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1.
Rev Assoc Med Bras (1992) ; 65(9): 1144-1150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618328

RESUMO

OBJECTIVE: In view of the high incidence of polycystic ovary syndrome (PCOS) and the unsatisfactory therapeutic effects of dimethyldiguanide or clomifene citrate alone, our study aimed to investigate the therapeutic effects of dimethyldiguanide combined with clomifene citrate in the treatment of PCOS. METHODS: A total of 79 patients with POCS and 35 healthy females were included, and endometrial biopsies were obtained. The sterol regulatory element-binding protein-1 (SREBP1) expression in endometrial tissues was detected by qRT-PCR. POC patients were randomly divided into group A (n=40) and group B (n=39). Patients in group A were treated with dimethyldiguanide combined with clomifene citrate, while patients in group B were treated with clomifene citrate alone. The number of mature follicles and cervical mucus score, follicular development rate and single follicle ovulation rate, cycle pregnancy rate, early miscarriage rate, ovulation rate, endometrial thickness, positive rate of three lines sign, follicle stimulating hormone level and luteinizing hormone level were compared between the two groups. RESULTS: The expression level of SREBP1 was higher in PCOS patients than that in the healthy control. SREBP1 expression was inhibited after treatment, while the inhibitory effects of combined treatment were stronger than those of clomifene citrate alone. Compared with clomifene citrate alone, the combined treatment improved cervical mucus score, follicle development rate, single follicle ovulation rate, endometrial thickness, positive rate of three lines sign, and follicle-stimulating hormone level. CONCLUSION: The therapeutic effect of combined treatment is better than clomifene citrate alone in the treatment of PCOS.


Assuntos
Clomifeno/uso terapêutico , Fármacos para a Fertilidade Feminina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Adulto , Muco do Colo Uterino/efeitos dos fármacos , Clomifeno/farmacologia , Quimioterapia Combinada , Endométrio/fisiopatologia , Feminino , Fármacos para a Fertilidade Feminina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Folículo Ovariano/efeitos dos fármacos , Indução da Ovulação , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Adulto Jovem
2.
Acta Crystallogr C Struct Chem ; 75(Pt 9): 1250-1258, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31484813

RESUMO

A drug-drug anhydrous pharmaceutical salt containing tolbutamide {systematic name: 3-butyl-1-[(4-methylbenzene)sulfonyl]urea, TOL, C12H18N2O3S} and metformin (systematic name: 1-carbamimidamido-N,N-dimethylmethanimidamide, MET, C4H11N5) was created based on antidiabetic drug combinations to overcome the poor pharmaceutical properties of the parent drugs. Proton transfer and the proportion of the two components were confirmed by 1H NMR spectroscopy and single-crystal X-ray diffraction analysis. Comprehensive characterization of the new pharmaceutical salt crystal, 2-[(dimethylamino)(iminiumyl)methyl]guanidine (butylcarbamoyl)[(4-methylbenzene)sulfonyl]azanide, C4H12N5+·C12H17N2O3S-, was performed and showed enhancement of the pharmaceutical properties, such as lower hygroscopicity and greater accelerated stability than the parent drug MET, and higher solubility and dissolution rate than TOL. The property alterations were correlated with the crystal packing features and potential hydrogen-bonding sites through observed changes in the crystal structures.


Assuntos
Hipoglicemiantes/farmacologia , Metformina/farmacologia , Tolbutamida/farmacologia , Cristalografia por Raios X , Combinação de Medicamentos , Ligações de Hidrogênio , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Metformina/síntese química , Metformina/química , Estrutura Molecular , Solubilidade , Tolbutamida/síntese química , Tolbutamida/química
3.
Medicine (Baltimore) ; 98(36): e17081, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31490412

