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1.
Intern Med ; 58(19): 2773-2781, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31243210

RESUMO

Objective Circulating endothelial progenitor cells (EPCs) are regulated by stromal cell-derived factor-1alpha (SDF-1α) and are reduced in type 2 diabetes mellitus (DM). SDF-1α is a substrate of dipeptidyl-peptidase-4 (DPP-4), so we investigated whether or not DPP-4-inhibitors modulate EPC levels in type 2 DM patients with coronary artery disease (CAD). Methods Thirty patients with CAD and type 2 DM treated using an ordinary regimen were enrolled. EPC and SDF-1α levels were compared between those receiving additional 24-week treatment with a DPP-4-inhibitor (n=11) and no additional treatment (n=19). We determined the HbA1c, 1.5-Anhydro-D-glucitol (1,5-AG), coronary flow reserve (CFR), brain natriuretic peptide (BNP), E/e', and circulating EPC proportion and SDF-1α levels at baseline and the end of follow-up. The CFR was assessed using a dual-sensor-equipped guidewire. The primary endpoints were changes in the EPC count, SDF-1α levels, and CFR from baseline to the end of follow-up. The secondary endpoints were changes in the HbA1c and 1,5-AG, which are useful clinical markers of postprandial hyperglycemia, as well as the BNP and E/e'. Results After the 6-month follow-up, compared with ordinary regimen subjects, the patients receiving a DPP-4-inhibitor showed no significant increase in the EPC proportion (-0.01±0.50 vs. 0.02±0.77%, p=0.87), SDF-1α level (-600.4±653.6 vs. -283.2±543.1 pg/mL, p=0.18), or CFR (0.0±0.2 vs. 0.1±0.6, p=0.20), whereas both the 1.5-AG level (2.4±4.6 vs. -0.7±2.5 µg/dL, p=0.07) and HbA1c (-0.8±1.8 vs. 0.0±0.7%, p=0.02) were improved. There were no significant differences between the two groups in changes in the BNP and E/e'. Conclusion DPP-4 inhibition with sitagliptin did not increase or decrease the EPC proportion, SDF-1α level, or CFR, although the glycemic control was improved.


Assuntos
Quimiocina CXCL12/sangue , Doença da Artéria Coronariana/fisiopatologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Células Progenitoras Endoteliais/efeitos dos fármacos , Reserva Fracionada de Fluxo Miocárdico/fisiologia , Fosfato de Sitagliptina/uso terapêutico , Idoso , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/complicações , Diabetes Mellitus Tipo 2/sangue , Dipeptidil Peptidase 4/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Feminino , Seguimentos , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Fatores de Tempo
2.
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
3.
Biomed Pharmacother ; 113: 108733, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30861410

RESUMO

Chronic stimulation of the ß-adrenergic sympathetic system induces vascular dysfunction which is associated with increased inflammatory cytokines production. A recently proposed therapy to control vascular injury through inflammatory processes involves inhibition of the enzyme dipeptidyl peptidase-IV (DPP4). The present study investigates whether the inhibition of DPP4 prevents the increase in inflammatory markers induced by isoproterenol and restores endothelial function in vivo and in vitro. Male Wistar rats were divided into four groups: vehicle (VHC), an isoproterenol-treated group (ISO), a sitagliptin-treated group (SITA), and an isoproterenol and sitagliptin-treated group (ISO + SITA). The ISO group exhibited significantly increased contractile responses to phenylephrine associated with reduced endothelial participation, which was totally prevented by DPP4 inhibition. In vitro incubation with isoproterenol had no effect on vascular smooth muscle cells, however isoproterenol increased the activity of DPP4 and the expression of inflammatory cytokines in endothelial cells, while sitagliptin reduced the level of cytokines to basal level. In conclusion, we have shown that beta-adrenergic receptor activation can increase DPP4 activity, which was associated with vascular dysfunction and cytokine expression in endothelial cells. The important role of DPP4 was further supported by sitagliptin, which reversed vascular changes induced by isoproterenol in vivo and in vitro.


Assuntos
Agonistas Adrenérgicos beta/toxicidade , Inibidores da Dipeptidil Peptidase IV/farmacologia , Isoproterenol/toxicidade , Fosfato de Sitagliptina/farmacologia , Animais , Citocinas/metabolismo , Dipeptidil Peptidase 4/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipoglicemiantes/farmacologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Fenilefrina/farmacologia , Ratos , Ratos Wistar
4.
Int J Clin Pract ; 73(5): e13335, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30810254

