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1.
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
2.
Life Sci ; 234: 116738, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31398418

RESUMO

AIMS: Oxidative stress has been linked to the development and progression of diabetic nephropathy (DN). The present study evaluated whether the dipeptidyl peptidase-4 inhibitor sitagliptin attenuates glomerular lesions and oxidative stress evoked by chronic hyperglycemia, by a mechanism independent of insulin secretion and glycemia normalization. MAIN METHODS: A rat model of DN caused by streptozotocin injection was established and the effects of sitagliptin (5 mg/kg/day) were evaluated after two weeks of treatment. KEY FINDINGS: Sitagliptin treatment did not change body weight, glycemic and lipid profiles. However, histopathological observation revealed that sitagliptin attenuates diabetes-induced glomerular lesions on diabetic rats. Sitagliptin also ameliorated the increase in DPP-4 content and promoted the stabilization of GLP-1 in the diabetic kidney. Furthermore, sitagliptin treatment significantly attenuated the increase of free-radical formation and the decrease of antioxidant defenses, attenuating therefore the oxidative stress in the kidneys of diabetic animals. SIGNIFICANCE: The results suggest that sitagliptin treatment alleviates kidney oxidative stress in type 1 diabetic rats, which could play a key role in reducing the progression of DN.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glomérulos Renais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosfato de Sitagliptina/uso terapêutico , Animais , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Masculino , Ratos , Ratos Wistar , Fosfato de Sitagliptina/farmacologia
3.
J Biochem Mol Toxicol ; 33(10): e22386, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31454128

RESUMO

Deltamethrin (DLM) is a synthesized organophosphorus acaricide and bug spray, broadly utilized for veterinary and farming purposes. Although its exposure to humans and animals causes toxicity in the kidney and other primary organs, our objective was to assess the defensive effects of sitagliptin (Sita) and additionally curcumin (Cur) in the DLM-intoxicated rats' kidney. DLM-intoxicated rats revealed a huge increase of various biochemical parameters in serum identified with kidney damage: uric acid, urea, and creatinine. DLM intoxication altogether increased renal lipid peroxidation, and critically restrained antioxidative biomarkers including superoxide dismutase, glutathione, and glutathione peroxidase. Likewise, it increased the tumor necrosis factor-α, interleukin 6 (IL-6) and IL-1ß level in serum. Additionally, DLM intoxication diminished the outflow of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in rats. Both Sita and Cur act against DLM-prompted serum along with renal tissue biochemical parameters when utilized alone or in a mix alongside DLM intoxication. Besides this, both Sita and Cur delivered synergetic nephroprotective, antioxidative, and anti-inflammatory impacts. Consequently, it could be presumed that Sita as well as Cur administration can limit the poisonous impacts of DLM by their free radical-scavenging, strong antioxidant, and Nrf2/HO-1 pathway upregulation activity.


Assuntos
Acaricidas/toxicidade , Curcumina/farmacologia , Citocinas/metabolismo , Heme Oxigenase-1/metabolismo , Hipoglicemiantes/farmacologia , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Nitrilos/toxicidade , Piretrinas/toxicidade , Fosfato de Sitagliptina/farmacologia , Animais , Biomarcadores/metabolismo , Sinergismo Farmacológico , Masculino , Ratos , Ratos Wistar
4.
Inflamm Res ; 68(10): 857-866, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31236602

RESUMO

OBJECTIVE: The probably effects of sitagliptin and vitamin D3 (VitD3) on proliferation capacity and cytokines production were investigated in type 2 diabetes mellitus (T2DM) in vitro. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 35 patients with T2DM and 26 healthy controls (HCs). CFSE-labeled PBMCs stimulated with phytohamagglutinin (PHA, 5 µg/mL) in the presence/absence of sitagliptin (200 mg/mL) with/without VitD3 (10-8 M) for 4 days. The proliferation of CD4+ T helper cells and non-CD4+ cells was analyzed using flow cytometry. The supernatant levels of IFN-γ, IL-17, IL-4, TGB-ß and IL-37 were detected using ELISA. RESULTS: The proliferation of CD4+ T cells in response to PHA was higher in T2DM patients compared with HCs. The production of IFN-γ and IL-17 in PHA-stimulated cultures was higher, and the levels of IL-4 and IL-37 were lower in T2DM patients compared to HCs. The addition of sitagliptin or VitD3 to the cultures decreased the CD4+ T cells and non-CD4+ cells proliferation in patients and HCs. Sitagliptin with VitD3 was more effective in suppression of proliferation, decreasing of IL-17 and enhancing of IL-37 production. CONCLUSION: Sitagliptin plus VitD3 effectively reduces the proliferative T cells response and modulates pro-inflammatory/anti-inflammatory cytokines production.


