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1.
Chem Biol Interact ; 314: 108842, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31586451

RESUMO

BACKGROUND AND AIMS: Chronic psychosocial stress is a risk factor for cardiovascular disease. In view of the important role of dipeptidyl peptidase-4 (DPP-4) in human pathophysiology, we studied the role of DPP-4 in stress-related vascular aging in mice, focusing on oxidative stress and the inflammatory response. METHODS AND RESULTS: Male mice were randomly divided into a non-stress group and an immobilization stress group treated for 2 weeks. Chronic stress accelerates aortic senescence and increases plasma DPP-4 levels. Stress increased the levels of gp91phox, p22phox, p47phox, p67phox, p53, p27, p21, p16INK4A, vascular cell adhesion molecule-1, intracellular adhesion molecule-1, monocyte chemoattractant protein-1, matrix metalloproteinase-2 (MMP-2), MMP-9, cathepsin S (Cat S), and Cat K mRNAs and/or protein in the aorta of the stressed mice and decreased their levels of endothelial nitric oxide synthase and SirTuin1 (SirT1). DPP-4 inhibitors can improve stress-induced targeting molecules and morphological changes. In vitro, the inhibition of DPP-4 also alleviated the changes in the oxidative and inflammatory molecules in response to hydrogen peroxide in human umbilical vein endothelial cells. CONCLUSIONS: DPP-4 inhibition can improve vascular aging in stressed mice, possibly by improving oxidative stress production and vascular inflammation. Our results suggest that DPP-4 may become a new therapeutic target for chronic stress-related vascular aging in metabolic cardiovascular diseases.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Aorta/metabolismo , Aorta/patologia , Dipeptidil Peptidase 4/sangue , Dipeptidil Peptidase 4/química , Regulação para Baixo/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Peróxido de Hidrogênio/metabolismo , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Pirimidinas/farmacologia , Sirtuína 1/metabolismo , Estresse Fisiológico
2.
Environ Sci Pollut Res Int ; 26(29): 29597-29605, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31446595

RESUMO

Glucagon-like peptide-1 (GLP-1) is involved in postprandial glucose homeostasis. Secretion of which involves a cholinergic pathway. Anticholinergic agent like atropine could act as a competitive antagonist of acetylcholine at muscarinic receptors. This review explores studies that assess the role of atropine in GLP-1 secretion. We selected published original articles from PubMed, Science Direct, The Cochrane Library, Trip, Google and the reference lists of the selected articles. Reporting was done according to the PRISMA statement. Relevant standard and previously published tools were used to assess the risk of bias of the selected articles. Twelve articles out of 185 search results fulfilled the review criteria. Eight were in vivo studies (six animal and two human studies), three were ex vivo studies and one was an in vitro study. Animal studies had rats, mice, pigs and monkeys as the subjects. Human studies involved healthy men and women. Majority of the studies reported an atropine-mediated attenuation of GLP-1 secretion and postprandial secretion of GLP-1 was mainly affected. However, atropine failed to significantly affect GLP-1 secretion when dipeptidyl peptidase-4 (DPP-4) enzyme was inhibited.


Assuntos
Atropina/farmacologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Adulto , Animais , Dipeptidil Peptidase 4/metabolismo , Feminino , Humanos , Masculino , Camundongos , Período Pós-Prandial , Ratos , Suínos
3.
J Agric Food Chem ; 67(38): 10604-10613, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31466448

RESUMO

The aim of this study was to investigate the dipeptidyl peptidase-IV (DPP-IV) inhibition and metabolic stability of a casein-derived peptide Val-Pro-Tyr-Pro-Gln (VPYPQ) and its fragments as well as their release from casein following hydrolysis. Results showed that VPYPQ was the most potent DPP-IV inhibitory peptide among them with an IC50 value of 41.45 µM. This might be due to its two internal Pro residues at positions 2 and 4. Moreover, VPYPQ was resistant to hydrolysis by gastrointestinal enzymes and was relatively more stable to hydrolysis by DPP-IV and peptidases in plasma compared with its fragments. Additionally, oral administration of VPYPQ at a dose of 90 µmol/kg body weight could reduce the postprandial blood glucose levels in mice. More importantly, VPYPQ could be released efficiently from casein following hydrolysis by a combination of papain and in vitro digestion, reaching up to 3211.15 µg/g. Therefore, VPYPQ was a promising casein-derived DPP-IV inhibitor.