RESUMO

OBJECTIVE: The purpose of this study was to assess the efficacy and hypoglycemic risk of sitagliptin versus that of GLP-1 receptor agonists in the management of obese/overweight patients with T2DM. METHODS: EMBASE, PubMed, Cochrane Library, and ClinicalTrials.gov were searched; randomized controlled trials comparing the efficacy of sitagliptin versus that of GLP-1 receptor agonists in obese/overweight patients with T2DM were included. The mean BMI of participants for each study was ≥30 kg/m. We conducted a meta-analysis according to the methods specified in the Cochrane Handbook for Systematic Reviews of Interventions. RevMan 5.1 software was used to perform the meta-analysis. The Cochrane Q test and I statistics were used to estimate the heterogeneity among studies. The results are expressed as the mean difference (MD) or risk ratio (RR) with 95% confidence intervals. RESULTS: A total of 8 eligible studies were included in our meta-analysis. Compared with GLP-1 receptor agonists, sitagliptin was less effective at reducing HbA1c (0.42 [0.27, 0.56]), FPG (0.78 [0.36, 1.19]), PPG (2.61 [1.35, 3.87]), and body weight (1.42 [0.71, 2.14]). Conversely, there were no significant differences in SBP reduction (0.38 [-1.14, 1.89]), DBP reduction (-0.30 [-1.00, 0.39]), and hypoglycemic risk (1.09 [0.50, 2.35]). CONCLUSION: For obese/overweight patients, sitagliptin may exert a less potent effect on HbA1C, FPG, PPG, and weight reduction than GLP-1 receptor agonists, but these drugs had a similar efficacy in reducing blood pressure; furthermore, there was no significant difference in hypoglycemic risk.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Obesidade/complicações , Fosfato de Sitagliptina/uso terapêutico , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/farmacologia , Fosfato de Sitagliptina/farmacologia
4.
Curr Top Med Chem ; 19(16): 1436-1444, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31512997

RESUMO

Type 2 diabetes is a major health issue worldwide with complex metabolic and endocrine abnormalities. Hyperglycemia, defects in insulin secretion and insulin resistance are classic features of type 2 diabetes. Insulin signaling regulates metabolic homeostasis by regulating glucose and lipid turnover in the liver, skeletal muscle and adipose tissue. Major treatment modalities for diabetes include the drugs from the class of sulfonyl urea, Insulin, GLP-1 agonists, SGLT2 inhibitors, DPP-IV inhibitors and Thiazolidinediones. Emerging antidiabetic therapeutics also include classes of drugs targeting GPCRs in the liver, adipose tissue and skeletal muscle. Interestingly, recent research highlights several shared intermediates between insulin and GPCR signaling cascades opening potential novel avenues for diabetic drug discovery.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Hipoglicemiantes/farmacologia , Receptor de Insulina/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglicemiantes/química , Receptor de Insulina/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo
5.
Int J Nanomedicine ; 14: 4741-4754, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456635

