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1.
Nutrients ; 11(1)2019 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-30621149

RESUMO

Opioid peptides released during digestion of dietary proteins such as casein, were suggested to contribute to autism development, leading to the announcement of opioid excess hypothesis of autism. This paper examines role of enzyme proline dipeptidyl peptidase-4 (DPPIV; EC 3.4.14.5) and it is exogenous substrate, ß-casomorphin-7 (BCM7) in autism etiology. Our study included measurements of DPPIV and BCM7 concentrations in serum and urine, which were analyzed with ELISA assays and activity of DPPIV was measured by colorimetric test. The effect of opioid peptides from hydrolysed bovine milk on DPPIV gene expression in peripheral blood mononuclear cells (PBMC) in autistic and healthy children was determined using the Real-Time PCR (Polymerase Chain Reaction) method. Our research included 51 healthy children and 86 children diagnosed with autism spectrum disorder (ASD, ICDF84). We determined that the concentration of BCM7 in serum was significantly, 1.6-fold, higher in the ASD group than in controls (p < 0.0001). Concentration of DPPIV was found to also be significantly higher in serum from ASD children compared to the control group (p < 0.01), while we did not notice significant difference in enzymatic activity of serum DPPIV between the two study groups. We confirmed correlation according to the gender between analyzed parameters. The inspiration for this study emanated from clinical experience of the daily diet role in relieving the symptoms of autism. Despite this, we have concluded that milk-derived opioid peptides and DPPIV are potentially factors in determining the pathogenesis of autism; conducted studies are still limited and require further research.


Assuntos
Transtorno do Espectro Autista/enzimologia , Dipeptidil Peptidase 4/fisiologia , Leite/química , Peptídeos Opioides/fisiologia , Animais , Transtorno do Espectro Autista/sangue , Transtorno do Espectro Autista/etiologia , Criança , Pré-Escolar , Dipeptidil Peptidase 4/sangue , Dipeptidil Peptidase 4/genética , Endorfinas/sangue , Endorfinas/farmacologia , Endorfinas/fisiologia , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/enzimologia , Masculino , Peptídeos Opioides/sangue , Peptídeos Opioides/urina , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/fisiologia , Prolina , Fatores Sexuais
2.
Cell Metab ; 29(2): 320-334.e5, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30393019

RESUMO

Dipeptidyl peptidase-4 (DPP-4) controls glucose homeostasis through enzymatic termination of incretin action. We report that plasma DPP-4 activity correlates with body weight and fat mass, but not glucose control, in mice. Genetic disruption of adipocyte Dpp4 expression reduced plasma DPP-4 activity in older mice but did not perturb incretin levels or glucose homeostasis. Knockdown of hepatocyte Dpp4 completely abrogated the obesity-associated increase in plasma DPP-4 activity, reduced liver cytokine expression, and partially attenuated inflammation in adipose tissue without changes in incretin levels or glucose homeostasis. In contrast, circulating levels of soluble DPP4 (sDPP4) were dissociated from inflammation in mice with endothelial-selective or global genetic inactivation of Dpp4. Remarkably, inhibition of DPP-4 enzymatic activity upregulated circulating levels of sDPP4 originating from endothelial or hematopoietic cells without inducing systemic or localized inflammation. Collectively, these findings reveal unexpected complexity in regulation of soluble versus enzymatic DPP-4 and control of inflammation and glucose homeostasis.


Assuntos
Dipeptidil Peptidase 4/fisiologia , Glucose/metabolismo , Hepatócitos/metabolismo , Incretinas/metabolismo , Inflamação/imunologia , Obesidade/metabolismo , Células 3T3-L1 , Animais , Citocinas/metabolismo , Hepatócitos/citologia , Camundongos , Camundongos Endogâmicos C57BL
3.
Pharmacol Res ; 135: 18-24, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30030170

RESUMO

Diabetes is a chronic metabolic disease characterized by hyperglycemia and several associated biochemical abnormalities. Diabetes leads to multiorgan complications that collectively reduce life expectancy. Hematopoietic stem cells (HSCs) are nested within bone marrow (BM) niches whence they can be mobilized to the peripheral circulation. Clinically, this is done for HSC collection and autologous or allogenic transplantation. A great amount of data from basic and clinical studies support that diabetic patients are poor HSC mobilizers owing to BM remodeling. Dysfunction of the BM shares pathophysiological features and pathways with typical chronic diabetic complications that affect other issues (e.g. the retina and the kidney). From a clinical perspective, impaired HSC mobilization translates into the failure to collect a minimum number of CD34+ cells to achieve a safe engraftment after transplantation. Furthermore, blunted mobilization is associated with reduced steady-state levels of circulating HSCs, which have been consistently described in diabetic patients and associated with increased risk of adverse outcomes, including cardiovascular events and death. In this review, we discuss the most clinically relevant pharmacological options to overcome impaired HSC mobilization in diabetes. These therapeutic strategies may result in an improved outcome of diabetic patients undergoing HSC transplantation and restore circulating HSC levels, thereby protecting from adverse cardiovascular outcomes.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Células-Tronco Hematopoéticas/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Glicemia/efeitos dos fármacos , Diabetes Mellitus/sangue , Diabetes Mellitus/fisiopatologia , Dipeptidil Peptidase 4/fisiologia , Humanos , Hipoglicemiantes/farmacologia , Receptores CXCR4/antagonistas & inibidores
4.
J Pharmacol Sci ; 135(4): 164-173, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29249634

