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2.
Clin Immunol ; 230: 108824, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34391936

RESUMO

The current intersection of the COVID-19 and HIV-1 pandemics, has raised concerns about the risk for poor COVID-19 outcomes particularly in regions like sub-Saharan Africa, disproportionally affected by HIV. DPP4/CD26 has been suggested to be a potential therapeutic target and a biomarker for risk in COVID-19 patients with high risk co-morbidities. We therefore evaluated soluble DPP4 (sDPP4) levels and activity in plasma of 131 HIV-infected and 20 HIV-uninfected South African individuals. Flow cytometry was performed to compare cell surface expression of DPP4/CD26 and activation markers on peripheral blood mononuclear cells of extreme clinical phenotypes. Progressors had lower specific DPP4 activity and lower frequency of CD3+ T-cells expressing CD26 than HIV-1 controllers, but more activated CD3+CD26+ T-cells. The frequency of CD26-expressing T-cells negatively correlated with HLA-DR+ and CD38+ T-cells. Divergent DPP4/CD26 expression between HIV-1 controllers and progressors may have implications for risk and treatment of COVID-19 in people living with HIV.


Assuntos
COVID-19/complicações , Dipeptidil Peptidase 4/metabolismo , Infecções por HIV/complicações , HIV-1 , SARS-CoV-2 , Adulto , Contagem de Linfócito CD4 , Estudos de Casos e Controles , Comorbidade , Estudos Transversais , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Fatores de Risco , África do Sul , Carga Viral , Adulto Jovem
3.
Viruses ; 13(8)2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34452531

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a global pandemic causing over 195 million infections and more than 4 million fatalities as of July 2021.To date, it has been demonstrated that a number of mutations in the spike glycoprotein (S protein) of SARS-CoV-2 variants of concern abrogate or reduce the neutralization potency of several therapeutic antibodies and vaccine-elicited antibodies. Therefore, the development of additional vaccine platforms with improved supply and logistic profile remains a pressing need. In this work, we have validated the applicability of a peptide-based strategy focused on a preventive as well as a therapeutic purpose. On the basis of the involvement of the dipeptidyl peptidase 4 (DPP4), in addition to the angiotensin converting enzyme 2 (ACE2) receptor in the mechanism of virus entry, we analyzed peptides bearing DPP4 sequences by protein-protein docking and assessed their ability to block pseudovirus infection in vitro. In parallel, we have selected and synthetized peptide sequences located within the highly conserved receptor-binding domain (RBD) of the S protein, and we found that RBD-based vaccines could better promote elicitation of high titers of neutralizing antibodies specific against the regions of interest, as confirmed by immunoinformatic methodologies and in vivo studies. These findings unveil a key antigenic site targeted by broadly neutralizing antibodies and pave the way to the design of pan-coronavirus vaccines.


Assuntos
Dipeptidil Peptidase 4/química , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , COVID-19/tratamento farmacológico , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Chlorocebus aethiops , Dipeptidil Peptidase 4/metabolismo , Epitopos de Linfócito T/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Domínios Proteicos , Receptores de Coronavírus/química , Receptores de Coronavírus/metabolismo , SARS-CoV-2/química , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero , Internalização do Vírus
4.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360529

RESUMO

Nowadays, type II diabetes mellitus, more specifically ensuing diabetic nephropathy, and severe COVID-19 disease are known to be closely associated. The exact mechanisms behind this association are less known. An implication for the angiotensin-converting enzyme 2 remains controversial. Some researchers have started looking into other potential actors, such as neuropilin-1, mitochondrial glutathione, vitamin D, and DPP4. In particular, neuropilin-1 seems to play an important role in the underlying mechanism linking COVID-19 and diabetic nephropathy. We suggest, based on the findings in this review, that its up-regulation in the diabetic kidney facilitates viral entry in this tissue, and that the engagement of both processes leads to a depletion of neuropilin-1, which was demonstrated to be strongly associated with the pathogenesis of DN. More studies are needed to confirm this hypothesis, and research should be directed towards elucidating the potential roles of all these suggested actors and eventually discovering new therapeutic strategies that could reduce the burden of COVID-19 in patients with diabetic nephropathy.