Assuntos
Caseínas/química , Preparações de Ação Retardada/química , Inibidores da Dipeptidil Peptidase IV/química , Peptídeos/química , Animais , Biocatálise , Glicemia/metabolismo , Preparações de Ação Retardada/administração & dosagem , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Teste de Tolerância a Glucose , Humanos , Hidrólise , Camundongos , Peptídeo Hidrolases/química , Peptídeo Hidrolases/metabolismo , Peptídeos/administração & dosagem , Ratos , Ratos Sprague-Dawley
4.
Nat Commun ; 10(1): 3068, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296843

RESUMO

Most neutralizing antibodies against Middle East respiratory syndrome coronavirus (MERS-CoV) target the receptor-binding domain (RBD) of the spike glycoprotein and block its binding to the cellular receptor dipeptidyl peptidase 4 (DPP4). The epitopes and mechanisms of mAbs targeting non-RBD regions have not been well characterized yet. Here we report the monoclonal antibody 7D10 that binds to the N-terminal domain (NTD) of the spike glycoprotein and inhibits the cell entry of MERS-CoV with high potency. Structure determination and mutagenesis experiments reveal the epitope and critical residues on the NTD for 7D10 binding and neutralization. Further experiments indicate that the neutralization by 7D10 is not solely dependent on the inhibition of DPP4 binding, but also acts after viral cell attachment, inhibiting the pre-fusion to post-fusion conformational change of the spike. These properties give 7D10 a wide neutralization breadth and help explain its synergistic effects with several RBD-targeting antibodies.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Infecções por Coronavirus/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/metabolismo , Anticorpos Neutralizantes/ultraestrutura , Anticorpos Antivirais/sangue , Anticorpos Antivirais/metabolismo , Anticorpos Antivirais/ultraestrutura , Linhagem Celular Tumoral , Infecções por Coronavirus/sangue , Infecções por Coronavirus/virologia , Cristalografia por Raios X , Dipeptidil Peptidase 4/metabolismo , Modelos Animais de Doenças , Mapeamento de Epitopos , Epitopos/imunologia , Feminino , Células HEK293 , Humanos , Camundongos , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Testes de Neutralização , Ligação Proteica/imunologia , Domínios Proteicos/imunologia , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/ultraestrutura , Glicoproteína da Espícula de Coronavírus/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/ultraestrutura , Células Vero , Internalização do Vírus
5.
Eur J Med Chem ; 180: 509-523, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31336309

RESUMO

A series of novel xanthine derivatives 2a-l incorporating benzoic acid moieties were rapidly generated by using strategy of scaffold-hopping from our previously reported scaffold uracil to xanthine, a scaffold of approved drug linagliptin. After systematic structure-activity relationship (SAR) study around benzoic acid moieties, 5 novel DPP-4 inhibitors with low picomolar potency range (IC50 < 1 nM) and excellent selectivity against various DPP-4 homologues were identified, in which the best one, compound 2f, with the IC50 value of 0.1 nM for DPP-4, showed 22-fold improvement in inhibitory activity compared to lead compound uracil 1, its activity was 45-fold more potent than alogliptin. 2e, 2f, 2i and 2k were selected for pharmacokinetic evaluation, and 2f and 2i showed the better pharmacokinetic profiles after iv administration, but poor oral bioavailability. To improve the oral pharmacokinetic profile, prodrug design approach was performed around 2f and 2i. Esters of 2f and 2i were synthesized and evaluated for stability, toxicity and pharmacokinetics. Compound 3e, the methyl ester of compound 2f, was identified to demonstrate good stability, low toxicity and improved oral bioavailability, with 3-fold higher blood concentration compared to 2f in rats. The following in vivo evaluations revealed 3e provided a sustained pharmacodynamics effect for 48h, and robustly improved glucose tolerance in normal ICR and db/db mice in dose-dependent manner. Chronic treatments investigations demonstrated that 3e achieved more beneficial effects on fasting blood glucose levels and glucose tolerance than alogliptin in type 2 diabetic db/db mice. The overall results have shown that compound 3e has the potential to efficacious, safety and long-acting treatment for T2DM.