RESUMO

Dipeptidyl peptidase-4 (DPP-4) inhibitors are hypoglycemic agents. DPP-4 inhibitor has cardioprotective effects after transverse aortic constriction (TAC), but role of DPP-4 on cardiac fibrosis after TAC is not well known. Our aim was to determine the effects of DPP-4 on cardiac fibrosis in murine TAC model. Wild-type mice and DPP-4 knockout mice were subjected to TAC. Wild-type mice were then treated with vehicle or DPP-4 inhibitor. DPP-4 activities in serum and heart tissue were significantly increased at 2 weeks after TAC, but they were significantly decreased by DPP-4 inhibitor treatment. The inhibition of DPP-4 did not affect left ventricular hypertrophy, but improved cardiac function and decreased myocardial and perivascular fibrosis after TAC. The inhibition of DPP-4 decreased the collagen type III/I ratio in myocardium. These results suggest that DPP-4 inhibition ameliorates the progression of heart failure after TAC by changing the quality and quantity of cardiac fibrosis.


Assuntos
Cardiotônicos , Dipeptidil Peptidase 4/fisiologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Miocárdio/patologia , Animais , Aorta , Estenose da Valva Aórtica/complicações , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Constrição Patológica , Dipeptidil Peptidase 4/metabolismo , Modelos Animais de Doenças , Fibrose , Insuficiência Cardíaca/patologia , Hipertensão/complicações , Hipertrofia , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Pressão
5.
Metabolism ; 73: 125-134, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28637594

RESUMO

OBJECTIVE: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is attributed to a "multi-hits hypothesis" involving insulin resistance, oxidative stress and inflammation. Dipeptidyl peptidase-4 (DPP4) was identified as a novel adipokine capable of enhancing the"multi-hits". Hence, we investigated the association between plasma DPP4 activity and NAFLD in nondiabetic Chinese population. DESIGN AND METHODS: We performed a cross-sectional study using data from 1105 subjects (36-79years) in Guilin between 2015 and 2016. Plasma DPP4 activity, homeostatic model assessment of insulin resistance (HOMA-IR), oxidative stress parameters, and inflammatory markers were measured in all participants. NAFLD and its severity were diagnosed by ultrasound after the exclusion of alcohol abuse and other liver diseases. RESULTS: Participants in the highest quartile of DPP4 activity had higher HOMA-IR, nitrotyrosine, 8-iso-PGF2a, interleukin-6, CRP, alanine aminotransferase, aspartate aminotransferase and γ-glutamyltransferase compared with those in the lowest quartile (all P<0.05). Plasma DPP4 activity gradually increased across the groups according to the ultrasonographic severity of steatosis (P<0.001 for the trend). In the highest DPP4 quartile, NAFLD risk was higher (odds ratio 1.88; 95% CI 1.04-3.37) than in the lowest quartile after adjustment for confounders. The risk for NAFLD increased more with higher levels of DPP4 activity, HOMA-IR, nitrotyrosine, 8-iso-PGF2a, interleukin-6 and CRP. CONCLUSIONS: Plasma DPP4 activity is significantly associated with NAFLD. The underlying mechanisms may be partly attributed to the interactions between insulin resistance, oxidative stress, inflammation, and DPP4.