Assuntos
COVID-19/complicações , COVID-19/imunologia , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Dipeptidil Peptidase 4/metabolismo , Glutationa/metabolismo , Humanos , Neuropilina-1/metabolismo , Vírus da SARS/imunologia , Vitamina D/metabolismo
5.
Front Immunol ; 12: 686480, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220840

RESUMO

Sjögren's Syndrome (SS) is an autoimmune exocrinopathy characterized by the progressive damage of salivary and lacrimal glands associated with lymphocytic infiltration. Identifying new non-invasive biomarkers for SS diagnosis remains a challenge, and alterations in saliva composition reported in patients turn this fluid into a source of potential biomarkers. Among these, proteases are promising candidates since they are involved in several key physio-pathological processes. This study evaluated differentially expressed proteases in SS individuals' saliva using synthetic fluorogenic substrates, zymography, ELISA, and proteomic approaches. Here we reported, for the first time, increased activity of the serine protease dipeptidyl peptidase-4/CD26 (DPP4/CD26) in pSS saliva, the expression level of which was corroborated by ELISA assay. Gelatin zymograms showed that metalloproteinase proteolytic band profiles differed significantly in intensity between control and SS groups. Focusing on matrix metalloproteinase-9 (MMP9) expression, an increased tendency in pSS saliva (p = 0.0527) was observed compared to the control group. Samples of control, pSS, and sSS were analyzed by mass spectrometry to reveal a general panorama of proteases in saliva. Forty-eight protein groups of proteases were identified, among which were the serine proteases cathepsin G (CTSG), neutrophil elastase (ELANE), myeloblastin (PRTN3), MMP9 and several protease inhibitors. This work paves the way for proteases to be explored in the future as biomarkers, emphasizing DPP4 by its association in several autoimmune and inflammatory diseases. Besides its proteolytic role, DPP4/CD26 acts as a cell surface receptor, signal transduction mediator, adhesion and costimulatory protein involved in T lymphocytes activation.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Peptídeo Hidrolases/análise , Proteômica/métodos , Saliva/metabolismo , Síndrome de Sjogren/metabolismo , Adulto , Biomarcadores/metabolismo , Estudos de Casos e Controles , Catepsina G , Feminino , Humanos , Elastase de Leucócito , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Serina Endopeptidases , Transdução de Sinais , Síndrome de Sjogren/diagnóstico
6.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209788

RESUMO

ACE2 has been established as the main receptor for SARS-CoV-2. Since other human coronaviruses are known to use co-receptors for viral cell entry, it has been suggested that DPP4 (CD26) could be a potential additional binding target or co-receptor, supported by early molecular docking simulation studies. However, recent biophysical studies have shown this interaction to be very weak. We have conducted detailed molecular docking simulations to predict the potential binding interactions between the receptor binding domain (RBD) of the spike protein of SARS-CoV-2 and DPP4 and compare them with the interactions observed in the experimentally determined structure of the complex of MERS-CoV with DPP4. Whilst the overall binding mode of the RBD of SARS-CoV-2 to DPP4 is predicted to be similar to that observed in the MERS-CoV-DPP4 complex, including a number of equivalent interactions, important differences in the amino acid sequences of SARS-CoV-2 and MERS-CoV result in substantially weakened interactions with DPP4. This is shown to arise from differences in the predicted proximity, nature and secondary structure at the binding interface on the RBD of SARS-CoV-2. These findings do not support DPP4 being a significant receptor for SARS-CoV-2.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Simulação de Acoplamento Molecular , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , Sítios de Ligação , COVID-19/patologia , COVID-19/virologia , Cristalografia por Raios X , Dipeptidil Peptidase 4/química , Humanos , Ligação Proteica , Domínios Proteicos , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/química , Termodinâmica
7.
Exp Anim ; 70(4): 541-552, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34219073

RESUMO

Exposure to chronic psychosocial stress is a risk factor for various pulmonary diseases. In view of the essential role of dipeptidyl peptidase 4 (DPP4) in animal and human lung pathobiology, we investigated the role of DPP4 in stress-related lung injury in mice. Eight-week-old male mice were randomly divided into a non-stress group and a 2-week immobilization stress group. Non-stress control mice were left undisturbed. The mice subjected to immobilized stress were randomly assigned to the vehicle or the DPP4 inhibitor anagliptin for 2 weeks. Chronic stress reduced subcutaneous and inguinal adipose volumes and increased blood DPP4 levels. The stressed mice showed increased levels in the lungs of genes and/or proteins related to oxidative stress (p67phox, p47phox, p22phox and gp91phox), inflammation (monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, and intracellular adhesion molecule-1), apoptosis (caspase-3, -8, -9), senescence (p16INK4A, p21, and p53) and proteolysis (matrix metalloproteinase-2 to -9, cathepsin S/K, and tissue inhibitor of matrix metalloproteinase-1 and -2), and reduced levels of eNOS, Sirt1, and Bcl-2 proteins; and these effects were reversed by genetic and pharmacological inhibitions of DPP4. We then exposed human umbilical vein endothelial cells in vitro to hydrogen peroxide; anagliptin treatment was also observed to mitigate oxidative and inflammatory molecules in this setting. Anagliptin can improve lung injury in stressed mice, possibly by mitigating vascular inflammation, oxidative stress production, and proteolysis. DPP4 may become a new therapeutic target for chronic psychological stress-related lung disease in humans and animals.