Assuntos
Colecalciferol/farmacologia , Diabetes Mellitus Tipo 2/imunologia , Hipoglicemiantes/farmacologia , Fosfato de Sitagliptina/farmacologia , Linfócitos T/efeitos dos fármacos , Vitaminas/farmacologia , Adulto , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/imunologia , Feminino , Humanos , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologia
5.
Inflamm Res ; 68(7): 581-595, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31073849

RESUMO

OBJECTIVE: Hypercholesterolemia is associated with the development of a pro-inflammatory state and is a documented risk factor for progression to insulin resistance, nonalcoholic fatty liver and cardiovascular diseases. Sitagliptin is an incretin enhancer that improves glucose tolerance by inhibiting dipeptidyl peptidase-4, but it also has reported anti-inflammatory effects. The current study was thus undertaken to examine the interactions of dietary Cholesterol (Cho) and sitagliptin on markers of inflammation. METHODS: Male Sprague-Dawley rats were provided diets high in Cho and gavaged with vehicle or an aqueous suspension of sitagliptin (100 mg/kg/day) from day 10 through day 35. Molecular methods were used to analyze the lipid profile and inflammatory markers in liver and serum samples. H&E-stained liver sections were used for histopathological evaluation. Hepatic influx of mononuclear cells and necrosis were assessed by immunohistochemistry. RESULTS: Sitagliptin reduced triglyceride and Cho levels in serum of rats on the control diet but these effects were abrogated in rats on the high-Cho diet. Sitagliptin produced a significant increase in the expression of hepatic inflammatory markers (Tnfa, Il1b, and Mcp1) and a corresponding increase in serum TNFα and IL-1ß in rats on the high-Cho diet, but it had no effect on rats on the control diet. Additionally, sitagliptin had no effect on liver morphology in rats on the control diet, but it produced hepatic histopathological changes indicative of necrosis and mononuclear cell infiltration in rats on the high-Cho diet. These mononuclear cells were identified as macrophages and T cells. CONCLUSION: When provided in the context of a high-Cho diet, these findings reveal previously unrecognized hepato-inflammatory effects of sitagliptin that are accompanied by evidence of hepatic necrosis and mononuclear cell infiltration.


Assuntos
Colesterol na Dieta/farmacologia , Citocinas/metabolismo , Hipercolesterolemia/metabolismo , Incretinas/farmacologia , Fígado/efeitos dos fármacos , Fosfato de Sitagliptina/farmacologia , Animais , Hipercolesterolemia/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Ratos Sprague-Dawley
6.
J Immunoassay Immunochem ; 40(4): 386-395, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31068055

RESUMO

The current study aims to determine the inhibition activity gelatin against dipeptidyl aminopeptidase 4 (DP-4). Two commercial gelatins, i.e., bovine and fish skin gelatin and one extracted (in our laboratory) gelatin, i.e., fish bone gelatin were selected for analysis. Each gelatin have same protein pattern (75-245 kDa) on sodium dodecyl sulfate polyacrylamide gel electrophoresis with mean of protein concentration of 1.72 mg/mL. The inhibition activity was measured on the capacity to inhibit DP-4 by using Gly-Pro-p-nitroanilide as their substrate. The sitagliptin was used as standard comparison. Based on the percent inhibition, gelatin has been shown to be the prospective DP-4 inhibitor.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Gelatina/farmacologia , Inibidores de Serino Proteinase/farmacologia , Fosfato de Sitagliptina/farmacologia , Animais , Bovinos , Relação Dose-Resposta a Droga , Peixes , Gelatina/química , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/química , Fosfato de Sitagliptina/síntese química , Fosfato de Sitagliptina/química , Relação Estrutura-Atividade
7.
Int J Mol Sci ; 20(8)2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31010001