Assuntos
Dipeptidil Peptidase 4/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Adulto , Idoso , China/epidemiologia , Estudos Transversais , Dipeptidil Peptidase 4/fisiologia , Humanos , Inflamação , Resistência à Insulina , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Estresse Oxidativo , Ultrassonografia
6.
Artigo em Inglês | MEDLINE | ID: mdl-28452380

RESUMO

BACKGROUND AND AIMS: Proteolytic enzymes contribute to the progression of various cancers. We previously reported increased expression of the proline specific peptidases dipeptidyl peptidase-IV (DPP-IV) and its closest paralogue fibroblast activation protein (FAP) in human glioblastomas. Here we analyze the molecular heterogeneity of DPP-IV and FAP in glioblastomas. METHODS: ELISA, isoelectric focusing, 1D and 2D electrophoresis followed by WB or enzyme overlay assay were utilized to analyze DPP-IV and FAP isoforms. Cell fractionation using a Percoll gradient and deglycosylation with PNGase F were performed to analyze the possible basis of DPP-IV and FAP microheterogeneity. RESULTS: Molecular forms of DPP-IV with an estimated molecular weight of 140-160 kDa and a pI predominantly 5.8 were detected in human glioblastoma; in some tumors additional isoforms with a more acidic (3.5-5.5) as well as alkaline (8.1) pI were revealed. Using 2D electrophoresis, two to three molecular forms of FAP with an alkaline (7.0-8.5) pI and an estimated MW of 120-140 kDa were identified in glioblastoma tissues. In glioma cell lines in vitro, several isoforms of both enzymes were expressed, however the alkalic forms present in glioblastoma tissues were not detected. Removal of N-linked oligosaccharides decreased the estimated molecular weight of both enzymes; the overall pattern of molecular forms nevertheless remained unchanged. CONCLUSION: Several isoforms of DPP-IV and FAP are present in glioblastoma tissue. The absence of alkaline isoforms of both enzymes in glioma cell lines however suggests that isoforms from other, most likely stromal, cell types contribute to the overall pattern seen in glioblastoma tissues.


Assuntos
Encéfalo/enzimologia , Dipeptidil Peptidase 4/fisiologia , Gelatinases/fisiologia , Glioblastoma/enzimologia , Proteínas de Membrana/fisiologia , Serina Endopeptidases/fisiologia , Encéfalo/patologia , Fracionamento Celular , Eletroforese , Estabilidade Enzimática , Ensaio de Imunoadsorção Enzimática , Heterogeneidade Genética , Humanos , Imuno-Histoquímica , Focalização Isoelétrica , Células Tumorais Cultivadas
7.
Osteoporos Int ; 28(5): 1631-1640, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28150034

RESUMO

There was no association of plasma DPP-4 activity levels with bone mineral density (BMD), body composition, or incident hip fractures in a cohort of elderly community-dwelling adults. INTRODUCTION: Dipeptidyl peptidase IV (DPP-4) inactivates several key hormones including those that stimulate postprandial insulin secretion, and DPP-4 inhibitors (gliptins) are approved to treat diabetes. While DPP-4 is known to modulate osteogenesis, the relationship between DPP-4 activity and skeletal health is uncertain. The purpose of the present study was to examine possible associations between DPP-4 activity in elderly subjects enrolled in the Cardiovascular Health Study (CHS) and BMD, body composition measurements, and incident hip fractures. METHODS: All 1536 male and female CHS participants who had evaluable DXA scans and plasma for DPP-4 activity were included in the analyses. The association between (1) BMD of the total hip, femoral neck, lumbar spine, and total body; (2) body composition measurements (% lean, % fat, and total body mass); and (3) incident hip fractures and plasma levels of DPP-4 activity were determined. RESULTS: Mean plasma levels of DPP-4 activity were significantly higher in blacks (227 ± 78) compared with whites (216 ± 89) (p = 0.04). However, there was no significant association of DPP-4 activity with age or gender (p ≥ 0.14 for both). In multivariable adjusted models, there was no association of plasma DPP-4 activity with BMD overall (p ≥ 0.55 for all) or in gender stratified analyses (p ≥ 0.23). There was also no association of DPP-4 levels and incident hip fractures overall (p ≥ 0.24) or in gender stratified analyses (p ≥ 0.39). CONCLUSION: Plasma DPP-4 activity, within the endogenous physiological range, was significantly associated with race, but not with BMD, body composition, or incident hip fractures in elderly community-dwelling subjects.


Assuntos
Composição Corporal/fisiologia , Densidade Óssea/fisiologia , Dipeptidil Peptidase 4/sangue , Fraturas do Quadril/sangue , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus/sangue , Diabetes Mellitus/etnologia , Diabetes Mellitus/fisiopatologia , Dipeptidil Peptidase 4/fisiologia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Fraturas do Quadril/etnologia , Fraturas do Quadril/fisiopatologia , Humanos , Incidência , Estudos Longitudinais , Masculino , Fatores Sexuais , Estados Unidos/epidemiologia
8.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 42(1): 108-112, 2017 Jan 28.
Artigo em Chinês | MEDLINE | ID: mdl-28216506

RESUMO

Dipeptidyl peptidase-4 (DPP-4) is known as a highly conserved type II transmembraneous glycoprotein widely distributed in a variety of tissues and cells, and expressed in the peripheral blood as a soluble form. It has been reported that DPP4 play a distinct role in the physiological and pathological processes, such as immune regulation, inflammatory reaction, cell adhesion, and cell apoptosis. DPP4 inhibitor showes an incredible effect on the control of blood glucose and it is thought as a newly-developed drug for diabetes, especially in regulation of post-prandial glycemia. It has been reported that DPP4 plays a potential role in many respiratory diseases, especially in the pathogenesis of asthma.