RESUMO

AIMS: Soluble dipeptidyl peptidase-4 (sDPP-4) is secreted by hepatocytes and induces adipose tissue inflammation and insulin resistance. Sodium-glucose co-transporter-2 (SGLT2) inhibitors can improve hepatic steatosis by inhibiting hepatic de novo lipogenesis. We investigated the effects of dapagliflozin (an SGLT2 inhibitor) on serum levels of sDPP-4 in patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). METHODS: Fifty-seven patients with type 2 diabetes and NAFLD were randomized to a dapagliflozin group (5 mg/d for 24 weeks) (n = 33) or the control group (n = 24). Serum levels of sDPP-4 were measured with a commercial ELISA kit. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were measured by dual bioelectrical impedance analysis. RESULTS: In a total of 57 patients, baseline serum sDPP-4 was positively correlated with aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transferase (GGT) and HOMA-IR Both VAT and SAT areas decreased significantly in the dapagliflozin group alone. Liver enzymes were decreased at 24 weeks in the dapagliflozin group, but were unchanged in the control group. Although both groups showed significant reduction of serum sDPP-4 after 24 weeks of treatment, the magnitude of decrease was significantly larger in the dapagliflozin group. Changes in liver enzymes during treatment with dapagliflozin were positively correlated with the change in serum sDPP-4, but not with changes in VAT volume or HbA1c. CONCLUSIONS: Improvement of liver dysfunction after treatment with dapagliflozin was associated with a decrease in serum sDPP-4, suggesting that reduction of serum sDPP-4 by SGLT2 inhibitors may be a therapeutic strategy for NAFLD/NASH in patients with type 2 diabetes that is independent of glucose lowering or weight loss.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Dipeptidil Peptidase 4/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Feminino , Glucosídeos , Hepatite/complicações , Humanos , Inflamação/complicações , Resistência à Insulina/fisiologia , Gordura Intra-Abdominal/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Gordura Subcutânea/efeitos dos fármacos , Perda de Peso/fisiologia , gama-Glutamiltransferase/antagonistas & inibidores
5.
Food Res Int ; 115: 283-291, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30599943

RESUMO

Angiotensin-converting enzyme (ACE) and dipeptidyl peptidase-IV (DPP-IV) play critical roles in the development of hypertension and type 2 diabetes, respectively. Inhibiting ACE and DPP-IV activity using peptides has become part of new therapeutic strategies for supporting medicinal treatment of both diseases. In this study, oilseed proteins, including soybean, flaxseed, rapeseed, sunflower and sesame are evaluated for the possibility of generating ACE and DPP-IV inhibitory peptides using different integrated bioinformatic approaches (UniProt knowledgebase, ProtParam, BLAST, BIOPEP, PeptideRanker, Pepsite2 and ToxinPred), and three bovine proteins (ß-lactoglobulin, ß-casein and κ-casein) as comparisons. Compared with bovine proteins, the potency indices of ACE and DPP-IV inhibitory peptides, calculated using the BIOPEP database, suggest that oilseed proteins may be considered as good precursors of ACE inhibitory peptides but generate a relative lower yield of DPP-IV inhibitory peptides following subtilisin, pepsin (pH = 1.3) or pepsin (pH > 2) hydrolysis. Average scores aligned using PeptideRanker confirmed oilseed proteins as significant potential sources of bioactive peptides: over 105 peptides scored over 0.8. Pepsite2 predicted that these peptides would largely bind via Gln281, His353, Lys511, His513, Tyr520 and Tyr523 of ACE to inhibit the enzyme, while Trp629 would be the predominant binding site of peptides in reducing DPP-IV activity. All peptides were capable of inhibiting ACE and DPP-IV whilst 65 of these 105 peptides are not currently recorded in BIOPEP database. In conclusion, our in silico study demonstrates that oilseed proteins could be considered as good precursors of ACE and DPP-IV inhibitory peptides as well as so far unexplored peptides that potentially have roles in ACE and DPP-IV inhibition and beyond.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Dipeptidil Peptidase 4/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/isolamento & purificação , Peptídeos/antagonistas & inibidores , Peptídeos/isolamento & purificação , Peptidil Dipeptidase A/efeitos dos fármacos , Sementes/química , Inibidores da Enzima Conversora de Angiotensina/química , Animais , Sítios de Ligação , Brassica napus/química , Caseínas/química , Bovinos , Biologia Computacional , Simulação por Computador , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV/química , Linho/química , Helianthus/química , Hipertensão , Lactoglobulinas/química , Leite/química , Pepsina A , Óleos Vegetais , Sesamum/química , Soja/química , Subtilisinas
6.
Transl Res ; 205: 51-63, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30452888

