeptidil Peptidase 4/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Desenho de Drogas , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/metabolismo , Patentes como Assunto
16.
Clin Biochem ; 69: 15-20, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31129183

RESUMO

OBJECTIVE: Despite the current guidelines for the management of type 2 diabetes mellitus (T2DM), patients still struggle with the hyperglycemia consequences. Imbalance in zinc homeostasis, in particular, renders diabetic patients more susceptible to the damages of oxidative stress. This study aimed to evaluate the effects of zinc supplementation on the superoxide dismutase gene expression and enzyme activity in overweight individuals with T2DM. Additionally, biochemical parameters, such as fasting blood glucose (FBG), insulin, glycated hemoglobin (HbA1c), homeostasis model of assessment-insulin resistance (HOMA-IR), serum levels of zinc and lipid profile, were assessed. METHODS: In this randomized, double-blind, placebo-controlled trial, 70 overweight (BMI > 25) T2DM patients were selected based on the inclusion criteria. They were divided into two groups for supplementation of daily 50 mg zinc gluconate or placebo for 8 weeks. Blood samples were collected from all the individuals in the zinc group and controls for analysis. RESULTS: The results showed that, in comparison with the control group, zinc supplementation increased both gene expression and enzyme activity of SOD (p < 0.01) as well as the levels of insulin (p = 0.02) among the patients in the zinc group. Moreover, there was a meaningful reduction in the levels of FBG, HbA1c and HOMA-IR value (p < 0.001), triglycerides and total cholesterol (p < 0.05) after the zinc treatment. CONCLUSIONS: Taken together, the current study suggests that daily supplementation with 50 mg zinc gluconate could be a useful approach for the management of overweight T2DM. CLINICAL TRIAL REGISTRATION: IRCT2015083102.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Sobrepeso/complicações , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Zinco/administração & dosagem , Adulto , Idoso , Biomarcadores/sangue , Glicemia/análise , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Método Duplo-Cego , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Placebos , RNA Mensageiro/metabolismo
17.
Artigo em Inglês | MEDLINE | ID: mdl-30954797

RESUMO

α-Glucosidase (AG) is an important drug target for the treatment of type 2 diabetes mellitus in humans due to the potential effect of down regulating glucose absorption in patients. In our previous study, salvianolic acid A (SAA) was found to exhibit potent AG inhibitory activity, whereas the interaction mechanism was still ambiguous. Herein, the interaction mechanism of SAA and AG was investigated by multi-spectroscopic methods along with molecular docking. As a result, it was found that SAA reversibly inhibited AG in a competitive manner with IC50 of 16.44 ±â€¯0.18 µM, and the inhibition belonged to a multi-phase kinetics process with a first-order reaction. The intrinsic fluorescence of AG could be strongly quenched by SAA through a static quenching mechanism. The negative Gibbs free energy change and positive values of enthalpy and entropy change revealed that the binding of SAA to AG was spontaneous and dominated mainly by hydrophobic interactions, and only a single binding site was determined for them. Analysis of synchronous fluorescence, ANS-binding fluorescence, circular dichroism and Fourier transform infrared spectra suggested that the binding of SAA to AG induced rearrangement and conformational changes of the enzyme. Besides, further molecular modelling validated that SAA could bind to the active domain and prevent the entrance of substrate, resulting in the inhibition of AG activity. These findings provide new insights into understanding the interaction mechanism of SAA on AG.


Assuntos
Ácidos Cafeicos/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Lactatos/farmacologia , alfa-Glucosidases/metabolismo , Ácidos Cafeicos/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/enzimologia , Inibidores de Glicosídeo Hidrolases/química , Humanos , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Cinética , Lactatos/química , Simulação de Acoplamento Molecular , Ligação Proteica , Termodinâmica , alfa-Glucosidases/química
18.
Clin Chim Acta ; 495: 54-59, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30946812