Assuntos
Dipeptidil Peptidase 4/fisiologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Doenças Respiratórias/fisiopatologia , Apoptose/fisiologia , Asma/etiologia , Asma/fisiopatologia , Glicemia/efeitos dos fármacos , Adesão Celular/fisiologia , Humanos , Hipoglicemiantes , Inflamação/fisiopatologia , Doenças Respiratórias/etiologia
9.
Crit Rev Immunol ; 36(3): 239-267, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28008806

RESUMO

Obliterative bronchiolitis is the primary noninfectious pulmonary complication after allogeneic hematopoietic cell transplantation and the only pathognomonic manifestation of pulmonary chronic graft-versus-host disease (cGVHD). In our recent study, we identified a novel effect of IL-26, which is absent in rodents, on transplant related-obliterative bronchiolitis. Sublethally irradiated NOD/Shi-scidIL2rγnull mice transplanted with human umbilical cord blood gradually exhibited obliterative bronchiolitis with increased collagen deposition and predominant infiltration with human IL-26+CD26+CD4 T cells. Moreover, we showed that IL-26 increased collagen synthesis in fibroblasts in vitro and that collagen contents were increased in a murine GVHD model using IL26 transgenic mice. In vitro analysis demonstrated a significant increase in IL-26 production by CD4 T cells following CD26 costimulation, while immunoglobulin Fc domain fused with the N-terminal of caveolin-1, the ligand for CD26, (Cav-Ig) effectively inhibited production of IL-26. Administration of Cav-Ig before or after onset of GVHD impeded the development of clinical and histologic features of GVHD without interrupting engraftment of donor-derived human cells, with preservation of the graft-versus-leukemia effect. We concluded that cGVHD of the lungs is caused in part by IL-26+CD26+CD4 T cells, and that treatment with Cav-Ig could be beneficial for cGVHD prevention and therapy.


Assuntos
Bronquiolite Obliterante/terapia , Linfócitos T CD4-Positivos/fisiologia , Caveolina 1/uso terapêutico , Dipeptidil Peptidase 4/fisiologia , Doença Enxerto-Hospedeiro/terapia , Interleucinas/fisiologia , Proteínas Recombinantes de Fusão/uso terapêutico , Animais , Bronquiolite Obliterante/etiologia , Doença Crônica , Doença Enxerto-Hospedeiro/etiologia , Humanos , Camundongos
10.
Acta cir. bras ; 31(12): 807-812, Dec. 2016. graf
Artigo em Inglês | LILACS | ID: biblio-837655

RESUMO

ABSTRACT PURPOSE: To investigate the role of bradykinin in a rat lung transplantation (LTx) model and preliminarily discuss the relationship between bradykinin and CD26/DPP-4. METHODS: Rats were randomly divided into four groups: Control (CON), Sham, low potassium dextranglucose (LPD), and AB192 (n=15/group). Orthotopic single LTx was performed in the LPD and AB192 groups. The donor lungs were flush-perfused and preserved with low potassium dextranglucose (LPD) or LPD+CD26/DPP-4 catalytic inhibitor (AB192). LTx was performed after 18 h cold ischemia time and harvested two days post-LTx. Blood gas analysis (PO2), wet/dry weight ratio (W/D), myeloperoxidase activity (MPO), and lipid peroxidation (MDA) were analyzed at 48 hr after transplantation. Immunohistochemical (IHC) analysis was performed in the same sample and validated by Western-Blot. RESULTS: Compared to the LPD group, the AB192 group showed higher PO2, lower W/D ratio, and decreased MPO and MDA. IHC studies showed strong bradykinin β2 receptor (B2R) staining in the LPD group, especially in inflammatory cells, alveolar macrophages, and respiratory epithelial cells. Expression of B2R by Western-Blot was significantly different between the AB192 and LPD groups. CONCLUSION: Bradykinin may be a competitive substrate of DPP-4, and decreased bradykinin levels may enhance protective effects against ischemia/reperfusion injury during LTx.