RESUMO

Background: Ipomoea batatas (L.) Lam.(Ib) has high content of various beneficial nutrients which helps in improving and maintaining human health. It is well known as a functional food and also a valuable source of unique natural products. It contains various phenolic and flavonoid bioactive compounds. Methods: In this study, using the outer peel of two varieties of Ib : Korean red skin sweet potato and Korean pumpkin sweet potato, silver nanoparticles (AgNPs) were synthesized (termed Ib1-AgNps and Ib2-AgNps), respectively. Characterization of Ib1-AgNPs and Ib2-AgNPs was carried out through scanning electron microscopy, Fourier-transform infrared (FT-IR) spectroscopy, energy-dispersive X-ray analysis, X-ray powder diffraction and UV-Vis spectroscopy. Further, the bio-potential of the synthesized AgNPs was investigated by antidiabetic (α-glucosidase assay), antioxidant (free radical scavenging assays), antibacterial (disc diffusion method) and cytotoxicity assays (cell viability against HepG2 cells). Results: FT-IR spectroscopy revealed the contribution of bioactive compounds existing in Ib1 and Ib2 extracts, in the biosynthesis and equilibrium of the AgNPs. Although the Ib2-AgNPs had a higher atomic percentage of Ag in comparison with Ib1-AgNPs, in the antidiabetic assay, the inhibition percentage of α-glucosidase was higher for AgNPs of Ib1 than Ib2, at all three concentrations examined. From the cytotoxicity results, HepG2 cancer cells were more sensitive to the Ib1-AgNPs in comparison to the Ib2-AgNPs-treated HepG2 cells. The antioxidant prospective was higher in Ib2-AgNPs than Ib1-AgNPs. Moreover, the Ib2-AgNPs showed inhibitory action against all five tested pathogenic bacteria, producing an inhibition zone of 8.74-11.52 mm while Ib1-AgNPs had an inhibitory effect on four of them, with an 8.67-11.23 (mm) inhibition zone. Conclusions: Overall, the results concluded that the Ib2-AgNPs exhibited relatively higher functional activity than Ib1-AgNPs, which might be credited to the greater abundance of bioactive compounds existing in Ib2 extract that acted as reducing as well as capping agents in the synthesis of Ib2-AgNPs. Overall, the current study highlights a novel cost-effective and eco-friendly AgNPs synthesis using food waste peels with biocompatibility and could be potentially utilized in biomedical and pharmaceutical industries.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Ipomoea batatas/química , Nanopartículas Metálicas/química , Prata/farmacologia , Bactérias/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Hipoglicemiantes/farmacologia , Concentração Inibidora 50 , Nanopartículas Metálicas/ultraestrutura , Testes de Sensibilidade Microbiana , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X , alfa-Glucosidases/metabolismo
6.
Life Sci ; 234: 116776, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31425698

RESUMO

Glucagon-like peptide-1 is a peptide of incretin family which is used in the management of diabetes as glucagon-like peptide-1 receptor agonist (GLP-1RA). Dipeptidyl peptidase-4 enzyme metabolizes glucagon-like peptide-1 and various dipeptidyl peptidase-4 enzyme inhibitors (DPP-4i) are also used in the management of diabetes. These antidiabetic agents provide anti-hyperglycemic effects via several molecular mechanisms including promoting insulin secretion, suppression of glucagon secretion and slowing the gastric emptying. There is some research suggesting that they can induce insulin sensitivity in peripheral tissues. In this study, we review the possible molecular mechanisms by which GLP-1RA and DPP-4i can improve insulin resistance and increase insulin sensitivity in insulin-dependent peripheral tissues.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Animais , Diabetes Mellitus/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Glucose/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Estresse Oxidativo/efeitos dos fármacos
7.
Adv Exp Med Biol ; 1155: 87-99, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468388

RESUMO

The present study has investigated the effect of adding taurine (TAU) to a treatment of diabetes with metformin (MET), a hypoglycemic, and lovastatin (LOV), an antihyperlipidemic. To this end, male Sprague-Dawley rats, agent, 250-275 g in weight, were made diabetic with a single 60 mg/kg intraperitoneal (i.p.) dose of streptozocin (STZ) in 10 mM citrate buffer pH 4.5, and, after 14 days, treated daily with oral doses of MET (2.4 mM/kg), LOV (0.075 mM/kg) or TAU (2.4 mM/kg), and with binary and ternary combinations of these agents. Rats receiving only 10 mM citrate buffer pH 4.5 or only STZ served as negative and positive controls, respectively. In addition, rats receiving insulin (INS, 4 units/kg) by the subcutaneous route served as a reference treatment. All the rats were sacrificed on day 57 and their bloods collected into heparinized tubes. The corresponding plasma samples were analyzed for their glucose (GLC), insulin (INS), glycated hemoglobin (HbA1c), cholesterol (CHOL) and triglycerides (TG) contents. In comparison to normal rats, diabetic ones showed marked increases in GLC (+313%), HbA1c (+207%), CHOL (+66%) and TG (+188) and a profound decrease of INS levels (-76%) (p < 0.001 vs. control values). Among the various treatments, one with INS produced the greatest lowering effect on the plasm a GLC (+23%, p < 0.05), INS (+23%, p < 0.05) and TG (+3%), with the remaining changes being similar to those seen with MET. A treatment with MET reduced all the diabetic changes by at least threefold; and one with LOV had a significant (p < 0.001) lowering effect on the plasma CHOL and TG but was without an effect on the plasma GLC, INS and HbA1c. In common with LOV, TAU reduced the diabetic levels of both CHOL and TG and, in addition, reduced the diabetic plasma GLC and raised the corresponding INS level. Among binary combinations, one with LOV-MET provided a greater effect than MET alone only in terms of the plasma CHOL and TG; and one with LOV-TAU was only significantly better than TAU alone in lowering the TG levels. However, a treatment with LOV-MET-TAU led to reductions in all the plasma parameters examined that were much greater than those achieved with any of the individual agents or with their binary combinations (at p ≤ 0.05).