RESUMO

Dipeptidyl peptidase IV (DPPIV) inhibitors are antidiabetic agents that exert renoprotective actions independently of glucose lowering. Cardiac dysfunction is one of the main outcomes of chronic kidney disease (CKD); however, the effects of DPPIV inhibition on cardiac impairment during CKD progression remain elusive. This study investigated whether DPPIV inhibition mitigates cardiac dysfunction and remodeling in rats with a 5/6 renal ablation and evaluated if these effects are associated with changes in the cardiac renin-angiotensin system (RAS). To this end, male Wistar rats underwent a 5/6 nephrectomy (Nx) or sham operation, followed by an 8-week treatment period with the DPPIV inhibitor sitagliptin (IDPPIV) or vehicle. Nx rats had lower glomerular filtration rate, overt albuminuria and higher blood pressure compared to sham rats, whereas CKD progression was attenuated in Nx + IDPPIV rats. Additionally, Nx rats exhibited cardiac hypertrophy and fibrosis, which were associated with higher cardiac DPPIV activity and expression. The sitagliptin treatment prevented cardiac fibrosis and mitigated cardiac hypertrophy. The isovolumic relaxation time (IRVT) was higher in Nx than in sham rats, which was suggestive of CKD-associated-diastolic dysfunction. Sitagliptin significantly attenuated the increase in IRVT. Levels of angiotensin II (Ang II) in the heart tissue from Nx rats were higher while those of angiotensin-(1-7) Ang-(1-7) were lower than that in sham rats. This cardiac hormonal imbalance was completely prevented by sitagliptin. Collectively, these results suggest that DPPIV inhibition may delay the onset of cardiovascular impairment in CKD. Furthermore, these findings strengthen the hypothesis that a crosstalk between DPPIV and the renin-angiotensin system plays a role in the pathophysiology of cardiorenal syndromes.


Assuntos
Angiotensina II/metabolismo , Angiotensina I/metabolismo , Cardiotônicos/uso terapêutico , Miocárdio/metabolismo , Fragmentos de Peptídeos/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Fosfato de Sitagliptina/uso terapêutico , Angiotensina I/sangue , Angiotensina II/sangue , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cardiotônicos/farmacologia , Diástole/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Rim/efeitos dos fármacos , Rim/fisiopatologia , Testes de Função Renal , Masculino , Miocárdio/patologia , Fragmentos de Peptídeos/sangue , Peptidil Dipeptidase A/metabolismo , Ratos Wistar , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Fosfato de Sitagliptina/farmacologia , Regulação para Cima/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
8.
Pharmazie ; 74(4): 239-242, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30940309

RESUMO

Diabetic nephropathy (DN) is a common cause of end-stage kidney disease (ESKD) all over the world. Sitagliptin, an inhibitor of DPP-IV plays a beneficial role in type 2 diabetic nephropathy. The purpose of this study was to explore the effect and mechanism of sitagliptin on renal injury in type 1 diabetic mice. Streptozotocin (STZ) induced type 1 diabetic mice were treated with oral administration of sitagliptin (15 mg/kg/ day) for 4 weeks. The results showed that sitagliptin treatment did not change the levels of blood glucose in STZ induced type 1 diabetic mice. Sitagliptin attenuates diabetic nephropathy by significantly inhibiting 24 h proteinuria, renal injury and fibrosis. Sitagliptin can inhibit the expression level of TGF-ß1 and the other related fibrosis factors in renal tissue of type 1 diabetic mice while delaying the progression of type 1 diabetic nephropathy. These results indicated that sitagliptin treatment is potentially a new strategy for treating type 1 diabetic nephropathy.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Inibidores da Dipeptidil Peptidase IV/farmacologia , Fosfato de Sitagliptina/farmacologia , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Proteinúria/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Estreptozocina , Fator de Crescimento Transformador beta1/genética
9.
Immunopharmacol Immunotoxicol ; 41(2): 299-311, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30907193

RESUMO

Objective: Gene expression level of T helper cell transcription factors and cytokines production in type-2 diabetes mellitus (T2DM) patients treated with mono- or combined sitagliptin and vitamin D3 (VitD3) were evaluated. Methods: Fifty-four nephropathic and 57 non-nephropathic T2DM patients were divided into the subgroups based on their treatment with/without sitagliptin and VitD3. The expression of T-bet, RORγt, BCL6, and FOXP3 was evaluated using real-time PCR. The levels of IFN-γ, IL-6, IL-17, IL-21, TGF-ß, and IL-37 were assessed in PBMC supernatants using ELISA. Results: The production of IFN-γ and IL-17 was increased in untreated (without sitagliptin and VitD3) nephropathic and non-nephropathic T2DM patients compared with healthy controls, whereas FOXP3 expression was decreased. Treatment with sitagliptin alone or in combination with VitD3 reduced the production of IFN-γ in the patients. Production of IL-17 and IL-21 and the expression of RORγt and BCL6 was diminished in patients treated with combined sitagliptin and VitD3, whereas the production of IL-37 and FOXP3 expression were increased in the patients treated with sitagliptin or sitagliptin plus VitD3. Conclusion: These data demonstrate that sitagliptin in combination with VitD3 may accelerate the process of T2DM treatment by exerting synergic anti-inflammatory effects on immune system through upregulation of FOXP3 and IL-37, and downregulation of RORγt and BCL6 as well as IFN-γ, IL-17 and IL-21 production. Combined sitagliptin and VitD3 can be safely utilized to modulate the inflammatory conditions of T2DM.