Assuntos
Animais , Masculino , Ratos , Bradicinina/fisiologia , Traumatismo por Reperfusão/patologia , Transplante de Pulmão , Dipeptidil Peptidase 4/fisiologia , Disfunção Primária do Enxerto/patologia , Pulmão/irrigação sanguínea , Imuno-Histoquímica , Peroxidação de Lipídeos , Traumatismo por Reperfusão/fisiopatologia , Traumatismo por Reperfusão/metabolismo , Distribuição Aleatória , Western Blotting , Modelos Animais de Doenças , Disfunção Primária do Enxerto/fisiopatologia , Antagonistas de Receptor B2 da Bradicinina/metabolismo , Pulmão/efeitos dos fármacos
12.
Int J Cardiol ; 223: 770-775, 2016 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-27573605

RESUMO

BACKGROUND: The present study determined whether dipeptidyl peptidase-4 (DPP-4) inhibition by alogliptin improves coronary flow reserve (CFR) and left ventricular election fraction (LVEF) in patients with type 2 DM and CAD. MATERIALS AND METHODS: Twenty patients with type 2 DM and known or suspected CAD were randomly allocated to receive diet therapy plus alogliptin (n=10; mean age, 73.3±6.6y) or a control group given diet therapy and glimepiride (n=10; mean age, 76.7±7.3y). Breath-hold PC cine MR images of the coronary sinus (CS) were acquired using a 1.5T MR scanner and 32 channel cardiac coils to assess blood flow of the CS at rest and during adenosine triphosphate (ATP) infusion. The CFR was calculated as CS blood flow during ATP infusion divided by that at rest. The CFR and LVEF were evaluated by MRI at baseline and at three months after starting therapy. RESULTS: Hemoglobin A1c (HbA1c) was significantly reduced in both groups (alogliptin, 7.2±0.6% to 6.6±0.5%, p=0.034; control, 6.9±0.4% to 6.4±0.3%, p=0.008). However, CFR and LVEF significantly improved only in the alogliptin group (alogliptin: CFR, 2.15±0.61 to 2.85±0.80, p=0.042; LVEF, 59.4±6.3% to 68.0±8.6%, p=0.03; control: CFR, 2.17±0.37 to 2.38±0.32, p=0.19; LVEF, 58.2±9.1 to 60.3±8.8%, p=0.61). The % increases in CFR and in LVEF positively correlated (R=0.47 by Spearman's correlation coefficient; p=0.036). CONCLUSION: The inhibition of DPP-4 by alogliptin improved CFR and LVEF evaluated by MRI in patients with type 2 DM and CAD and the improvement in CFR was associated with increased LV systolic function.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Reserva Fracionada de Fluxo Miocárdico/efeitos dos fármacos , Imagem Cinética por Ressonância Magnética/métodos , Piperidinas/uso terapêutico , Uracila/análogos & derivados , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Diabetes Mellitus Tipo 2/epidemiologia , Dipeptidil Peptidase 4/fisiologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Feminino , Reserva Fracionada de Fluxo Miocárdico/fisiologia , Humanos , Masculino , Piperidinas/farmacologia , Estudos Prospectivos , Uracila/farmacologia , Uracila/uso terapêutico , Função Ventricular Esquerda/fisiologia
13.
Stem Cells Dev ; 25(8): 575-85, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26943017

RESUMO

Dipeptidyl peptidase 4 (DPP4)/CD26 truncates certain proteins, and this posttranslational modification can influence their activity. Truncated (T) colony-stimulating factors (CSFs) are decreased in potency for stimulating proliferation of hematopoietic progenitor cells (HPCs). T-CXCL12, a modified chemokine, is inactive as an HPC chemotactic, survival, and enhancing factor for replating or ex-vivo expansion of HPCs. Moreover, T-CSFs and T-CXCL12 specifically downmodulates the positively acting effects of their own full-length molecule. Other chemokines have DPP4 truncation sites. In the present study, we evaluated effects of DPP4 inhibition (by Diprotin A) or gene deletion of HPC on chemokine inhibition of multicytokine-stimulated HPC, and on chemokine-enhancing effects on single CSF-stimulated HPC proliferation, as well as effects of DPP4 treatment of a number of chemokines. Myelosuppressive effects of chemokines with, but not without, a DPP4 truncation site were greatly enhanced in inhibitory potency by pretreating target bone marrow (BM) cells with Diprotin A, or by assaying their activity on dpp4/cd26(-/-) BM cells. DPP4 treatment of myelosuppressive chemokines containing a DPP4 truncation site produced a nonmyelosuppressive molecule, but one which had the capacity to block suppression by that unmodified chemokine both in vitro and in vivo. Additionally, DPP4 treatment ablated the single cytokine-stimulated HPC-enhancing activity of CCL3/MIP-1α and CCL4/MIP-1ß, and blocked the enhancing activity of each unmodified molecule, in vitro and in vivo. These results highlight the functional posttranslational modulating effects of DPP4 on chemokine activities, and information offering additional biological insight into chemokine regulation of hematopoiesis.