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Lovastatina/farmacologia , Metformina/farmacologia , Taurina/farmacologia , Animais , Glicemia , Carboidratos/sangue , Hipolipemiantes/farmacologia , Insulina , Lipídeos/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Estreptozocina
8.
Chem Pharm Bull (Tokyo) ; 67(8): 824-838, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366832

RESUMO

We synthesized and evaluated novel 5-[2-(thiophen-2-yl)propan-2-yl]-4H-1,2,4-triazole derivatives as 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors. Optimization of the thiophene ring and the substituents on the 1,2,4-triazole ring produced 3,4-dicyclopropyl-5-{2-[3-fluoro-5-(trifluoromethyl)thiophen-2-yl]propan-2-yl}-4H-1,2,4-triazole monohydrochloride (9a), which showed potent and selective inhibitory activity against human 11ß-HSD1. Compound 9a was also metabolically stable against human and mouse liver microsomes. Oral administration of 9a to diabetic ob/ob mice lowered corticosterone levels in adipose tissue, and thereby reduced plasma glucose and insulin levels in a dose-dependent manner.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Triazóis/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Administração Oral , Animais , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Células HEK293 , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Obesos , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/administração & dosagem , Triazóis/química
9.
Expert Opin Investig Drugs ; 28(9): 741-747, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31398075

RESUMO

Introduction: Type 2 diabetes is a complex metabolic disorder defined by hyperglycemia which occurs because of impaired insulin secretion and sensitivity. There is an ongoing need to develop novel therapies that are effective and safe with minimal side effects and long-term durability. TTP399 is a hepatoselective, glucokinase activator with potential for treating type 2 diabetes. Areas covered: This is a review of the available data regarding the mechanism of action and the pharmacokinetics of TTP399. The efficacy and safety of the drug for treatment of type 2 diabetes will also be examined with an emphasis on the results of a randomized, controlled phase 2 study. Expert opinion: TTP399 could offer significant advantages over currently available therapies for type 2 diabetes. It successfully lowers glucose without side effects such as hypoglycemia, weight gain or dyslipidemia. Larger trials are required to understand long-term efficacy and safety of this medication in various patient populations and to elucidate its effect on the pathologic processes underpinning type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/fisiopatologia , Glucoquinase/efeitos dos fármacos , Glucoquinase/metabolismo , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Fígado/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Expert Opin Investig Drugs ; 28(9): 811-820, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31402716