Assuntos
Colecalciferol/farmacologia , Diabetes Mellitus Tipo 2/imunologia , Fatores de Transcrição Forkhead/imunologia , Interleucina-1/imunologia , Fosfato de Sitagliptina/farmacologia , Linfócitos T Auxiliares-Indutores/imunologia , Regulação para Cima/efeitos dos fármacos , Adulto , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T Auxiliares-Indutores/patologia
10.
Biomed Pharmacother ; 111: 1088-1102, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841422

RESUMO

This study tested whether sitagliptin and shock wave (SW)-assisted circulatory-derived autologous endothelial progenitor cell (EPC) therapy would effectively preserve residual renal function in chronic kidney disease (CKD) induced by 5/6 left-nephrectomy/remove right kidney plus daily feeding high-protein diet (HPD) in rat. Adult-male SD rats (n = 40) were categorized into group 1 (sham-operated control with HPD), group 2 (HPD-CKD), group 3 [HPD-CKD + EPC (1.2 × 106 cell)/intra-vessel administration by day 14 after CKD-induction], group 4 [HPD-CKD + SW (0.12 mJ/mm2/180 shorts) at days 14/21/28 after CKD-induction by ultrasound-guided application] and group 5 [HPD-CKD + SW + EPC + sitagliptin (Sita; 600 mg/kg/day since day 14 after CKD induction)]. All animals were euthanized by day 60. By day 60, renal blood flow (RBF) was highest in group 1 and progressively increased from groups 2 to 5, whereas the levels of creatinine/BUN/proteinuria exhibited an opposite pattern of RBF among the five groups (all p < 0.001). The circulating levels of GLP-1/SDF-1α and protein levels of angiogenesis (VEGF/SDF-1α/CXCR4) and GLP-1R in kidney were progressively increased from groups 1 to 5, whereas circulating DPP4 activity exhibited an opposite pattern of SDF-1α among the groups (all p < 0.0001). The protein expressions of oxidative-stress (NOX-1/NOX-2/oxidized protein), apoptosis (Bax/caspase-3/PARP), fibrosis (Smad3/TGF-ß) and inflammation (TNF-α/NF-κB/MMP-2) and kidney injury score displayed an opposite pattern, whereas the protein expressions of TMP2, endothelial-cell markers (CD31/eNOS) and podocyte integrity biomarkers (podocin/ZO-1/synaptopodin) exhibited an identical pattern of RBF among the groups (all p < 0.001). In conclusion Sita associated SW-assisted EPC effectively protected residual renal function in CKD.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Células Progenitoras Endoteliais/fisiologia , Rim/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Fosfato de Sitagliptina/farmacologia , Animais , Biomarcadores/metabolismo , Terapia Baseada em Transplante de Células e Tecidos/métodos , Creatinina/metabolismo , Células Progenitoras Endoteliais/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipoglicemiantes/farmacologia , Rim/metabolismo , Rim/fisiopatologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Proteinúria/tratamento farmacológico , Proteinúria/metabolismo , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia
11.
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
12.
Inflammation ; 42(2): 449-462, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30707388