Assuntos
Dipeptidil Peptidase 4/genética , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inflamação/genética , Lesão Pulmonar/prevenção & controle , Estresse Oxidativo , Animais , Dipeptidil Peptidase 4/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Fisiológico , Estresse Psicológico
8.
J Med Chem ; 64(14): 9639-9648, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34190540

RESUMO

Approved and potent reported dipeptidyl peptidase-4 (DPP-4) inhibitors with gliptin-like structures are classified here according to their structures and mechanisms of the inhibition in three groups: (i) those with pyrrolidine or analogs as P1 fragment with α-aminoacyl linker, (ii) structures with trifluorophenyl moiety or analogs as P1 fragment with ß-aminobutanoyl linker, and (iii) DPP-4 inhibitors with pyrimidine-2,4-dione or analogs as P1' fragment. The structure-activity relationship analysis was performed for those whose cocrystallized structures with the enzyme were published. While inhibitors with pyrrolidine and trifluorophenyl moiety or analogs as P1 fragment bind in a similar way in S1, S2 and S2 extensive domains of the enzyme, the binding mode of pyrimidine-2,4-dione derivatives/analogs differs with additional interactions in S1' and S2' pockets. Three general schemes of fragmented gliptins and gliptin-like structures with the enzyme and protein-ligand interaction fingerprints were made, which might be useful in the creation of DPP-4 inhibitor's design strategies.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Pirrolidinas/farmacologia , Cristalografia por Raios X , Inibidores da Dipeptidil Peptidase IV/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Pirrolidinas/química , Relação Estrutura-Atividade
9.
IUBMB Life ; 73(8): 1005-1015, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34118117

RESUMO

The kidney is one of the main targets attacked by viruses in patients with a coronavirus infection. Until now, SARS-CoV-2 has been identified as the seventh member of the coronavirus family capable of infecting humans. In the past two decades, humankind has experienced outbreaks triggered by two other extremely infective members of the coronavirus family; the MERS-CoV and the SARS-CoV. According to several investigations, SARS-CoV causes proteinuria and renal impairment or failure. The SARS-CoV was identified in the distal convoluted tubules of the kidney of infected patients. Also, renal dysfunction was observed in numerous cases of MERS-CoV infection. And recently, during the 2019-nCoV pandemic, it was found that the novel coronavirus not only induces acute respiratory distress syndrome (ARDS) but also can induce damages in various organs including the liver, heart, and kidney. The kidney tissue and its cells are targeted massively by the coronaviruses due to the abundant presence of ACE2 and Dpp4 receptors on kidney cells. These receptors are characterized as the main route of coronavirus entry to the victim cells. Renal failure due to massive viral invasion can lead to undesirable complications and enhanced mortality rate, thus more attention should be paid to the pathology of coronaviruses in the kidney. Here, we have provided the most recent knowledge on the coronaviruses (SARS, MERS, and COVID19) pathology and the mechanisms of their impact on the kidney tissue and functions.


Assuntos
COVID-19/mortalidade , Infecções por Coronavirus/mortalidade , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Vírus da SARS/patogenicidade , SARS-CoV-2/patogenicidade , Síndrome Respiratória Aguda Grave/mortalidade , Tropismo Viral/genética , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/genética , COVID-19/patologia , COVID-19/virologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Regulação da Expressão Gênica , Humanos , Rim/metabolismo , Rim/patologia , Rim/virologia , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Ligação Proteica , Receptores Virais/genética , Receptores Virais/metabolismo , Vírus da SARS/genética , Vírus da SARS/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Síndrome Respiratória Aguda Grave/genética , Síndrome Respiratória Aguda Grave/patologia , Síndrome Respiratória Aguda Grave/virologia , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Análise de Sobrevida
10.
Proc Natl Acad Sci U S A ; 118(25)2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34099577