RESUMO

Introduction: More than 424 million adults have diabetes mellitus (DM). This number is expected to increase to 626 million by 2045. The majority (90-95%) of people with DM has type 2-diabetes (T2DM). The continued prevalence of DM and associated complications has prompted investigators to find new therapies. One of the most recent additions to the anti-diabetic armamentarium are inhibitors of sodium-glucose co-transporters 1 and 2 (SGLT1, SGLT2). Areas covered: The authors review the status of SGLT2 inhibitors for the treatment of T2DM and place an emphasis on those agents in early phase clinical trials. Data and information were retrieved from American Diabetes Association, Diabetes UK, ClinicalTrials.gov, PubMed, and Scopus websites. The keywords used in the search were T2DM, SGLT1, SGLT2, and clinical trials. Expert opinion: The benefits of SGLT inhibitors include reductions in serum glycated hemoglobin (HbA1c), body weight, blood pressure and cardiovascular and renal events. However, SGLT inhibitors increase the risk of genitourinary tract infections, diabetic ketoacidosis, and bone fractures. The development of SGLT inhibitors with fewer side effects and as combination therapies are the key to maximizing the therapeutic effects of this important class of anti-diabetic drug.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Adulto , Animais , Diabetes Mellitus Tipo 2/fisiopatologia , Desenvolvimento de Medicamentos/métodos , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/efeitos dos fármacos , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
11.
DNA Cell Biol ; 38(10): 1134-1142, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31433203

RESUMO

Diabetes mellitus is a complicated metabolic disease characterized by hyperglycemia. Diabetic nephropathy (DN) is a progressive kidney disease, which results in mortality in diabetic patients. The present study was designed to investigate the effect of applying spironolactone (S), captopril (C), and their combination (S+C) on some renal performance indices and microRNAs' (miRNAs) expression. A total of 35 two-month-old male Wistar rats were provided for the study. Intraperitoneal injection of freshly dissolved streptozotocin (60 mg/kg) in cold citrate buffer was used to induce diabetes. Blood samples were examined through calorimetry to assess serum concentrations of glucose, blood urea nitrogen (BUN), and creatinine. To measure the microalbuminuria and transforming growth factor-ß (TGF-ß) levels and to evaluate the miRNAs expression levels of the kidney tissue, the ELISA method and the real-time PCR were used. The obtained results serve as in vivo evidence for the positive relationship between miR-192 and TGF-ß levels in the DN rats. A significant increase and decrease were found for miR-29a/b/c and the miR-192 expression of DN after treatment with S, C, and S+C. TGF-ß levels and microalbuminuria of diabetic rats also increased. The results obtained from this research study suggest that S, C, and S + C can improve DN by targeting miR-192 and miR-29 family and changing their expression. These findings suggest that miR-192 and miRs-29a/b/c can be potential targets for DN remediation.


Assuntos
Captopril/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Espironolactona/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Diuréticos/farmacologia , Combinação de Medicamentos , Reposicionamento de Medicamentos , Hiperglicemia/induzido quimicamente , Hiperglicemia/genética , Hiperglicemia/patologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos , Ratos Wistar , Estreptozocina/administração & dosagem , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento
12.
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
13.
Life Sci ; 233: 116711, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31374233

RESUMO

AIMS: Insulin is a central peptide hormone required for carbohydrate metabolism; however, its role in diabetes-associated pulmonary disease is unknown. Here, we investigated the preventative effect of insulin against hyperglycemia-induced pulmonary vascular leakage and its molecular mechanism of action in the lungs of diabetic mice. MAIN METHODS: Vascular endothelial growth factor (VEGF) activated transglutaminase 2 (TGase2) by sequentially elevating intracellular Ca2+ and reactive oxygen species (ROS) levels in primary human pulmonary microvascular endothelial cells (HPMVECs). KEY FINDINGS: Insulin inhibited VEGF-induced TGase2 activation, but did not affect intracellular Ca2+ elevation and ROS generation. Insulin prevented VEGF-induced vascular leakage by inhibiting TGase2-mediated c-Src phosphorylation, disassembly of VE-cadherin and ß-catenin, and stress fiber formation. Insulin replacement therapy prevented hyperglycemia-induced TGase2 activation, but not ROS generation, in the lungs of diabetic mice. Insulin also prevented vascular leakage and cancer metastasis in the diabetic lung. Notably, vascular leakage was not detectable in the lungs of TGase2-null (Tgm2-/-) diabetic mice. SIGNIFICANCE: These findings demonstrate that insulin prevents hyperglycemia-induced pulmonary vascular leakage in diabetic mice by inhibiting VEGF-induced TGase2 activation rather than ROS generation.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Proteínas de Ligação ao GTP/antagonistas & inibidores , Hemorragia/prevenção & controle , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Pneumopatias/prevenção & controle , Transglutaminases/antagonistas & inibidores , Animais , Proteínas de Ligação ao GTP/fisiologia , Hemorragia/etiologia , Hemorragia/patologia , Humanos , Pneumopatias/etiologia , Pneumopatias/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Masculino , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Melanoma Experimental/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transglutaminases/fisiologia , Células Tumorais Cultivadas
14.
Life Sci ; 232: 116640, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31295470