RESUMO

In diabetes, stromal cell-derived factor-1 (SDF-1) expression and progenitor cell recruitment are reduced. Dipeptidyl peptidase-4 (DPP-4) inhibits SDF-1 expression and progenitor cell recruitment. Here we examined the impact of the DPP-4 inhibitor, MK0626, on progenitor cell kinetics in the context of wound healing. Wildtype (WT) murine fibroblasts cultured under high-glucose to reproduce a diabetic microenvironment were exposed to MK0626, glipizide, or no treatment, and SDF-1 expression was measured with ELISA. Diabetic mice received MK0626, glipizide, or no treatment for 6 weeks and then were wounded. Immunohistochemistry was used to quantify neovascularization and SDF-1 expression. Gene expression was measured at the RNA and protein level using quantitative polymerase chain reaction and ELISA, respectively. Flow cytometry was used to characterize bone marrow-derived mesenchymal progenitor cell (BM-MPC) population recruitment to wounds. BM-MPC gene expression was assayed using microfluidic single cell analysis. WT murine fibroblasts exposed to MK0626 demonstrated increased SDF-1 expression. MK0626 treatment significantly accelerated wound healing and increased wound vascularity, SDF-1 expression, and dermal thickness in diabetic wounds. MK0626 treatment increased the number of BM-MPCs present in bone marrow and in diabetic wounds. MK0626 had no effect on BM-MPC population dynamics. BM-MPCs harvested from MK0626-treated mice exhibited increased chemotaxis in response to SDF-1 when compared to diabetic controls. Treatment with a DPP-4 inhibitor significantly improved wound healing, angiogenesis, and endogenous progenitor cell recruitment in the setting of diabetes.


Assuntos
Diabetes Mellitus Experimental/complicações , Dipeptidil Peptidase 4/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Neovascularização Patológica , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/fisiopatologia , Animais , Quimiocina CXCL12/metabolismo , Glipizida/farmacologia , Células-Tronco Hematopoéticas/citologia , Camundongos , Camundongos Endogâmicos C57BL , Triazóis/farmacologia
7.
Peptides ; 108: 34-45, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30179653

RESUMO

Protease inhibition has become a new possible approach in the inflammatory bowel disease (IBD) therapy. A serine exopeptidase, dipeptidyl peptidase IV (DPP IV) is responsible for inactivation of incretin hormone, glucagon-like peptide 2 (GLP-2), a potent stimulator of intestinal epithelium regeneration and growth. Recently we showed that the novel peptide analog of endomorphin-2, EMDB-1 (Tyr-Pro-D-ClPhe-Phe-NH2) is a potent blocker of DPP IV and exhibits an anti-inflammatory activity in vivo. The aim of this study was to design, synthesize and characterize the therapeutic activity and mechanism of action of a series of novel EMDB-1 analogs. The inhibitory potential of all peptides was evaluated using the fluorometric screening assay employing Gly-Pro-Aminomethylcoumarin (AMC) to measure DPP IV activity. Consequently, one compound, namely DI-1 was selected and its therapeutic activity evaluated using mouse models of experimental colitis (induced by TNBS and DSS). Macro- and microscopic score, ulcer score, colonic wall thickness as well as myeloperoxidase activity were measured. We showed that DI-1 blocks DPP IV in vitro (IC50 = 0.76 ± 0.04 nM) and attenuates acute, semichronic and relapsing TNBS- as well as DSS-induced colitis in mice after topical administration. Its anti-inflammatory action is associated with the increase of colonic GLP-2 but not GLP2 receptor or DPP IV expression. Our results validate DPP IV as a pharmacological target for the anti-IBD drugs and its inhibitors, such as DI-1, have the potential to become valuable anti-inflammatory therapeutics.


Assuntos
Colite/tratamento farmacológico , Dipeptidil Peptidase 4/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Modelos Animais de Doenças , Peptídeos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Colite/enzimologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/uso terapêutico
9.
J Ethnopharmacol ; 220: 67-74, 2018 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-29604377

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Pomegranate fruit is considered an antidiabetic medicine in certain systems of traditional medicine. In addition, pomegranate polyphenols are known as powerful antioxidants with beneficial effects such as the reduction of oxidative / inflammatory stress and the increase of protective signalling such as antioxidant enzymes, neurotrophic factors and cytoprotective proteins. AIM OF THE STUDY: This work evaluates the effects of pomegranate juice, its main polyphenols known as ellagic acid and punicalagin, as well as its main metabolite urolithin A, on physiological and pharmacological targets of metabolic diseases such as obesity and diabetes. MATERIALS AND METHODS: For this purpose, enzyme inhibition bioassays of lipase, α-glucosidase and dipeptidyl peptidase-4 were carried out in cell-free systems. Similarly, adipocytes derived from 3T3-L1 cells were employed to study the effects of ellagic acid, punicalagin and urolithin A on adipocyte differentiation and triglyceride (TG) accumulation. RESULTS: Pomegranate juice, ellagic acid, punicalagin and urolithin A were able to inhibit lipase, α-glucosidase and dipeptidyl peptidase-4. Furthermore, all tested compounds but significantly the metabolite urolithin A displayed anti-adipogenic properties in a dose-dependent manner as they significantly reduced TG accumulation and gene expression related to adipocyte formation such as adiponectin, PPARγ, GLUT4, and FABP4 in 3T3-L1 adipocytes. CONCLUSION: These results may explain from a molecular perspective the beneficial effects and traditional use of pomegranate in the prevention of metabolic-associated disorders such as obesity, diabetes and related complications.