RESUMO

Sitagliptin is a dipeptidyl peptidase-4 inhibitor (iDPP-4), which has been used for type 2 diabetes treatment. Recently, iDPP-4 has been described as a promising treatment of type 1 diabetes (T1D) but is still necessary to evaluate immune effects of sitagliptin. C57BL/6 mice were induced by multiple low doses of streptozotocin. Diabetes incidence, insulin, glucagon, glucagon-like peptide-1 (GLP-1) serum levels, and inflammatory cytokine levels were quantified in pancreas homogenate after 30 and 90 days of treatment. In addition, frequencies of inflammatory and regulatory T cell subsets were determined in the spleen and in the pancreatic lymph nodes. iDPP-4 decreased blood glucose level while increased GLP-1 and insulin levels. After long-term treatment, treated diabetic mice presented decreased frequency of CD4+CD26+ T cells and increased percentage of CD4+CD25hiFoxp3+ T cells in the spleen. Besides, pancreatic lymph nodes from diabetic mice treated with iDPP-4 presented lower percentage of CD11b+ cells and decreased levels of inflammatory cytokines in the pancreas. Treatment of type 1 diabetic mice with iDPP-4 improved metabolic control, decreased inflammatory profile in the pancreatic microenvironment, and increased systemic regulatory T cell frequency. Therefore, we suggest the long-term use of sitagliptin as a feasible and effective therapy for T1D.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Pâncreas/metabolismo , Fosfato de Sitagliptina/farmacologia , Animais , Glicemia/efeitos dos fármacos , Citocinas/metabolismo , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/efeitos dos fármacos , Insulina/metabolismo , Linfonodos , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/citologia , Fosfato de Sitagliptina/uso terapêutico , Estreptozocina , Subpopulações de Linfócitos T , Resultado do Tratamento
13.
Eur J Pharmacol ; 850: 180-189, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30768981

RESUMO

Inflammation and oxidative stress are the two processes crucial in atherogenesis. Platelet-activating factor acetylhydrolase (PAF-AH), a plasma lipoprotein-associated enzyme, degrades pro-inflammatory lipids generated within oxidatively modified lipoproteins. Extensive evidence shows that incretin-based drugs, a new class of anti-diabetic agents, can provide cardiovascular protection that cannot be attributed to their glucose-lowering effects. The present study was undertaken to determine whether the antiatherogenic effects of the GLP-1(glucagon-like peptide-1) receptor agonist (exenatide) and DPP-4(dipeptidyl peptidase-4) inhibitors (sitagliptin) may occur via the regulation of platelet-activating factor acetylhydrolase (PAF-AH) activity/mass and inhibition of low-density lipoprotein (LDL) oxidation in the fructose-fed rats. Normal and fructose-fed rats (8 wk) were treated (4 wk) with sitagliptin (5 and 10 mg/kg p.o.) or with exenatide (5 and 10 µg/kg, s.c.). Plasma PAF-AH activity and phosphatidylcholine (PC) concentration were measured colorimetrically. Plasma PAF-AH concentration, oxidized LDL (oxLDL), hexanoyl-Lys adduct (HEL), lyso-PC, apolipoprotein A-I (apoA-I), apoB, platelet-activating factor (PAF), monocyte chemoattractant protein-1 (MCP-1) and endothelin-1 (ET-1) were measured by ELISA. The four-week exenatide (5 µg/kg, sc.) treatment of fructose fed-rats significantly increased plasma PAF-AH activity (+33%, P < 0.001) and decreased the level of circulating oxLDL (-42%, P < 0.05) and MCP-1 (-23%, P < 0.01). These changes were accompanied by the decrease in plasma PC/lyso-PC (-47%, P < 0.001) and apoB/apoA-I ratio (-75%, P < 0.001). The effect of exenatide on enzyme activity was associated with only a minor effect on metabolic parameters and was independent of weight reduction. Exenatide but not sitagliptin inhibits oxidative modification of LDL probably due to favorable effect on plasma PAF-AH activity.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/sangue , Exenatida/farmacologia , Frutose/efeitos adversos , Fosfato de Sitagliptina/farmacologia , 1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Animais , Biomarcadores/metabolismo , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
14.
Nat Immunol ; 20(3): 257-264, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30778250

RESUMO

Post-translational modification of chemokines mediated by the dipeptidyl peptidase DPP4 (CD26) has been shown to negatively regulate lymphocyte trafficking, and its inhibition enhances T cell migration and tumor immunity by preserving functional chemokine CXCL10. By extending those initial findings to pre-clinical models of hepatocellular carcinoma and breast cancer, we discovered a distinct mechanism by which inhibition of DPP4 improves anti-tumor responses. Administration of the DPP4 inhibitor sitagliptin resulted in higher concentrations of the chemokine CCL11 and increased migration of eosinophils into solid tumors. Enhanced tumor control was preserved in mice lacking lymphocytes and was ablated after depletion of eosinophils or treatment with degranulation inhibitors. We further demonstrated that tumor-cell expression of the alarmin IL-33 was necessary and sufficient for eosinophil-mediated anti-tumor responses and that this mechanism contributed to the efficacy of checkpoint-inhibitor therapy. These findings provide insight into IL-33- and eosinophil-mediated tumor control, revealed when endogenous mechanisms of DPP4 immunoregulation are inhibited.