RESUMO

Coronaviruses are pathogens of pandemic potential. Middle East respiratory syndrome coronavirus (MERS-CoV) causes a zoonotic respiratory disease of global public health concern, and dromedary camels are the only proven source of zoonotic infection. More than 70% of MERS-CoV-infected dromedaries are found in East, North, and West Africa, but zoonotic MERS disease is only reported from the Arabian Peninsula. We compared viral replication competence of clade A and B viruses from the Arabian Peninsula with genetically diverse clade C viruses found in East (Egypt, Kenya, and Ethiopia), North (Morocco), and West (Nigeria and Burkina Faso) Africa. Viruses from Africa had lower replication competence in ex vivo cultures of the human lung and in lungs of experimentally infected human-DPP4 (hDPP4) knockin mice. We used lentivirus pseudotypes expressing MERS-CoV spike from Saudi Arabian clade A prototype strain (EMC) or African clade C1.1 viruses and demonstrated that clade C1.1 spike was associated with reduced virus entry into the respiratory epithelial cell line Calu-3. Isogenic EMC viruses with spike protein from EMC or clade C1.1 generated by reverse genetics showed that the clade C1.1 spike was associated with reduced virus replication competence in Calu-3 cells in vitro, in ex vivo human bronchus, and in lungs of hDPP4 knockin mice in vivo. These findings may explain why zoonotic MERS disease has not been reported from Africa so far, despite exposure to and infection with MERS-CoV.


Assuntos
Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Zoonoses/virologia , África , Animais , Arábia , Linhagem Celular , Dipeptidil Peptidase 4/metabolismo , Técnicas de Introdução de Genes , Humanos , Cinética , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Fenótipo , Filogenia , Glicoproteína da Espícula de Coronavírus/metabolismo , Replicação Viral/fisiologia
11.
Nat Commun ; 12(1): 3534, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112801

RESUMO

Metabolic diseases are associated with an increased risk of severe COVID-19 and conversely, new-onset hyperglycemia and complications of preexisting diabetes have been observed in COVID-19 patients. Here, we performed a comprehensive analysis of pancreatic autopsy tissue from COVID-19 patients using immunofluorescence, immunohistochemistry, RNA scope and electron microscopy and detected SARS-CoV-2 viral infiltration of beta-cells in all patients. Using SARS-CoV-2 pseudoviruses, we confirmed that isolated human islet cells are permissive to infection. In eleven COVID-19 patients, we examined the expression of ACE2, TMPRSS and other receptors and factors, such as DPP4, HMBG1 and NRP1, that might facilitate virus entry. Whereas 70% of the COVID-19 patients expressed ACE2 in the vasculature, only 30% displayed ACE2-expression in beta-cells. Even in the absence of manifest new-onset diabetes, necroptotic cell death, immune cell infiltration and SARS-CoV-2 viral infection of pancreatic beta-cells may contribute to varying degrees of metabolic dysregulation in patients with COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/patologia , Células Secretoras de Insulina/virologia , Receptores de Coronavírus/metabolismo , SARS-CoV-2/isolamento & purificação , Serina Endopeptidases/metabolismo , Adulto , Idoso , Autopsia , Complicações do Diabetes/patologia , Complicações do Diabetes/virologia , Diabetes Mellitus/patologia , Dipeptidil Peptidase 4/metabolismo , Feminino , Proteínas HMGN/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Neuropilina-1/metabolismo , Especificidade de Órgãos/fisiologia
12.
PLoS One ; 16(5): e0252153, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34043673