RESUMO

INTRODUCTION AND AIM: Polycystic ovary syndrome is one of the most common causes of female infertility, affecting 5-10% of the population. Women with PCOS manifest hyperandrogenism, hyperinsulinemia, low-grade systemic inflammation, and polycystic ovaries. Unfortunately, current available medications are only symptomatic without relevant reported treatment. Therefore, a pressing need for alternative safe approaches is necessitated. To this end, the present study is designed to investigate therapeutic merits of the edible plant: Ocimum kilimandscharicum (Ok), in a letrozole PCOS rat model, and compare it to metformin. MATERIAL AND METHODS: PCOS rats were treated with Ok total extract and its different fractions at 100 mg/kg orally for 10 consecutive days. Moreover, phytochemical characterization was applied using HPLC/PDA/ESI-MS to identify different secondary metabolites in the bioactive fractions. KEY FINDINGS: Results revealed that the total extract (Ok) and ethyl acetate (EA) fraction improved insulin sensitivity and restored normal hormonal and lipid profiles as well as normal morphological structure of the reproductive system. Furthermore, elevation of SOD and reduction of VEGF levels in comparison with metformin were recorded. SIGNIFICANCE: These results suggest that Ok extract and EA fraction halt letrozole-induced reproductive dysfunctions and restore normal morphological and physiological functions in PCOS rats, even superior to metformin.


Assuntos
Inibidores da Aromatase/farmacologia , Hipoglicemiantes/farmacologia , Letrozol/farmacologia , Metformina/farmacologia , Ocimum/química , Ovário/efeitos dos fármacos , Ovário/fisiopatologia , Extratos Vegetais/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Idoso , Animais , Antioxidantes/metabolismo , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Citocinas/metabolismo , Modelos Animais de Doenças , Estrogênios/sangue , Estro , Feminino , Glicosídeos/metabolismo , Humanos , Hidroxibenzoatos/metabolismo , Insulina/sangue , Tamanho do Órgão/efeitos dos fármacos , Ovário/patologia , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/patologia , Síndrome do Ovário Policístico/fisiopatologia , Progesterona/sangue , Ratos , Ratos Wistar , Espectrometria de Massas por Ionização por Electrospray , Testosterona/sangue , Triglicerídeos/sangue , Útero/efeitos dos fármacos
15.
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
16.
Planta Med ; 85(11-12): 987-996, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31350736