Assuntos
Dipeptidil Peptidase 4/imunologia , Eosinófilos/imunologia , Interleucina-33/imunologia , Neoplasias Experimentais/imunologia , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Quimiocina CCL11/imunologia , Quimiocina CCL11/metabolismo , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Humanos , Interleucina-33/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/prevenção & controle , Fosfato de Sitagliptina/farmacologia
15.
Drug Dev Res ; 80(4): 446-452, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30714645

RESUMO

AIM: Sitagliptin (Sita) is a dipeptidyl peptidase-4 inhibitor which has been approved as a curing medicine for Type 2 diabetes (T2D) and has also reported its neuroprotective and antioxidant activity. This article describes the therapeutic effects of Sita on induced rat model of SE by kainic acid (KA) and investigated the antioxidative pathway of sita. METHODS: Sprague-Dawley male rats were used randomly divided in four groups: vehicle control, KA and Sita + KA in a 5 and 10 mg/kg doses respectively in further groups. SE in rats was induced by the administration of KA in Phosphate buffered saline (PBS) intraperitoneally (IP) in a dose of 15 mg/kg. Seizure intensity, oxidative stress parameters, TUNEL assay, histopathology, and Nrf2/HO-1 expressions were evaluated. RESULTS: Increment in the latency in SE results in delaying the initiation of disease in the pretreated rats by Sita compared to induce group (KA) as well the percentage of occurrence of SE was decreased. The content of MDA elevates whereas the SOD production decreases on administering the KA at various time intervals. Sita shows protective action against the KA-induced SE by reducing the oxidative stress thus inhibiting the change in SOD and MDA was observed after KA administration prior SE onset. Based on the above results, the study explains possible molecular mechanism of Sita. Sita Pretreatment showed significant elevation in expression of Nrf2 and HO-1 proteins in hippocampus region of the brain. CONCLUSION: Above parameters defines the potential effect of Sita on brain injury occurred due to SE by anti-oxidative pathway.


Assuntos
Heme Oxigenase (Desciclizante)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fosfato de Sitagliptina/farmacologia , Estado Epiléptico/tratamento farmacológico , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Fármacos Neuroprotetores/uso terapêutico , Ratos Sprague-Dawley , Transdução de Sinais , Fosfato de Sitagliptina/uso terapêutico , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo
16.
J Biomed Sci ; 26(1): 6, 2019 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-30634956

RESUMO

BACKGROUND: Pulmonary hypertension (PH) is a progressive disease leading to death ultimately. Our recently published data demonstrated that inhibiting dipeptidyl peptidase IV (DPP-4) alleviated pulmonary vascular remodeling in experimental PH. However, whether glucagon-like peptide-1 (GLP-1) mediated the protective effect of DPP-4 inhibition (DPP-4i) on PH is unclear. RESULTS: In the present study, GLP-1 receptor antagonist (exendin-3) abolished the protective effects of DPP-4 inhibitor (sitagliptin) on right ventricular systolic pressure (RVSP) and pulmonary vascular remodeling (PVR) in monocrotaline (MCT, 60 mg/kg)-induced PH in rat. Notably, activation of GLP-1 receptor by GLP-1 analogue liraglutide directly attenuated RVSP and PVR in MCT-induced PH, as well as bleomycin- and chronic hypoxia-induced PH. Moreover, liraglutide potently inhibited MCT-induced inflammation and suppressed MCT-induced down-regulation of vascular endothelial marker (VE-cadherin and vWF) in lung. In vitro studies showed liraglutide reversed TGF-ß1 (5 ng/ml) combining IL-1ß (5 ng/ml) induced endothelial-mesenchymal transition (EndMT) in human umbilical vein endothelial cells (HUVECs), which could be abolished by GLP-1 receptor antagonist (exendin-3). Furtermore, liraglutide suppressed TGF-ß1-IL-1ß-induced phosphorylation of both Smad3 and ERK1/2. CONCLUSIONS: Our data suggest that GLP-1 mediated the protective effects of DPP-4i on pulmonary vascular and RV remodeling in experimental PH, which may be attributed to the inhibitory effect on EndMT.