Assuntos
Adipogenia/efeitos dos fármacos , Cumarínicos/farmacologia , Lythraceae/química , Polifenóis/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipogenia/genética , Animais , Cumarínicos/administração & dosagem , Cumarínicos/isolamento & purificação , Dipeptidil Peptidase 4/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Relação Dose-Resposta a Droga , Ácido Elágico/administração & dosagem , Ácido Elágico/isolamento & purificação , Ácido Elágico/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Taninos Hidrolisáveis/administração & dosagem , Taninos Hidrolisáveis/isolamento & purificação , Taninos Hidrolisáveis/farmacologia , Lipase/metabolismo , Camundongos , Polifenóis/administração & dosagem , Polifenóis/isolamento & purificação , Triglicerídeos/metabolismo , alfa-Glucosidases/efeitos dos fármacos , alfa-Glucosidases/metabolismo
10.
Clin Sci (Lond) ; 132(4): 489-507, 2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29491123

RESUMO

Emerging evidence suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors used to treat type 2 diabetes may have nephroprotective effects beyond the reduced renal risk conferred by glycemic control. DPP-4 is a ubiquitous protein with exopeptidase activity that exists in cell membrane-bound and soluble forms. The kidneys contain the highest levels of DPP-4, which is increased in diabetic nephropathy. DPP-4 inhibitors are a chemically heterogeneous class of drugs with important pharmacological differences. Of the globally marketed DPP-4 inhibitors, linagliptin is of particular interest for diabetic nephropathy as it is the only compound that is not predominantly excreted in the urine. Linagliptin is also the most potent DPP-4 inhibitor, has the highest affinity for this protein, and has the largest volume of distribution; these properties allow linagliptin to penetrate kidney tissue and tightly bind resident DPP-4. In animal models of kidney disease, linagliptin elicited multiple renoprotective effects, including reducing albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis, independent of changes in glucagon-like peptide-1 (GLP-1) and glucose levels. At the molecular level, linagliptin prevented the pro-fibrotic endothelial-to-mesenchymal transition by disrupting the interaction between membrane-bound DPP-4 and integrin ß1 that enhances signaling by transforming growth factor-ß1 and vascular endothelial growth factor receptor-1. Linagliptin also increased stromal cell derived factor-1 levels, ameliorated endothelial dysfunction, and displayed unique antioxidant effects. Although the nephroprotective effects of linagliptin are yet to be translated to the clinical setting, the ongoing Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus (CARMELINA®) study will definitively assess the renal effects of this DPP-4 inhibitor. CARMELINA® is the only clinical trial of a DPP-4 inhibitor powered to evaluate kidney outcomes.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Dipeptidil Peptidase 4/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Linagliptina/farmacologia , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos
11.
J Drug Target ; 26(8): 670-675, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29378454

RESUMO

As well-known to the scientific community, Alzheimer's disease (AD) is an irreversible neurodegenerative disease that ends up with impairment of memory and cognition. Patient quality of life can be enhanced by targeting neurogenesis as a therapeutic paradigm. Preserving functional activity of SDF-1α and GLP-1 by DPPIV inhibition will enhance the homing of stem cells and modulate cell signalling pathways. The non-invasive approach presented in this article is a major advantage for managing AD, as regular/conventional stem-cell therapy necessarily relies on the application of regenerative stem cells exogenously. Using DPP-4 inhibitors to achieve the SDF-1α/CXCR4 axis stabilisation and augmenting GLP-1 levels, will enhance the homing/recruitment of brain resident and non-resident circulating stem cells/progenitor cells towards the sites of lesion to increase synaptic plasticity, a promising approach and also a novel one as well.