Assuntos
Quimiocina CCL3/fisiologia , Quimiocina CCL4/fisiologia , Dipeptidil Peptidase 4/fisiologia , Animais , Proliferação de Células , Quimiocina CCL3/química , Quimiocina CCL4/química , Dipeptidil Peptidase 4/química , Feminino , Hematopoese , Células-Tronco Hematopoéticas/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Processamento de Proteína Pós-Traducional , Proteólise
14.
Metabolism ; 65(2): 89-101, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26773932

RESUMO

OBJECTIVE: Studies have shown that dipeptidyl peptidase-4 (DPP-4) inhibitors have anti-inflammatory effects. Soluble DPP-4 (sDPP-4) has been considered as an adipokine of which actions need to be further characterized. METHODS: We investigated the pro-inflammatory actions of sDPP-4 and the anti-inflammatory effects of DPP-4 inhibition, using vildagliptin, as an enzymatic inhibitor, and mannose-6-phosphate (M6P) as a competitive binding inhibitor. RESULTS: In lipopolysaccharide (LPS)-stimulated RAW264.7 cells, vildagliptin suppressed the increased expression of inducible nitric oxide synthase (iNOS) and phosphorylated JNK (pJNK), activation of the NF-κB pathway, and the resultant NO and proinflammatory cytokine production. Although sDPP-4 alone did not affect the protein level of iNOS or pJNK or the production of NO in RAW264.7 cells, it did amplify iNOS expression, NO responses, and proinflammatory cytokine production in LPS-stimulated RAW264 cells. As a probable mechanism, we found that sDPP-4 caused dose-dependent increases in the expression levels of toll-like receptor 4 (TLR4) and TLR2 in RAW264.7 cells, and that these alterations were inhibited by vildagliptin, M6P, or bisindolylmaleimide II, a protein kinase C inhibitor. Either vildagliptin or M6P suppressed iNOS expression and NO and cytokine production in LPS+DPP-4-co-stimulated macrophages, while combined treatment of the co-stimulated cells with both agents had increased anti-inflammatory effects compared with either treatment alone. Intravenous injection of sDPP-4 to C57BL/6J mice increased the expression of both TLRs in kidney and white adipose tissues. CONCLUSION: Our findings suggest that sDPP-4 enhances inflammatory actions via TLR pathway, while DPP-4 inhibition with either an enzymatic or binding inhibitor has anti-inflammatory effects.


Assuntos
Adamantano/análogos & derivados , Dipeptidil Peptidase 4/fisiologia , Inflamação/etiologia , Manosefosfatos/farmacologia , Nitrilos/farmacologia , Pirrolidinas/farmacologia , Receptores Toll-Like/fisiologia , Adamantano/farmacologia , Animais , Células Cultivadas , Inibidores da Dipeptidil Peptidase IV/farmacologia , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , RNA Mensageiro/análise , Receptores Toll-Like/genética , Vildagliptina
15.
Acta Cir Bras ; 31(12): 807-812, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28076504

RESUMO

PURPOSE: : To investigate the role of bradykinin in a rat lung transplantation (LTx) model and preliminarily discuss the relationship between bradykinin and CD26/DPP-4. METHODS: : Rats were randomly divided into four groups: Control (CON), Sham, low potassium dextranglucose (LPD), and AB192 (n=15/group). Orthotopic single LTx was performed in the LPD and AB192 groups. The donor lungs were flush-perfused and preserved with low potassium dextranglucose (LPD) or LPD+CD26/DPP-4 catalytic inhibitor (AB192). LTx was performed after 18 h cold ischemia time and harvested two days post-LTx. Blood gas analysis (PO2), wet/dry weight ratio (W/D), myeloperoxidase activity (MPO), and lipid peroxidation (MDA) were analyzed at 48 hr after transplantation. Immunohistochemical (IHC) analysis was performed in the same sample and validated by Western-Blot. RESULTS: : Compared to the LPD group, the AB192 group showed higher PO2, lower W/D ratio, and decreased MPO and MDA. IHC studies showed strong bradykinin ß2 receptor (B2R) staining in the LPD group, especially in inflammatory cells, alveolar macrophages, and respiratory epithelial cells. Expression of B2R by Western-Blot was significantly different between the AB192 and LPD groups. CONCLUSION: : Bradykinin may be a competitive substrate of DPP-4, and decreased bradykinin levels may enhance protective effects against ischemia/reperfusion injury during LTx.