Assuntos
Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Incretinas/farmacologia , Liraglutida/farmacologia , Peptídeos/farmacologia , Substâncias Protetoras/farmacologia , Fosfato de Sitagliptina/farmacologia , Animais , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
17.
Neurotox Res ; 35(3): 635-653, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30673988

RESUMO

L-dopa is still considered as the gold standard therapy for Parkinson's disease (PD); however, L-dopa-induced dyskinesia (LID) is a serious complication of long-term L-dopa treatment. The present study investigated the therapeutic potential of sitagliptin and liraglutide in comparisons with L-dopa against PD. In addition, their capacity to modulate L-dopa dose and/or side effects was investigated, too. Rats were injected with rotenone (3 mg/kg/day, s.c.) for 10 consecutive days to induce the experimental PD. The rotenone-treated rats were administered sitagliptin (30 mg/kg/day, p.o.) and liraglutide (50 µg/kg, s.c.) for 16 days either alone or together with L-dopa/carbidopa (50/25 mg/kg/day, i.p.). Scoring of LID was done on days 2, 4, 8, 12, and 16 in all L-dopa-treated groups. Twenty-four hours after the last administered dose of tested drugs, the behavior of rats in each group was screened by using the open-field test. Sitagliptin and liraglutide revealed marked attenuation of LID scores; in addition, they markedly increased animals' motor performance. Moreover, they preserved substantia nigra pars compacta (SNpc) tyrosine hydroxylase (TH) and vesicular monoamine transporter 2-positive (VMAT2) cells with prominent increase of the striatal dopamine (DA) content. On the other hand, they significantly decreased nigral neuromelanin (NM)-positive cells, activated microglia, gliosis, and other pathological changes. In conclusion, sitagliptin and liraglutide could be a promising therapeutic challenger in PD, modifying L-dopa effect and/or allowing the use of L-dopa with fewer side effects.


Assuntos
Antiparkinsonianos/farmacologia , Carbidopa/farmacologia , Discinesia Induzida por Medicamentos/prevenção & controle , Levodopa/farmacologia , Liraglutida/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Fosfato de Sitagliptina/farmacologia , Animais , Antiparkinsonianos/efeitos adversos , Carbidopa/efeitos adversos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Combinação de Medicamentos , Discinesia Induzida por Medicamentos/metabolismo , Discinesia Induzida por Medicamentos/patologia , Levodopa/efeitos adversos , Liraglutida/efeitos adversos , Masculino , Atividade Motora/efeitos dos fármacos , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Parte Compacta da Substância Negra/efeitos dos fármacos , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia , Distribuição Aleatória , Ratos Wistar , Rotenona , Fosfato de Sitagliptina/efeitos adversos
18.
Neurosci Lett ; 696: 184-190, 2019 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-30597232

RESUMO

BACKGROUND: Sitagliptin is an anti-diabetic drug and its effects on Alzheimer's disease (AD) remain controversial. This study aimed to investigate the protective effect of sitagliptin on the cognition in AD and its underlying molecular mechanism. METHODS: The APP/PS1 (a model of AD) mice received daily gastric gavage administration of sitagliptin (20 mg/kg) for 8 weeks. Then animals were subjected to behavioral experiment or sacrificed to histological staining and protein level analysis. RESULTS: The MWM test showed that sitagliptin treatment significantly reduced the escape latency times in APP/PS1 mice in the learning phase (day 3-5) and elongated the time spent in the target quadrant in the probe test. Sitagliptin significantly reduced amyloid plaque deposition and elevated the spine density and the protein levels of synaptoneurosome GluA1- and GluA2-containing AMPA receptor (GluA1R and GluA2R) in the brain of the APP/PS1 mice. Sitagliptin treatment significantly up-regulated the brain BNDF protein and phosphorylation of tyrosine receptor kinase B (TrkB). Furthermore, exendin-(9-39) (a glucagon-like peptide-1 [GLP-1] receptor antagonist) and K252a (a Trk tyrosine kinase inhibitor) treatment significantly abolished the cognitive protective effect of sitagliptin in the MWM test. CONCLUSION: Sitagliptin treatment effectively protected the cognition function of the AD mice by regulating synaptic plasticity, at least partially, through activating GLP-1 and BDNF-TrkB signalings.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Fosfato de Sitagliptina/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon/efeitos dos fármacos , Camundongos , Receptores de AMPA/efeitos dos fármacos , Receptores de AMPA/metabolismo
19.
Mol Cell Biochem ; 455(1-2): 91-97, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30446906