Assuntos
Doença de Alzheimer/patologia , Dipeptidil Peptidase 4/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Hipocampo/patologia , Humanos
12.
Exp Hematol ; 57: 50-59.e6, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29031704

RESUMO

Chronic myeloid leukemia (CML) is a stem cell (SC) neoplasm characterized by the BCR/ABL1 oncogene. Although the disease can be kept under control using BCR/ABL1 tyrosine kinase inhibitors (TKIs) in most cases, some patients relapse or have resistant disease, so there is a need to identify new therapeutic targets in this malignancy. Recent data suggest that leukemic SCs (LSCs) in CML display the stem-cell (SC)-mobilizing cell surface enzyme dipeptidyl-peptidase IV (DPPIV = CD26) in an aberrant manner. In the present study, we analyzed the effects of the DPPIV blocker vildagliptin as single agent or in combination with the BCR/ABL1 TKI imatinib or nilotinib on growth and survival of CML LSCs in vitro and on LSC engraftment in an in vivo xenotransplantation nonobese diabetic SCID-IL-2Rγ-/- (NSG) mouse model. We found that nilotinib induces apoptosis in CML LSCs and inhibits their engraftment in NSG mice. In contrast, no substantial effects were seen with imatinib or vildagliptin. Nevertheless, vildagliptin was found to reduce the "mobilization" of CML LSCs from a stroma cell layer consisting of mouse fibroblasts in an in vitro co-culture model, suggesting reduced disease expansion. However, although vildagliptin and nilotinib produced cooperative effects in individual experiments, overall, no significant effects of coadministered vildagliptin over nilotinib or imatinib treatment alone were seen on the engraftment of CML cells in NSG mice. Gliptins may be interesting drugs in the context of CML and nilotinib therapy, but our preclinical studies did not reveal a major cooperative effect of the drug-combination vildagliptin + nilotinib on engraftment of CML cells in NSG mice.


Assuntos
Adamantano/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Terapia de Alvo Molecular , Nitrilos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirrolidinas/farmacologia , Adamantano/administração & dosagem , Adamantano/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose , Técnicas de Cocultura , Dipeptidil Peptidase 4/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Sinergismo Farmacológico , Fibroblastos , Proteínas de Fusão bcr-abl/efeitos dos fármacos , Humanos , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas de Neoplasias/antagonistas & inibidores , Nitrilos/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Pirrolidinas/administração & dosagem , Células Tumorais Cultivadas , Vildagliptina , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Biochim Biophys Acta Gen Subj ; 1862(3): 403-413, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29154902

RESUMO

BACKGROUND: During the development of obesity the expansion of white adipose tissue (WAT) leads to a dysregulation and an excessive remodeling of extracellular matrix (ECM), leading to fibrosis formation. These ECM changes have high impact on WAT physiology and may change obesity progression. Blocking WAT fibrosis may have beneficial effects on the efficacy of diet regimen or therapeutical approaches in obesity. Since dipeptidyl peptidase IV (DPP-IV) inhibitors prevent fibrosis in tissues, such as heart, liver and kidney, the objective of this study was to assess whether vildagliptin, a DPP-IV inhibitor, prevents fibrosis in WAT in a mouse model of obesity, and to investigate the mechanisms underlying this effect. METHODS: We evaluated the inhibitory effect of vildagliptin on fibrosis markers on WAT of high-fat diet (HFD)-induced obese mice and on 3T3-L1 cell line of mouse adipocytes treated with a fibrosis inducer, transforming growth factor beta 1 (TGFß1). RESULTS: Vildagliptin prevents the increase of fibrosis markers in WAT of HFD-fed mice and reduces blood glucose, serum triglycerides, total cholesterol and leptin levels. In the in vitro study, the inhibition of DPP-IV with vildagliptin, neuropeptide Y (NPY) treatment and NPY Y1 receptor activation prevents ECM deposition and fibrosis markers increase induced by TGFß1 treatment. CONCLUSIONS: Vildagliptin prevents fibrosis formation in adipose tissue in obese mice, at least partially through NPY and NPY Y1 receptor activation. GENERAL SIGNIFICANCE: This study highlights the importance of vildagliptin in the treatment of fibrosis that occur in obesity.


Assuntos
Adamantano/análogos & derivados , Tecido Adiposo Branco/efeitos dos fármacos , Dipeptidil Peptidase 4/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipolipemiantes/uso terapêutico , Nitrilos/uso terapêutico , Obesidade/tratamento farmacológico , Pirrolidinas/uso terapêutico , Células 3T3-L1 , Adamantano/farmacologia , Adamantano/uso terapêutico , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo Branco/patologia , Animais , Glicemia/análise , Colágeno/metabolismo , Dieta Hiperlipídica , Inibidores da Dipeptidil Peptidase IV/farmacologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fibrose , Hipolipemiantes/farmacologia , Leptina/sangue , Leptina/fisiologia , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Neuropeptídeo Y/agonistas , Neuropeptídeo Y/farmacologia , Neuropeptídeo Y/fisiologia , Nitrilos/farmacologia , Obesidade/patologia , Pirrolidinas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/genética , Receptores de Neuropeptídeo Y/agonistas , Receptores de Neuropeptídeo Y/fisiologia , Fator de Crescimento Transformador beta1/farmacologia , Vildagliptina
14.
J Biomol Struct Dyn ; 36(2): 318-334, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28027711