Assuntos
Ácido Benzoico/farmacologia , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Pró-Fármacos/farmacologia , Xantina/farmacologia , Animais , Ácido Benzoico/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Relação Dose-Resposta a Droga , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade , Xantina/síntese química , Xantina/química
6.
Eur J Med Chem ; 180: 99-110, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31301567

RESUMO

Biologically active or bioactive peptides are unique amino acid sequences found encrypted in food proteins. These peptides, upon hydrolysis, can exert positive physiological effects on human health, different from that of their native protein. These effects are brought about by their interaction with specific targets in the body, thereby, mimicking physiologically relevant peptides. Peptides are derived from food proteins, they are popular natural alternatives for the management of common metabolic disorders. In the present study, we aimed to identify bioactive peptide sequences (less than 3 kDa) from fat globule membrane protein (FGMP) hydrolysates of buffalo colostrum using a combination of empirical, computational and in vitro methods. The empirical approach aided in the identification of 89 FGMP peptides (m/z-415 to 2939) which were annotated and profiled for bioactivity. Few lead peptides were analyzed by molecular docking for the inhibitory potential of Angiotensin Converting Enzyme (ACE) and Dipeptidyl Peptidase-IV (DPP-IV). A heptapeptide (m/z-723.3) synthesized was found to inhibit ACE (IC50: 74.27 µM) and DPP-IV (IC50: 3.83 mM).


Assuntos
Dipeptidil Peptidase 4/metabolismo , Descoberta de Drogas , Peptídeos/farmacologia , Peptidil Dipeptidase A/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Relação Estrutura-Atividade
7.
Cells ; 8(6)2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31181665

RESUMO

Halophila stipulacea is a well-known invasive marine sea grass in the Mediterranean Sea. Having been introduced into the Mediterranean Sea via the Suez Channel, it is considered a Lessepsian migrant. Although, unlike other invasive marine seaweeds, it has not demonstrated serious negative impacts on indigenous species, it does have remarkable invasive properties. The present in-silico study reveals the biotechnological features of H. stipulacea by showing bioactive peptides from its rubisc/o protein. These are features such as antioxidant and hypolipideamic activities, dipeptidyl peptidase-IV and angiotensin converting enzyme inhibitions. The reported data open up new applications for such bioactive peptides in the field of pharmacy, medicine and also the food industry.


Assuntos
Hydrocharitaceae/metabolismo , Peptídeos/metabolismo , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Antioxidantes/química , Antioxidantes/metabolismo , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Hidrólise , Imunomodulação , Peptídeo Hidrolases/química , Peptídeo Hidrolases/metabolismo , Peptídeos/química , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Ubiquitina/agonistas , Ubiquitina/metabolismo
8.
Eur J Pharm Sci ; 136: 104950, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31173870

RESUMO

BACKGROUND: Yogliptin is a novel xanthine dipeptidyl peptidase-4 (DPP-4) inhibitor targeting type 2 diabetes. After promising preclinical pharmacological studies, the first human trial of yogliptin was designed. METHODS: A randomized, double-blind, parallel, placebo-controlled phase I single-dose escalation study was designed to evaluate the pharmacokinetics, pharmacodynamics, and tolerability after single oral doses of yogliptin in healthy Chinese subjects. Healthy subjects were assigned to nine cohorts, which received a single dose of yogliptin at 2.5, 5, 10, 25, 50, 100, 200, 400, or 600 mg. Two subjects in each cohort received placebo. Blood samples were collected before dosing and up to 192 h afterwards. Urine samples were collected until 120 h after dosing. Plasma and urine drug concentrations were determined using liquid chromatography coupled with tandem mass spectrometry, and DPP-4 activity was measured using a semi-quantitative, fluorescence-based kinetic assay. RESULTS: A total of 104 subjects were enrolled, 103 of whom completed the study (mean age, 25.3 years; mean weight, 58.8 kg; mean BMI, 21.8 kg/m2). A total of 27 adverse events (AEs) occurred in 25 of 86 yogliptin subjects (29.1%), and 3 AEs occurred in 3 of 18 placebo subjects (16.7%). Yogliptin was absorbed with a median time of maximum observed concentration (Tmax) of 3.0 h and was eliminated slowly with a t1/2 of 25.45-43.84 h. The maximum observed concentration (Cmax) and area under the curve (AUC) varied slightly more than dose-proportionally over the dose range from 2.5 to 400 mg. The fraction of drug excreted in urine ranged from 8.39% to 24.77%. Mean DPP-4 inhibition at 24 h after dosing ranged from 97.7% to 99.5%, and DPP-4 inhibition was >80% for 72 h at doses from 25 to 400 mg. DPP-4 inhibition was >80% for 1 week in the group receiving 400 mg. CONCLUSION: Yogliptin was well tolerated in healthy subjects, with no dose-limiting toxicity observed in the range from 2.5 to 600 mg. Yogliptin inhibited plasma DPP-4 activity for 72 h at single doses of 25-200 mg and for 1 week at 400 mg, suggesting that once-weekly dosing of yogliptin is possible in type 2 diabetes patients. TRIAL REGISTRATION: ChiCTR-IIR-17010311 (Chictr.org).