RESUMO

Cisplatin has been extensively used as a chemotherapeutic agent since around 40 years, though its usage is limited due to severe adverse effects like neurotoxicity that might be because of oxidative stress. Hence, the present study was planned to investigate the possible protective role of sitagliptin against cisplatin-associated neurotoxic, biochemical, and behavioral alterations in male Wistar rats. Sitagliptin is a dipeptidyl peptidase-4 inhibitor that shows dual effects by improving the control on metabolism as well as decreasing the debility in cognitive function that is associated with increased insulin sensitivity and antioxidant property. For the in vitro assay, cultured rat pheochromocytoma (PC12) cells were exposed to different concentrations (10, 20, and 50 mM) of sitagliptin for 24 h. Cisplatin at 5 mM concentrations was added and cell viability was assessed using MTT assay. For in vivo study, animals were divided into four groups. Group I (Vehicle control): animals were administered 0.9% (w/v) of normal saline (1 mL/100 g; p.o.). Group II (Cisplatin): animals were treated with cisplatin (2 mg/kg; i.p.). Group III (Cisplatin + sitagliptin): animals were administered cisplatin along with sitagliptin. Group IV (Sitagliptin): animals were given sitagliptin (10 mg/kg; p.o.). All the treatments were administered for 8 weeks. On last day of treatment, behavioral evaluations including locomotor and rotarod studies were performed. In addition, several antioxidant enzymes were also estimated from cerebellum tissues; such as levels of thiobarbituric acid reactive substance (TBARS) were determined as a marker of lipid peroxidation, reduced glutathione (GSH) and catalase (CAT) were also estimated. Histological study of cerebellum tissue was also performed after performing the behavioral study. Exposure to cisplatin decreased cell viability in PC12 cells which were significantly increased by co-treatment with sitagliptin. In in vivo study, cisplatin significantly elevated the level of TBARS and reduced the level of antioxidant enzymes such as GSH and CAT which were significantly restored in sitagliptin + cisplatin group of rats. In addition, cisplatin impaired performance on the locomotor and rotarod activities, whereas sitagliptin significantly improved the performance of both activities. These results suggested the neuroprotective influence of sitagliptin by protecting cerebellum part of brain against cisplatin-induced toxicity.


Assuntos
Comportamento Animal/efeitos dos fármacos , Cisplatino/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Fosfato de Sitagliptina/farmacologia , Animais , Cisplatino/farmacologia , Masculino , Síndromes Neurotóxicas/sangue , Células PC12 , Ratos , Ratos Wistar
20.
Toxicol Appl Pharmacol ; 365: 30-40, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30576699

RESUMO

BACKGROUND: Since many diabetic patients require combination therapy, the use of herbal remedies with anti-diabetic activity represents a vital option in diabetes mellitus (DM) management. It has been reported that quercetin has hypoglycemic alongside anti-inflammatory and antioxidant activities. AIM: The present study aimed to investigate the effectiveness of combining quercetin with sitagliptin; a selective dipeptidyl peptidase-IV (DPP-IV) inhibitor, in the management of streptozotocin (STZ)-induced diabetic rats. METHODS: DM was induced by a single injection of STZ (45 mg/kg, i.p.) in male adult albino Wistar rats. Diabetic rats were orally treated with sitagliptin (70 mg/kg), quercetin (50 mg/kg) or their combination daily for three consecutive weeks. Serum levels of glucose, C-peptide, total cholesterol, triglycerides, malondialdehyde (MDA), superoxide dismutase, (SOD), reduced glutathione (GSH), tumor necrosis factor alpha, (TNF-α), nuclear factor kappa-B, (NF-κB) and adiponectin were estimated. In addition, histopathological, morphometrical and immunohistochemical examinations of pancreatic tissues were conducted. RESULTS: The combined administration of quercetin and sitagliptin normalized serum C-peptide, MDA, and significantly increased SOD, GSH and decreased NF-κB more than sitagliptin alone. Moreover, this combination normalized Islet number, ß-cells' number, area and perimeter alongside restoring the immunostaining intensity of ß-cells. CONCLUSION: Our results suggest the use of quercetin/sitagliptin combination for treating DM based on the observed improvements in glycemic control, metabolic profile, oxidative and inflammatory status, islet structure as well as ß-cells function compared with either treatment alone.


Assuntos
Antioxidantes/farmacologia , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Quercetina/farmacologia , Fosfato de Sitagliptina/farmacologia , Estreptozocina , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Peptídeo C/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/patologia , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Glutationa/sangue , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Malondialdeído/sangue , NF-kappa B/sangue , Ratos Wistar , Superóxido Dismutase/sangue
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