RESUMO

Human dipeptidyl peptidase IV (hDDP-IV) has a considerable importance in inactivation of glucagon-like peptide-1, which is related to type 2 diabetes. One approach for the treatment is the development of small hDDP-IV inhibitors. In order to design better inhibitors, we analyzed 5-(aminomethyl)-6-(2,4-dichlrophenyl)-2-(3,5-dimethoxyphenyl)pyrimidin-4-amine and a set of 24 molecules found in the BindingDB web database for model designing. The analysis of their molecular properties allowed the design of a multiple linear regression model for activity prediction. Their docking analysis allowed visualization of the interactions between the pharmacophore regions and hDDP-IV. After both analyses were performed, we proposed a set of nine molecules in order to predict their activity. Four of them displayed promising activity, and thus, had their docking performed, as well as, the pharmacokinetic and toxicological study. Two compounds from the proposed set showed suitable pharmacokinetic and toxicological characteristics, and therefore, they were considered promising for future synthesis and in vitro studies.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Hipoglicemiantes/química , Sítios de Ligação , Dipeptidil Peptidase 4/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/química , Humanos , Hipoglicemiantes/uso terapêutico , Modelos Moleculares , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
15.
Arch Pharm (Weinheim) ; 350(12)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29152780

RESUMO

Prevention of the formation of advanced glycation end-products (AGEs) is a reliable approach to achieve control over hyperglycemia and the associated pathogenesis of diabetic vascular complications. In these terms, new synthetic approaches to 6-nitroazolo[1,5-a]pyrimidines have been developed on the basis of the promising antiglycation activity of their structural analogues, such as azolo[5,1-c][1,2,4]triazine-4(1H)-ones. A number of nitroazolopyrimidines were obtained by using nitration, chlorodeoxygenation, and amination reactions, and their antidiabetic properties were elucidated in vitro. It was shown that triazolo[1,5-a]pyrimidine-7(4H)-ones exhibit a higher antiglycation activity than the corresponding 7-alkylamino analogs and aminoguanidine, as the reference compound. It is suggested that this kind of activity can be associated with the chelating properties possessed by the synthesized 6-nitro-7-oxoderivatives. Furthermore, the compounds obtained were tested for their inhibitory activity against dipeptidyl peptidase 4 (DPP4), glycogen phosphorylase, and α-glucosidase in vitro, but their activities proved to be significantly inferior to those of the reference compounds.


Assuntos
Produtos Finais de Glicação Avançada/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Pirimidinas/farmacologia , Complicações do Diabetes/prevenção & controle , Dipeptidil Peptidase 4/efeitos dos fármacos , Desenho de Drogas , Glicogênio Fosforilase/antagonistas & inibidores , Guanidinas/farmacologia , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Técnicas In Vitro , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , alfa-Glucosidases/efeitos dos fármacos
16.
JCI Insight ; 2(21)2017 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-29093273

RESUMO

The secretion of insulin and glucagon from the pancreas and the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) from the gastrointestinal tract is essential for glucose homeostasis. Several novel treatment strategies for type 2 diabetes (T2D) mimic GLP-1 actions or inhibit incretin degradation (DPP4 inhibitors), but none is thus far aimed at increasing the secretion of endogenous incretins. In order to identify new potential therapeutic targets for treatment of T2D, we performed a meta-analysis of a GWAS and an exome-wide association study of circulating insulin, glucagon, GIP, and GLP-1 concentrations measured during an oral glucose tolerance test in up to 7,828 individuals. We identified 6 genome-wide significant functional loci associated with plasma incretin concentrations in or near the SLC5A1 (encoding SGLT1), GIPR, ABO, GLP2R, F13A1, and HOXD1 genes and studied the effect of these variants on mRNA expression in pancreatic islet and on metabolic phenotypes. Immunohistochemistry showed expression of GIPR, ABO, and HOXD1 in human enteroendocrine cells and expression of ABO in pancreatic islets, supporting a role in hormone secretion. This study thus provides candidate genes and insight into mechanisms by which secretion and breakdown of GIP and GLP-1 are regulated.