RESUMO

The rise of diabetes incidence in Nigeria enhances the use of popular remedies that may interact with conventional therapies. The aqueous extracts of 27 popular Nigerian "antidiabetic" plants were tested for their in vitro effects on glutathione levels within HepG2 cells, P-glycoprotein (P-gp)-mediated Rh-123 efflux activity in Caco-2 vincristine-resistant cells, and modulation of glibenclamide transport in Caco-2 monolayers. The extract from Ximenia americana significantly depleted intracellular glutathione at 100 µg/mL similarly to the reference buthionine sulphoximine (p < 0.05). Other 10 extracts raised glutathione levels. Eight extracts inhibiting P-gp efflux in a concentration-dependent manner (p < 0.01) were selected for further evaluation in a bi-directional transport model across Caco-2 monolayers: Annona senegalensis, Bridellia ferruginea, Cassytha filiformis, Daniellia ogea, Khaya ivorensis, Syzygium guineense, Terminalia avicennioides, and X. americana. When interferences in paracellular transport were discarded, only 3 of them may be modulating the efflux ratio of glibenclamide (efflux ratio: 2.65 ± 0.13) in the same manner the reference drug verapamil (efflux ratio: 1.14 ± 0.25, p < 0.01) does: Syzygium guineense (efflux ratio: 1.70 ± 0.23, p < 0.01), Terminalia avicennioides (efflux ratio: 1.80 ± 0.25, p < 0.05), and X. americana (efflux ratio: 1.66 ± 0.10, p < 0.01). HPLC-UV analyses for P-gp inhibitors in these extracts revealed several phenolic compounds such as rutin, gallic acid, and ellagic acid reported to decrease P-gp expression and/or directly modify its function. In conclusion, some popular herbal medicines used by Nigerian diabetic patients are here shown to potentially affect glibenclamide absorption at concentrations that could be reached in the intestinal tract.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Glibureto/metabolismo , Hipoglicemiantes/farmacologia , Medicina Tradicional Africana , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Células CACO-2/efeitos dos fármacos , Células Hep G2/efeitos dos fármacos , Interações Ervas-Drogas , Humanos
17.
Zhongguo Zhong Yao Za Zhi ; 44(11): 2324-2330, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31359659

RESUMO

The aim of this paper was to investigate the preventive effects of Keluoxin Capsules(KLX) on diabetic retinopathy in db/db mice. One hundred male db/db diabetic mice(45-55 g, 8 weeks) were randomly divided into 5 groups(model, KLX low dose, KLX middle dose, KLX high dose, Dobesilate) and 20 male C57 BL/KsJdb~(+/+) were taken as control group. Body weight and fasting blood-glucose were detected every week. Mice were administrated with saline(control and model group), KLX(780, 1 560, 3 120 mg·kg~(-1)·d~(-1), ig), Dobesilate(195 mg·kg~(-1)·d~(-1), ig) for 20 weeks, respectively. At the end of the administration, optical coherence tomography, fundus fluorescein angiography and electroretinogram of the retina were measured. The eyeball was extirpated and retina was isolated to make paraffin section, followed by HE staining and glial fibrillary acidic protein(GFAP) immunohistochemistry. The results indicated that KLX has no obvious effect on body weight and fasting blood level in db/db mice. However, KLX could significantly regulate the thickness of retinal ganglion layer and inner plexiform layer. KLX was able to remarkably reduce the quantity of diabetic microvessel. Meanwhile, KLX could notably improve retinal function. Moreover, KLX could observably modulate the cell arrangement and edema in each layer. There was no markable difference in retina according to the immunochemistry assay. In the present study, KLX exert marked preventive effects on diabetic retinopathy in db/db mice, which provided an experimental evidence for clinical use.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética/tratamento farmacológico , Hipoglicemiantes/farmacologia , Animais , Cápsulas , Angiofluoresceinografia , Masculino , Camundongos , Distribuição Aleatória , Retina/efeitos dos fármacos
18.
J Nanobiotechnology ; 17(1): 84, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291944