Assuntos
Bradicinina/fisiologia , Dipeptidil Peptidase 4/fisiologia , Transplante de Pulmão , Pulmão/irrigação sanguínea , Disfunção Primária do Enxerto/patologia , Traumatismo por Reperfusão/patologia , Animais , Western Blotting , Antagonistas de Receptor B2 da Bradicinina/metabolismo , Modelos Animais de Doenças , Imuno-Histoquímica , Peroxidação de Lipídeos , Pulmão/efeitos dos fármacos , Masculino , Disfunção Primária do Enxerto/fisiopatologia , Distribuição Aleatória , Ratos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia
16.
PLoS One ; 10(12): e0145561, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26701103

RESUMO

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe acute respiratory failure and considerable extrapumonary organ dysfuction with substantial high mortality. For the limited number of autopsy reports, small animal models are urgently needed to study the mechanisms of MERS-CoV infection and pathogenesis of the disease and to evaluate the efficacy of therapeutics against MERS-CoV infection. In this study, we developed a transgenic mouse model globally expressing codon-optimized human dipeptidyl peptidase 4 (hDPP4), the receptor for MERS-CoV. After intranasal inoculation with MERS-CoV, the mice rapidly developed severe pneumonia and multi-organ damage, with viral replication being detected in the lungs on day 5 and in the lungs, kidneys and brains on day 9 post-infection. In addition, the mice exhibited systemic inflammation with mild to severe pneumonia accompanied by the injury of liver, kidney and spleen with neutrophil and macrophage infiltration. Importantly, the mice exhibited symptoms of paralysis with high viral burden and viral positive neurons on day 9. Taken together, this study characterizes the tropism of MERS-CoV upon infection. Importantly, this hDPP4-expressing transgenic mouse model will be applicable for studying the pathogenesis of MERS-CoV infection and investigating the efficacy of vaccines and antiviral agents designed to combat MERS-CoV infection.


Assuntos
Infecções por Coronavirus/complicações , Dipeptidil Peptidase 4/fisiologia , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Insuficiência de Múltiplos Órgãos/etiologia , Animais , Quimiocinas/metabolismo , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Feminino , Humanos , Técnicas Imunoenzimáticas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
PLoS One ; 10(4): e0121077, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25876091

RESUMO

Abdominal aortic aneurysm (AAA) is a life-threatening situation affecting almost 10% of elders. There has been no effective medication for AAA other than surgical intervention. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown to have a protective effect on cardiovascular disease. Whether DPP-4 inhibitors may be beneficial in the treatment of AAA is unclear. We investigated the effects of DPP-4 inhibitor sitagliptin on the angiotensin II (Ang II)-infused AAA formation in apoE-deficient (apoE-/-) mice. Mice with induced AAA were treated with placebo or 2.5, 5 or 10 mg/kg/day sitagliptin. Ang II-infused apoE-/- mice exhibited a 55.6% incidence of AAA formation, but treatment with sitagliptin decreased AAA formation. Specifically, administered sitagliptin in Ang II-infused mice exhibited decreased expansion of the suprarenal aorta, reduced elastin lamina degradation of the aorta, and diminished vascular inflammation by macrophage infiltration. Treatment with sitagliptin decreased gelatinolytic activity and apoptotic cells in aorta tissues. Sitaglipitn, additionally, was associated with increased levels of plasma active glucagon-like peptide-1 (GLP-1). In vitro studies, GLP-1 decreased reactive oxygen species (ROS) production, cell migration, and MMP-2 as well as MMP-9 activity in Ang II-stimulated monocytic cells. The results conclude that oral administration of sitagliptin can prevent abdominal aortic aneurysm formation in Ang II-infused apoE-/-mice, at least in part, by increasing of GLP-1 activity, decreasing MMP-2 and MMP-9 production from macrophage infiltration. The results indicate that sitagliptin may have therapeutic potential in preventing the development of AAA.


Assuntos
Aneurisma da Aorta Abdominal/prevenção & controle , Dipeptidil Peptidase 4/fisiologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/sangue , Monócitos/fisiologia , Fosfato de Sitagliptina/uso terapêutico , Angiotensina II/toxicidade , Animais , Aneurisma da Aorta Abdominal/enzimologia , Aneurisma da Aorta Abdominal/genética , Apolipoproteínas E/deficiência , Apoptose , Movimento Celular , Células Cultivadas , Quimiotaxia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Avaliação Pré-Clínica de Medicamentos , Fibroblastos/citologia , Humanos , Bombas de Infusão Implantáveis , Macrófagos/fisiologia , Masculino , Metaloproteinase 2 da Matriz/análise , Metaloproteinase 9 da Matriz/análise , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Fosfato de Sitagliptina/farmacologia , Células U937
18.
Med Clin (Barc) ; 143 Suppl 2: 8-11, 2014 Sep.
Artigo em Espanhol | MEDLINE | ID: mdl-25437459