Assuntos
Células Enteroendócrinas/metabolismo , Polipeptídeo Inibidor Gástrico/genética , Variação Genética , Peptídeo 1 Semelhante ao Glucagon/genética , Glucagon/metabolismo , Insulina/metabolismo , Sistema do Grupo Sanguíneo ABO/genética , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Dipeptidil Peptidase 4/efeitos dos fármacos , Células Enteroendócrinas/patologia , Feminino , Polipeptídeo Inibidor Gástrico/metabolismo , Hormônios Gastrointestinais , Trato Gastrointestinal/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 2/genética , Glucose/metabolismo , Teste de Tolerância a Glucose , Proteínas de Homeodomínio/genética , Humanos , Incretinas/metabolismo , Insulina/genética , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Mensageiro/metabolismo , Receptores dos Hormônios Gastrointestinais/genética , Transportador 1 de Glucose-Sódio/genética
17.
Endocrinology ; 158(10): 3592-3604, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28977602

RESUMO

Activation of the renin-angiotensin-aldosterone system is common in hypertension and obesity and contributes to cardiac diastolic dysfunction, a condition for which no treatment currently exists. In light of recent reports that antihyperglycemia incretin enhancing dipeptidyl peptidase (DPP)-4 inhibitors exert cardioprotective effects, we examined the hypothesis that DPP-4 inhibition with saxagliptin (Saxa) attenuates angiotensin II (Ang II)-induced cardiac diastolic dysfunction. Male C57BL/6J mice were infused with either Ang II (500 ng/kg/min) or vehicle for 3 weeks receiving either Saxa (10 mg/kg/d) or placebo during the final 2 weeks. Echocardiography revealed Ang II-induced diastolic dysfunction, evidenced by impaired septal wall motion and prolonged isovolumic relaxation, coincident with aortic stiffening. Ang II induced cardiac hypertrophy, coronary periarterial fibrosis, TRAF3-interacting protein 2 (TRAF3IP2)-dependent proinflammatory signaling [p-p65, p-c-Jun, interleukin (IL)-17, IL-18] associated with increased cardiac macrophage, but not T cell, gene expression. Flow cytometry revealed Ang II-induced increases of cardiac CD45+F4/80+CD11b+ and CD45+F4/80+CD11c+ macrophages and CD45+CD4+ lymphocytes. Treatment with Saxa reduced plasma DPP-4 activity and abrogated Ang II-induced cardiac diastolic dysfunction independent of aortic stiffening or blood pressure. Furthermore, Saxa attenuated Ang II-induced periarterial fibrosis and cardiac inflammation, but not hypertrophy or cardiac macrophage infiltration. Analysis of Saxa-induced changes in cardiac leukocytes revealed Saxa-dependent reduction of the Ang II-mediated increase of cardiac CD11c messenger RNA and increased cardiac CD8 gene expression and memory CD45+CD8+CD44+ lymphocytes. In summary, these results demonstrate that DPP-4 inhibition with Saxa prevents Ang II-induced cardiac diastolic dysfunction, fibrosis, and inflammation associated with unique shifts in CD11c-expressing leukocytes and CD8+ lymphocytes.


Assuntos
Adamantano/análogos & derivados , Aorta/efeitos dos fármacos , Diástole/efeitos dos fármacos , Dipeptídeos/farmacologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Coração/efeitos dos fármacos , Rigidez Vascular/efeitos dos fármacos , Adamantano/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Angiotensina II/toxicidade , Animais , Pressão Sanguínea/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Antígenos CD8/efeitos dos fármacos , Antígenos CD8/metabolismo , Cardiomegalia/induzido quimicamente , Dipeptidil Peptidase 4/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Ecocardiografia , Fibrose/induzido quimicamente , Expressão Gênica/efeitos dos fármacos , Coração/fisiopatologia , Inflamação , Interleucina-17/metabolismo , Interleucina-18/metabolismo , Linfócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-jun/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-jun/metabolismo , Transdução de Sinais , Vasoconstritores/toxicidade
18.
Int Heart J ; 58(5): 778-786, 2017 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-28966327

RESUMO

High mobility group box 1 (HMGB1), a ubiquitous DNA-binding protein, promotes angiogenesis and tissue repair, resulting in restored cardiac function after myocardial infarction (MI). Although dipeptidyl peptidase 4 (DPP4) degrades certain peptides, it remains unclear as to whether HMGB1 is a substrate of DPP4 and whether DPP4 inhibition prevents the cleavage of HMGB1.In transgenic mice with cardiac-specific overexpression of HMGB1 (TG) and wild-type mice (WT), a diabetic state was induced by streptozotocin, and MI was created by ligation of the left anterior descending coronary artery. To inhibit DPP4 activity, a DPP4 inhibitor anagliptin was used. The plasma levels of HMGB1, infarct size, echocardiographic data, angiogenesis, and vascular endothelial growth factor (VEGF) expression in the peri-infarct area were compared among non-diabetic MI WT/TG, diabetic MI WT/TG, and anagliptin-treated diabetic MI WT/TG mice.DPP4 activity was increased in the diabetic state and blocked by anagliptin administration. The HMGB1 plasma levels were reduced in the diabetic TG compared with the non-diabetic TG mice, but DPP4 inhibition with anagliptin increased HMGB1 plasma levels in the diabetic TG mice. The infarct area was significantly larger in the diabetic TG than in the non-diabetic TG mice, and it was reduced by DPP4 inhibition. Cardiac function, angiogenesis, and VEGF expression were impaired in the diabetic TG mice, but they were ameliorated by the DPP4 inhibition to levels similar to those found in the non-diabetic TG mice.The DPP4 inhibitor ameliorated cardiac function by inhibiting the inactivation of HMGB1 in diabetic mice after MI.