RESUMO

Adipose tissue inflammation is a major cause of the pathogenesis of obesity and comorbidities. To study the involvement of M1/M2 cytokine expression of adipose tissue in the regulatory mechanisms of dipeptidyl peptidase 4 (DPP4) and insulin resistance in diabetes, stromal vascular fractions (SVFs) were purified from inguinal adipose tissue of diabetic (Leprdb/db) and non-diabetic (Lepr+/+) mice followed by analysis of M1/M2 cytokine expression. SVFs of Leprdb/db mice exhibited increased TNF-α, IL-6, IL-1ß, CCL2, and DPP4 mRNA expression but decreased IL-10 mRNA expression. Plasma from Leprdb/db mice induced TNF-α, IL-6, IL-1ß, CCL2, and DPP4 mRNA expression and plasma from Lepr+/+ mice induced IL-10 mRNA expression in SVFs from Leprdb/db mice. Injection of Lepr+/+ plasma into the adipose tissue of Leprdb/db mice decreased mRNA expression of TNF-α, IL-6, IL-1ß, CCL2, and DPP4 and protein expression of pJNK and DPP4 in SVFs, reduced mRNA expression of ICAM, FMO3, IL-1ß, iNOS, TNF-α, IL-6, and DPP4 and protein expression of ICAM, FMO3, and DPP4 in liver, and suppressed mRNA expression of TNF-α, IL-6, IL-1ß, and DPP4 in Kupffer cells. Plasma from Leprdb/db mice did not induce M1 cytokine expression in SVFs from Leprdb/db-Jnk1-/- mice. Altogether, we demonstrate that diabetes induces M1 but decreases M2 cytokine expression in adipose tissue. Diabetic plasma-induced M1 expression is potentially through pJNK signaling pathways. Non-diabetic plasma reverses M1/M2 cytokine expression, plasma CCL2 levels, DPP4 activity, and Kupffer cell activation in diabetes. Our results suggest M1/M2 cytokine expression in adipose tissue is critical in diabetes-induced DPP4 activity, liver inflammation, and insulin resistance.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Dipeptidil Peptidase 4/metabolismo , Resistência à Insulina , Animais , Citocinas/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
13.
Nat Commun ; 12(1): 2680, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976191

RESUMO

Bioluminescent imaging (BLI) is one of the most powerful and widely used preclinical imaging modalities. However, the current technology relies on the use of transgenic luciferase-expressing cells and animals and therefore can only be applied to a limited number of existing animal models of human disease. Here, we report the development of a "portable bioluminescent" (PBL) technology that overcomes most of the major limitations of traditional BLI. We demonstrate that the PBL method is capable of noninvasive measuring the activity of both extracellular (e.g., dipeptidyl peptidase 4) and intracellular (e.g., cytochrome P450) enzymes in vivo in non-luciferase-expressing mice. Moreover, we successfully utilize PBL technology in dogs and human cadaver, paving the way for the translation of functional BLI to the noninvasive quantification of biological processes in large animals. The PBL methodology can be easily adapted for the noninvasive monitoring of a plethora of diseases across multiple species.


Assuntos
Fenômenos Biológicos , Diagnóstico por Imagem/métodos , Medições Luminescentes/métodos , Modelos Animais , Animais , Animais Geneticamente Modificados , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/metabolismo , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Cães , Luciferina de Vaga-Lumes/química , Luciferina de Vaga-Lumes/metabolismo , Humanos , Luciferases/química , Luciferases/genética , Luciferases/metabolismo , Medições Luminescentes/instrumentação , Estrutura Molecular , Reprodutibilidade dos Testes
14.
Int Heart J ; 62(3): 470-478, 2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-33994495

RESUMO

Exposure to psychosocial stress is a risk factor for cardiovascular disease, including vascular atherosclerosis-based cardiovascular disease (ACVD). Dipeptidyl peptidase-4 (DPP-4) is a complex enzyme that acts as a membrane-anchored cell surface exopeptidase. DPP-4 is upregulated in metabolic and inflammatory cardiovascular disorders. DPP-4 exhibits many physiological and pharmacological functions by regulating its extremely abundant substrates, such as glucagon-like peptide-1 (GLP-1). Over the last 10 years, emerging data have demonstrated unexpected roles of DPP-4 in extracellular and intracellular signaling, immune activation, inflammation, oxidative stress production, cell apoptosis, insulin resistance, and lipid metabolism. This mini-review focuses on recent novel findings in this field, highlighting a DPP-4-mediated regulation of GLP-1-dependent and -independent signaling pathways as a potential therapeutic molecular target in treatments of chronic psychological stress-related ACVD in humans and animals.


Assuntos
Aterosclerose/enzimologia , Dipeptidil Peptidase 4/metabolismo , Estresse Psicológico/enzimologia , Animais , Aterosclerose/etiologia , Biomarcadores/sangue , Ensaios Clínicos como Assunto , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Terapia de Alvo Molecular , Estresse Psicológico/sangue , Estresse Psicológico/complicações
15.
Molecules ; 26(7)2021 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-33916639