Assuntos
Inibidores da Dipeptidil Peptidase IV/farmacocinética , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Adolescente , Adulto , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Glicemia/efeitos dos fármacos , Estudos de Coortes , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Dipeptidil Peptidase 4/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Masculino
9.
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
10.
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
11.
J Immunol Res ; 2019: 6491738, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31089478

RESUMO

Middle East respiratory syndrome coronavirus (MERS-CoV) first emerged in late 2012. Since its emergence, a total of 2279 patients from 27 countries have been infected across the globe according to a World Health Organization (WHO) report (Feb. 12th, 2019). Approximately 806 patients have died. The virus uses its spike proteins as adhesive factors that are proinflammatory for host entry through a specific receptor called dipeptidyl peptidase-4 (DPP4). This receptor is considered a key factor in the signaling and activation of the acquired and innate immune responses in infected patients. Using potent antigens in combination with strong adjuvants may effectively trigger the activation of specific MERS-CoV cellular responses as well as the production of neutralizing antibodies. Unfortunately, to date, there is no effective approved treatment or vaccine for MERS-CoV. Thus, there are urgent needs for the development of novel MERS-CoV therapies as well as vaccines to help minimize the spread of the virus from infected patients, thereby mitigating the risk of any potential pandemics. Our main goals are to highlight and describe the current knowledge of both the innate and adaptive immune responses to MERS-CoV and the current state of MERS-CoV vaccine development. We believe this study will increase our understanding of the mechanisms that enhance the MERS-CoV immune response and subsequently contribute to the control of MERS-CoV infections.


Assuntos
Imunidade Adaptativa , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Imunidade Inata , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Humanos , Camundongos , Receptores Virais/metabolismo
12.
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
13.
Science ; 364(6438)2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31023895

RESUMO

Metabolic health depends on the capacity of adipose tissue progenitor cells to undergo de novo adipogenesis. The cellular hierarchy and mechanisms governing adipocyte progenitor differentiation are incompletely understood. Through single-cell RNA sequence analyses, we show that the lineage hierarchy of adipocyte progenitors consists of distinct mesenchymal cell types that are present in both mouse and human adipose tissues. Cells marked by dipeptidyl peptidase-4 (DPP4)/CD26 expression are highly proliferative, multipotent progenitors. During the development of subcutaneous adipose tissue in mice, these progenitor cells give rise to intercellular adhesion molecule-1 (ICAM1)/CD54-expressing (CD54+) committed preadipocytes and a related adipogenic cell population marked by Clec11a and F3/CD142 expression. Transforming growth factor-ß maintains DPP4+ cell identity and inhibits adipogenic commitment of DPP4+ and CD142+ cells. Notably, DPP4+ progenitors reside in the reticular interstitium, a recently appreciated fluid-filled space within and between tissues, including adipose depots.


Assuntos
Adipócitos/citologia , Adipogenia , Tecido Adiposo/citologia , Células-Tronco Mesenquimais/citologia , Adipócitos/enzimologia , Animais , Dipeptidil Peptidase 4/metabolismo , Fatores de Crescimento de Células Hematopoéticas/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Lectinas Tipo C/metabolismo , Células-Tronco Mesenquimais/enzimologia , Camundongos , Análise de Sequência de RNA , Análise de Célula Única , Tromboplastina/metabolismo , Fator de Crescimento Transformador beta/metabolismo
14.
J Diabetes Res ; 2019: 5238013, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30886868