Assuntos
Diabetes Mellitus Experimental/complicações , Dipeptidil Peptidase 4/efeitos dos fármacos , Proteína HMGB1/biossíntese , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Pirimidinas/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Western Blotting , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Ecocardiografia , Ensaio de Imunoadsorção Enzimática , Proteína HMGB1/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/etiologia , Miocárdio/patologia
19.
Exp Cell Res ; 356(1): 104-113, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28454879

RESUMO

BACKGROUND: Keloid is a skin fibrosis disease that characterised by invasive growth of fibroblasts and aberrant deposition of extracellular matrix. Studies indicated that keloid fibroblasts (KFs) is a class of 'activated' fibroblasts, which show accelerated proliferation and excessive extracellular matrix formation as compared with normal fibroblasts (NFs). However, the mechanism underlying keloid fibroblasts dysfunction is still unknown. OBJECTIVE: To verify CD26 expression difference between KFs and NFs, and investigate the function of CD26 positive fibroblasts in keloid progression. METHODS: KFs and NFs were isolated from Keloid tissues and normal skin tissues respectively. Flow cytometry was performed to isolate CD26+/CD26- fibroblasts from KFs and NFs. Proliferation of different fibroblasts were analyzed by CCK8 assay and Ki 67 straining. Profibrotic phenotype difference was detected by qRT-PCR, western blot, ELISA and immunofluorescence. Scratching experiment and transwell assay were used to assess invasion ability of CD26+/CD26- fibroblasts. Diprotin A was used as a CD26 inhibitor to further investigated the function of CD26 fibroblasts in keloid disease. RESULT: CD26 expression was increased in KFs, and the proportion of CD26+ fibroblasts was significantly increased in KFs. Cell viability analysis showed that CD26+ fibroblasts was more active in proliferation. Furthermore, the expression of profibrotic genes were increased in CD26+ fibroblasts, including TGF-ß1, IGF-1, IL6, collagen 1, collagen 3 and fibronectin. And meanwhile, CD26+ fibroblasts showed stronger invasion ability as compared to CD26- fibroblasts. Moreover, Diprotin A significantly suppressed proliferation and extracellular matrix secretion of CD26+ fibroblasts isolated from keloid tissues. CONCLUSION: Our findings suggest that CD26+ fibroblasts possess proliferation advantage in compare to CD26- fibroblasts, and the advantage caused expansion of CD26 positive fibroblast population promotes keloid progression.


Assuntos
Proliferação de Células/fisiologia , Citocinas/metabolismo , Dipeptidil Peptidase 4/metabolismo , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Queloide/patologia , Pele/patologia , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dipeptidil Peptidase 4/efeitos dos fármacos , Progressão da Doença , Feminino , Humanos , Masculino , Oligopeptídeos/farmacologia , Transdução de Sinais , Pele/citologia , Pele/metabolismo
20.
J Asian Nat Prod Res ; 19(10): 1036-1045, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28351157

RESUMO

Currently antidiabetic therapeutic strategies are mainly based on synthetic hypoglycemic agent. Antidiabetic drugs are associated with significant adverse effects of hypoglycemia, dysfunction of insulin and weight gain. Nowadays, the novel Dipeptidyl peptidase-IV (DPP-IV) inhibitors unique approach for the management of diabetes has been considered to be safe, as DPP-IV inhibitors reduce blood glucose level by monitoring hyperglycemia including positive effects on body weight as it remains neutral, improves glycated hemoglobin levels and do not induce hypoglycemia. Inhibitors help to protect degradation of Glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), gut hormones which helps to suppresses postprandial glucagon release, delay gastric emptying and regulate satiety. Therefore, the innovation of DPP-IV inhibitor based drugs regulates activity of incretin hormones such as GLP-1 and GIP. Commercially available DPP-IV inhibitors are chemically synthesized with good therapeutic value. However, the durability and long-term safety of DPP-IV inhibitors remains to be established. On the other hand, phytocompounds-based DPP-IV inhibitors are alternative and safe to use as compared to synthetic. Numerous novel antidiabetic compounds and group of compounds emerging in clinical development are through DPP-IV inhibition. This review summarized recent progress made on DPP-IV inhibitors from both synthetic as well as from natural sources.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Dipeptidil Peptidase 4/efeitos dos fármacos , Polipeptídeo Inibidor Gástrico/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Estrutura Molecular
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