RESUMO

BACKGROUND: Previous studies have revealed that alanine aminotransferase (ALT) may be one of the risk factors of developing diabetes. We aimed to demonstrate the independent effect of ALT on incident diabetes and to investigate whether the association between ALT and incident diabetes is modified by age and gender in the general Chinese population. METHODS: The present study was a retrospective cohort study, including 210,051 Chinese adult participants. The primary outcome was developing diabetes. The serum ALT activities were stratified by quintiles. We obtained data from 'DATADRYAD' website and used the data for secondary analysis. RESULTS: At a median follow-up of 3.0 y, 4144 of 210,051 (1.97%) participants developed diabetes. After adjustment for potential confounders, a significantly higher risk of the incident diabetes (HR: 1.43, 95% CI: 1.25-1.63) was found in participants in the fifth quintile (Q5, ≥31 U/L) compared to those in the first to fourth quintiles (Q1-4) for ALT activities. Among males aged 30 to 40 and 40 to 50 y with the fifth quintile of ALT activity had 2.4- and 1.5-fold increased odds of developing diabetes, respectively, in comparison with those in the lower ALT activities. Among females with age 30 to 40 and ≥ 70 y, the fifth quintile of ALT activity had 4.9- and 2.2-fold increased odds for incident diabetes. CONCLUSION: Our result indicated that the ALT activity was positively associated with the incident diabetes among Chinese persons. Moreover, 30-40 y individuals, whether male or female, with elevated ALT activities had the greatest increased risk for diabetes compared with persons with lower ALT activities in the same age group.


Assuntos
Alanina Transaminase/metabolismo , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/epidemiologia , Adulto , Distribuição por Idade , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Distribuição por Sexo
19.
Carbohydr Polym ; 209: 350-355, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30732817

RESUMO

This study investigated the in vitro and in silico inhibitory properties of fucoidan extracted from Turbinaria conoides against α-amylase and α-D-glucosidase. Extracted fucoidan contained 59 and 35% of fucose and sulphate and was characterized using 1H NMR. Dose dependent inhibition assays showed maximum of 85 and 72% of inhibition for α-amylase and α-D-glucosidase at 2.07 and 1.03 µM concentration of fucoidan. The IC50 value of fucoidan was found to be 1.07 and 0.68 µM against α-amylase and α-D-glucosidase. In silico studies (grid based docking) by Schrödinger software revealed that fucoidan as a potent inhibitor for both α-amylase and α-D-glucosidase based on number of interactions, hydrogen bond length and binding energy. Furthermore, fucoidan fulfilled the pharmacokinetic properties thus promising to develop fucoidan as drug for type 2 DM.


Assuntos
Simulação por Computador , Diabetes Mellitus Tipo 2/enzimologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Polissacarídeos/farmacologia , alfa-Amilases/antagonistas & inibidores , alfa-Glucosidases/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/metabolismo , Simulação de Acoplamento Molecular , Polissacarídeos/química , Polissacarídeos/metabolismo , Conformação Proteica , Relação Estrutura-Atividade , alfa-Amilases/química , alfa-Amilases/metabolismo , alfa-Glucosidases/química
20.
Pak J Pharm Sci ; 32(1): 61-68, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30772791

RESUMO

In the current research work, a series of new N-(alkyl/aralkyl)-N-(2,3-dihydro-1,4-benzodioxan-6-yl)-4-chlorobenzenesulfonamides has been synthesized by reacting 1,4-benzozzdioxan-6-amine (1) with 4-chlorobenzenesulfonyl chloride (2) to yield N-(2,3-dihydro-1,4-benzodioxan-6-yl)-4-chlorobenzenesulfonamide (3) which was further reacted with different alkyl/aralkyl halides (4a-n) to afford the target compounds (5a-n). Structures of the synthesized compounds were confirmed by IR, 1H-NMR, EI-MS spectral techniques and CHN analysis data. The results of enzyme inhibition showed that the molecules, N-2-phenethyl-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-chlorobenzenesulfonamide (5j) and N-(1-butyl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-chlorobenzenesulfonamide (5d), exhibited moderate inhibitory potential against acetylcholinesterase with IC50 values 26.25±0.11 µM and 58.13±0.15 µM respectively, whereas, compounds N-benzyl-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-chlorobenzenesulfonamide (5i) and N-(pentane-2-yl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-chlorobenzenesulfonamide (5f) showed moderate inhibition against α-glucosidase enzyme as evident from IC50 values 74.52±0.07 and 83.52±0.08 µM respectively, relative to standards Eserine having IC50 value of 0.04±0.0001 µM for cholinesterases and Acarbose having IC50 value 38.25±0.12 µM for α-glucosidase, respectively.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/enzimologia , Butirilcolinesterase/metabolismo , Diabetes Mellitus Tipo 2/enzimologia , Espectrometria de Massas , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Relação Estrutura-Atividade , alfa-Glucosidases/metabolismo
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