RESUMO

Modulation of the incretin effect has opened up a new strategy in the treatment of diabetes mellitus type 2 (DM2). To date, this physiological mechanism has been boosted in two ways: firstly, by pharmacological inhibition of the enzyme that physiologically degrades glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP4); secondly, through the development of GLP-1 agonists (GLP-1a) that are resistant to the action of DPP-4. Several clinical trials have shown the clinical superiority of GLPa, which seems to be linked to higher circulating levels of GLP-1. On the other hand, this higher efficacy also seems to be associated with the higher rate of adverse effects associated with aGLP-1 therapy compared with DPP-4 inhibition. These and other differentiating characteristics of the two drug families will determine the choice of drug therapy in the personalized treatment of hyperglycemia in patients with DM2.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/agonistas , Hipoglicemiantes/uso terapêutico , Incretinas/agonistas , Receptores de Glucagon/agonistas , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/fisiopatologia , Dipeptidil Peptidase 4/fisiologia , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Motilidade Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/fisiologia , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Modelos Biológicos , Medicina de Precisão , Espanha
19.
Med Clin (Barc) ; 143 Suppl 2: 12-7, 2014 Sep.
Artigo em Espanhol | MEDLINE | ID: mdl-25437460

RESUMO

Glucagon-like peptide 1 (GLP-1) is secreted from enteroendocrine L-cells in response to oral nutrient intake and elicits glucose-stimulated insulin secretion while suppressing glucagon secretion. Moreover slows gastric emptying -reducing postprandial glycemic excursions-, reduces body weight, systolic blood pressure and has beneficial effects in the cardiovascular and central nervous systems. Since the 1990s, the efficacy of GLP-1 in reducing blood glucose levels in type 2 diabetes (DM2) was well known. However, GLP-1 should be administered by chronic subcutaneous infusion because of the rapid cleavage by the enzyme dipeptidyl peptidase 4 (DPP-4). Hence, DPP-4 inhibitors -which increase pseudo-physiologically endogenous GLP-1 levels- were developed. In addition, several GLP-1 receptor agonists have been designed to avoid DPP-4-breakdown and/or rapid renal elimination and, therefore, induce a pharmacologic effect in the GLP-1 receptor: short-acting, long-acting, and prolonged-acting GLP-1 analogs. Each class has different structural, pharmacodynamic and clinical properties and could be administered in different therapeutical regimens giving us the opportunity to individualize the therapy of DM2.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Hipoglicemiantes/uso terapêutico , Receptores de Glucagon/agonistas , Sequência de Aminoácidos , Ensaios Clínicos como Assunto , Dipeptidil Peptidase 4/fisiologia , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Previsões , Gastroenteropatias/induzido quimicamente , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/farmacocinética , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1 , Meia-Vida , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/prevenção & controle , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Incretinas , Infusões Subcutâneas , Rim/metabolismo , Dados de Sequência Molecular , Estudos Multicêntricos como Assunto , Medicina de Precisão , Proteólise/efeitos dos fármacos
20.
Eur J Clin Invest ; 44(12): 1239-45, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25371066

RESUMO

The concept of leukaemic stem cells (LSCs) has been developed to explain the complex cellular hierarchy and biology of leukaemias and to screen for pivotal targets that can be employed to improve drug therapies through LSC eradication in these patients. Some of the newly discovered LSC markers seem to be expressed in a disease-specific manner and may thus serve as major research tools and diagnostic parameters. A useful LSC marker in chronic myeloid leukaemia (CML) appears to be CD26, also known as dipeptidylpeptidase IV. Expression of CD26 is largely restricted to CD34(+) /CD38(-) LSCs in BCR/ABL1(+) CML, but is not found on LSCs in other myeloid or lymphoid neoplasms, with the exception of lymphoid blast crisis of CML, BCR/ABL1p210 + acute lymphoblastic leukaemia, and a very few cases of acute myeloid leukaemia. Moreover, CD26 usually is not expressed on normal bone marrow (BM) stem cells. Functionally, CD26 is a cytokine-targeting surface enzyme that may facilitate the mobilization of LSCs from the BM niche. In this article, we review our current knowledge about the biology and function of CD26 on CML LSCs and discuss the diagnostic potential of this new LSC marker in clinical haematology.


Assuntos
Biomarcadores Tumorais/metabolismo , Dipeptidil Peptidase 4/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Células-Tronco Neoplásicas/metabolismo , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Biomarcadores Tumorais/fisiologia , Dipeptidil Peptidase 4/fisiologia , Detecção Precoce de Câncer , Previsões , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico
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