RESUMO

Background: The enzyme dipeptidyl peptidase 4 (DPP4) has been recently recognized as an adipo-myokine. However, studies that associate its constitutive activity with body composition, anthropometry, and insulin resistance (IR) are very scarce and included only healthy people. Methods: First, we investigated the relationships of constitutive DPP4 activity, body composition (assessed by bioelectrical impedance analysis), and measures of adiposity and IR in fifty-two subjects of both sexes, 18-50 years, and BMI ≥25.0 kg/m2 who comprised three groups according to glucose tolerance. Additionally, we evaluated associations among DPP4 activity and adipokines, gut peptides, and biochemical variables at fasting and 30 and 60 min after a standardized meal intake. Results: DPP4 activity was no different among the three groups. At fasting, pooled analysis showed it was positively correlated with measures of central adiposity, such as WC (P = 0.011) and WHR (P = 0.009), and with all measures of IR, but inversely related to indexes of general adiposity, such as fat mass percentage (P = 0.014) and BAI (P = 0.0003). DPP4 activity was also associated with lean mass (r = 0.57, P < 0.0001). After meal intake, DPP4 activity remained significantly associated with insulin, leptin, and resistin. In multiple regression analysis, BAI, WHR, percent lean mass, HOMA-IR, and leptin influenced DPP4 activity and explained approximately 26% of the variance on it. Conclusions: Constitutive DPP4 activity is positively associated with lean mass, central adiposity, and IR and negatively to general adiposity. Furthermore, it seems to be influenced by body composition and IR and could also be viewed as an adipo-myokine in subjects with excessive adiposity and different stages of glucose tolerance.


Assuntos
Composição Corporal/fisiologia , Dipeptidil Peptidase 4/metabolismo , Intolerância à Glucose/metabolismo , Resistência à Insulina/fisiologia , Adiposidade/fisiologia , Adolescente , Adulto , Índice de Massa Corporal , Impedância Elétrica , Jejum/sangue , Feminino , Humanos , Insulina/sangue , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
Viruses ; 11(3)2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30893947

RESUMO

Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic pathogen that causes respiratory infection in humans, ranging from asymptomatic to severe pneumonia. In dromedary camels, the virus only causes a mild infection but it spreads efficiently between animals. Differences in the behavior of the virus observed between individuals, as well as between humans and dromedary camels, highlight the role of host factors in MERS-CoV pathogenesis and transmission. One of these host factors, the MERS-CoV receptor dipeptidyl peptidase-4 (DPP4), may be a critical determinant because it is variably expressed in MERS-CoV-susceptible species as well as in humans. This could partially explain inter- and intraspecies differences in the tropism, pathogenesis, and transmissibility of MERS-CoV. In this review, we explore the role of DPP4 and other host factors in MERS-CoV transmission and pathogenesis-such as sialic acids, host proteases, and interferons. Further characterization of these host determinants may potentially offer novel insights to develop intervention strategies to tackle ongoing outbreaks.


Assuntos
Infecções por Coronavirus/transmissão , Interações Hospedeiro-Patógeno , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Infecções Respiratórias/transmissão , Tropismo Viral , Animais , Camelus/virologia , Quirópteros/virologia , Dipeptidil Peptidase 4/metabolismo , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Infecções Respiratórias/virologia , Replicação Viral
16.
Gynecol Endocrinol ; 35(8): 714-718, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30896318

RESUMO

Dipeptidyl peptidase-4 (DPP-4) plays a role in metabolic and inflammatory diseases. Increased adenosine deaminase (ADA) has been suggested to induce insulin resistance and inflammation. We measured serum DPP-4 and ADA activities. Serum ADA activity was significantly higher in PCOS group (p = .006), whereas there was no difference in serum DPP-4 activity between the groups (p > .05). When the study subjects were divided into four groups in terms of obesity; an increasing trend in serum ADA activity between the groups was observed and ADA activity was significantly higher in overweight and obese patients with PCOS than nonobese controls (p = .016), there were no significant differences between the other groups (p > .05). A positive correlation was found between ADA and BMI in the whole group (p = .022). Multivariate regression analyses revealed that significant determinants were diastolic blood pressure, ADA, and the presence of PCOS for DPP-4 (R2 = 0.344, F = 9.079, p < .001); the presence of PCOS and DPP-4 for ADA (R2 = 0.123, F = 6.302, p = .003). We demonstrated increased serum ADA activity as well as its association with obesity in PCOS, while there was no change in serum DPP-4 activity in women with PCOS.