RESUMO

BACKGROUND: Nanoceria has recently received much attention, because of its widespread biomedical applications, including antibacterial, antioxidant and anticancer activity, drug/gene delivery systems, anti-diabetic property, and tissue engineering. MAIN BODY: Nanoceria exhibits excellent antibacterial activity against both Gram-positive and Gram-negative bacteria via the generation of reactive oxygen species (ROS). In healthy cells, it acts as an antioxidant by scavenging ROS (at physiological pH). Thus, it protects them, while in cancer cells (under low pH environment) it acts as pro-oxidant by generating ROS and kills them. Nanoceria has also been effectively used as a carrier for targeted drug and gene delivery in vitro and in vivo models. Besides, nanoceria can also act as an antidiabetic agent and confer protection towards diabetes-associated organ pathophysiology via decreasing the ROS level in diabetic subjects. Nanoceria also possesses excellent potential in the field of tissue engineering. In this review, firstly, we have discussed the different methods used for the synthesis of nanoceria as these are very important to control the size, shape and Ce3+/Ce4+ ratio of the particles upon which the physical, chemical, and biological properties depend. Secondly, we have extensively reviewed the different biomedical applications of nanoceria with probable mechanisms based on the literature reports. CONCLUSION: The outcome of this review will improve the understanding about the different synthetic procedures and biomedical applications of nanoceria, which should, in turn, lead to the design of novel clinical interventions associated with various health disorders.


Assuntos
Cério/química , Nanopartículas/química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Cério/farmacologia , Sistemas de Liberação de Medicamentos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Engenharia Tecidual/métodos
19.
J Enzyme Inhib Med Chem ; 34(1): 1368-1372, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31347930

RESUMO

To develop multifunctional aldose reductase (AKR1B1) inhibitors for anti-diabetic complications, a novel series of 2-phenoxypyrido[3,2-b]pyrazin-3(4H)-one derivatives were designed and synthesised. Most of the derivatives were found to be potent and selective against AKR1B1, and 2-(7-chloro-2-(3,5-dihydroxyphenoxy)-3-oxopyrido[3,2-b]pyrazin-4(3H)-yl) acetic acid (4k) was the most active with an IC50 value of 0.023 µM. Moreover, it was encouraging to find that some derivatives showed strong antioxidant activity, and among them, the phenolic 3,5-dihydroxyl compound 4l with 7-bromo in the core structure was proved to be the most potent, even comparable to that of the well-known antioxidant Trolox. Thus the results suggested success in the construction of potent and selective AKR1B1 inhibitors with antioxidant activity.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Antioxidantes/farmacologia , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Pirazinas/farmacologia , Antioxidantes/química , Compostos de Bifenilo/química , Inibidores Enzimáticos/química , Hipoglicemiantes/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Picratos/química , Pirazinas/química , Relação Estrutura-Atividade
20.
Food Chem ; 300: 125245, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31352287

RESUMO

The natural bioactive polysaccharide was regarded as the effective nanocarrier for delivery of active ingredients for its biocompatibility and biodegradability. Moreover, the Fructus Mori polysaccharide has been proved to have good antioxidant and hypoglycemic activities. In this study, the Fructus Mori polysaccharide particles were prepared using antisolvent precipitation method. The bioactive polysaccharide particles exhibited smaller and rounder as the increase of the ethanol/water ratio. The average size, polydispersity index (PDI) and ξ-potential of the bioactive polysaccharide particles were 396.06 nm, 0.38 and -21.23 mV at ethanol/water ratio of 20:1. After spheroidization, the polysaccharide particles exhibited more stable when exposed to heat, increased ionic strength and alkaline conditions. Furthermore, the bioactive polysaccharide particle with the smallest size had the strongest protein adsorption capacity and bioavailability. Especially, the MFP-NP3 showed the ORAC value of 917.06 ±â€¯34.13 µmol TE/g, and the α-glucosidase inhibitory activity of 56.98 ±â€¯1.19% at 0.5 mg/mL. In addition, compared to the native Fructus Mori polysaccharide, the spheroidization enhanced the antioxidant ability and hypoglycemic activity.


Assuntos
Antioxidantes/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Morus/química , Nanopartículas/química , Polissacarídeos/química , Polissacarídeos/farmacocinética , Adsorção , Animais , Antioxidantes/química , Disponibilidade Biológica , Precipitação Química , Etanol , Frutas , Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Concentração Osmolar , Tamanho da Partícula , Ratos , Solventes/química
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