Assuntos
Adenosina Desaminase/sangue , Dipeptidil Peptidase 4/sangue , Obesidade/sangue , Obesidade/complicações , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/complicações , Adenosina Desaminase/metabolismo , Adulto , Índice de Massa Corporal , Estudos de Casos e Controles , Dipeptidil Peptidase 4/metabolismo , Feminino , Humanos , Resistência à Insulina/fisiologia , Adulto Jovem
17.
J Agric Food Chem ; 67(13): 3615-3623, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30879293

RESUMO

Soy1 (IAVPTGVA) and Lup1 (LTFPGSAED), two peptides from soybean and lupin protein hydrolysis, have been singled out as dipeptidyl peptidase IV (DPP-IV) activity inhibitors in different model systems. However, their activity is affected by their instability toward intestinal proteases. Here, an innovative strategy based on nanogels was developed in order to increase both their stability and antidiabetic properties through encapsulation into the RADA16 peptide. The nanogel formation was stimulated by a solvent-triggered approach, allowing us to produce stable nanogels ( G' = 1826 Pa, stress-failure ≥50 Pa) with shear-thinning propensity. ThT binding assay, and ATR-FTIR spectroscopy experiments showed that nanogels self-aggregated into stable cross-ß structures providing higher resistance against proteases (ex vivo experiments) and increased bioavailability of Soy1 and Lup1 peptides (in situ experiments on Caco-2 cells). Hence, this simple and harmless nanotechnological approach could be a key-step in making innovative nanomaterials for nutraceuticals delivering.


Assuntos
Inibidores da Dipeptidil Peptidase IV/química , Lupinus/química , Peptídeos/química , Soja/química , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Humanos , Hidrólise , Cinética , Nanoestruturas/química , Espectrometria de Massas em Tandem
18.
Physiol Int ; 106(1): 29-38, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30888218

RESUMO

PURPOSE: We previously found that homocysteine (Hcy)-induced apoptosis in endothelial cells coincided with increased NADPH oxidase (NOX) activity. In addition, in ischemic endothelial cells present in the heart, we showed that loss of serine protease dipeptidyl peptidase IV (DPP4) expression was correlated with induction of tissue factor (TF) expression. Since Hcy can initiate thrombosis through the induction of TF expression, in this study, we evaluated whether the inverse relation of TF and DPP4 is also Hcy-dependent and whether NOX-mediated reactive oxygen species (ROS) is playing a role herein. METHODS: Human umbilical vein endothelial cells (HUVECs) were incubated with 2.5 mM Hcy for 3 and 6 h. The effects of Hcy on DPP4 and TF expression and NOX2/p47phox-mediated nitrotyrosine (ROS) production were studied using digital-imaging microscopy. RESULTS: In HUVECs, high levels of Hcy showed a significant increase of TF expression and a concomitant loss of DPP4 expression after 6 h. In addition, NOX subunits NOX2 and p47phox were also significantly increased after 6 h of Hcy incubation and coincided with nitrotyrosine (ROS) expression. Interestingly, inhibition of NOX-mediated nitrotyrosine (ROS) with the use of apocynin not only reduced these effects, but also counteracted the effects of Hcy on TF and DPP4 expression. CONCLUSION: These results indicate that the inverse relation of TF and DPP4 in endothelial cells is also Hcy-dependent and related to NOX activity.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Homocisteína/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , NADPH Oxidases/metabolismo , Tromboplastina/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
19.
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
20.
Acta Derm Venereol ; 99(6): 602-609, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30848289

RESUMO

Dipeptidyl peptidase-4 inhibitors (DPP-4i or gliptins) increase the risk of developing bullous pemphigoid (BP). To clarify, whether gliptin-associated BP has special features, we analyzed the clinical, histopathological and immunological features of 27 BP patients, 10 of which previously used gliptin medication. Compared to those who had not previously received gliptins, subjects who had, showed higher BP180-NC16A ELISA (enzyme-linked immunosorbent assay) values, fewer neurological co-morbidities and shorter time to remission, but differences were not statistically significant. The HLA-DQB1*03:01 allele was more commonly present among the BP patients than the control population, but was not more common in those with gliptin history. To determine the effect of gliptins on the expression of the DPP-4/CD-26 protein we performed immunohistochemistry, which showed that the skin expression of DPP-4/CD-26 was increased in BP patients, but not affected by prior gliptin treatment. We conclude that DPP-4i medication is common among BP patients and prior gliptin treatment may be associated with some specific features.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Penfigoide Bolhoso/induzido quimicamente , Penfigoide Bolhoso/metabolismo , Idoso , Idoso de 80 Anos ou mais , Autoantígenos/metabolismo , Epiderme/metabolismo , Feminino , Genótipo , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Humanos , Queratinócitos/metabolismo , Laminina/metabolismo , Masculino , Pessoa de Meia-Idade , Colágenos não Fibrilares/metabolismo , Penfigoide Bolhoso/imunologia , Penfigoide Bolhoso/patologia
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