RESUMO

Valorization of vegetable oil waste residues is gaining importance due to their high protein and polyphenol contents. Protease inhibitors (PIs), proteins from these abundantly available waste residues, have recently gained importance in treating chronic diseases. This research aimed to use canola meal of genetically diverse Brassica napus genotypes, BLN-3347 and Rivette, to identify PIs with diverse functionalities in therapeutic and pharmacological applications. The canola meal PI purification steps involved: native PAGE and trypsin inhibition activity, followed by ammonium sulfate fractionation, anion exchange, gel filtration, and reverse-phase chromatography. The purified PI preparations were characterized using SDS-PAGE, isoelectric focusing (IEF), and N terminal sequencing. SDS-PAGE analysis of PI preparations under native reducing and nonreducing conditions revealed three polymorphic PIs in each genotype. The corresponding IEF of the genotype BLN-3347, exhibited three acidic isoforms with isoelectric points (pI) of 4.6, 4.0, and 3.9, while Rivette possessed three isoforms, exhibiting two basic forms of pI 8.65 and 9.9, and one acidic of pI 6.55. Purified PI preparations from both the genotypes displayed dipeptidyl peptidase-IV (DPP-IV) and angiotensin-converting enzyme (ACE) inhibition activities; the BLN-3347 PI preparation exhibited a strong inhibitory effect with lower IC50 values (DPP-IV 37.42 µg/mL; ACE 129 µg/mL) than that from Rivette (DPP-IV 67.97 µg/mL; ACE 376.2 µg/mL). In addition to potential human therapy, these highly polymorphic PIs, which can inhibit damaging serine proteases secreted by canola plant pathogens, have the potential to be used by canola plant breeders to seek qualitative trait locus (QTLs) linked to genes conferring resistance to canola diseases.


Assuntos
Anti-Hipertensivos/farmacologia , Brassica napus/química , Dipeptidil Peptidase 4/química , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Peptidil Dipeptidase A/química , Sequência de Aminoácidos , Anti-Hipertensivos/química , Anti-Hipertensivos/isolamento & purificação , Brassica napus/genética , Brassica napus/metabolismo , Dipeptidil Peptidase 4/metabolismo , Ensaios Enzimáticos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Genótipo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Focalização Isoelétrica , Cinética , Extração Líquido-Líquido/métodos , Peptidil Dipeptidase A/metabolismo , Extratos Vegetais/química
16.
Life Sci ; 278: 119496, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33894269

RESUMO

AIMS: Chronic lung allograft dysfunction (CLAD) after lung transplantation (Tx) is the clinical result of chronic airway rejection lesions (CARL), histomorphologically described as either obliterative remodeling of small airways or alveolar fibroelastosis, or as a combination of both. We here investigated the CD26-inhibitory effect on CD26-expressing CARL. MAIN METHODS: CARL were induced by BALB/c â†’ C57BL/6 mouse Tx under mild immunosuppression. CARL-related pro-fibrotic mediators were determined by RT-qPCR and western blotting (WB), EMT and ERK markers by WB. CD26 co-expression by immunofluorescence. CD26 was inhibited by Vildagliptin, gene depleted by CD26-/- mice. Primary lung fibroblasts were employed for ex vivo analyses. Samples from lung transplant patients with CLAD were analyzed by immunohistochemistry. KEY FINDINGS: CARL revealed a significantly higher expression of profibrotic proteins vs. normal lungs (p < 0.05). CD26 and EMT co-expressed in CARL with significantly higher Vimentin, Slug, Hif-1α, α-SMA expression vs. normal lungs (p < 0.05). Vildagliptin decreased the expression of α-SMA and N-cadherin in wild type (WT) lung fibroblasts (p < 0.05). Primary lung fibroblasts from WT and CD26-/- mice treated with TGF-ß1, IFN-γ, and FGF showed a reduction of EMT protein expression, proliferation, and reduced activation of ERK in CD26-/- mice vs. WT mice. CD26-positive cells were found in patient samples with CLAD in areas of loose fibrosis, but not in areas of dense fibrosis. SIGNIFICANCE: CD26 is expressed in CARL-developing lung transplants and CD26-inhibition downregulates fibrosis-forming mediators and fibroblast proliferation. CD26 thus qualifies as a target to attenuate the development of CARL mainly via modulation of ERK and the EMT pathway.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Pneumopatias/fisiopatologia , Actinas/metabolismo , Animais , Caderinas/metabolismo , Doença Crônica , Fibroblastos/metabolismo , Fibrose/patologia , Rejeição de Enxerto , Imunossupressão , Pulmão/metabolismo , Transplante de Pulmão , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fenótipo , Disfunção Primária do Enxerto , Vildagliptina/farmacologia
17.
Front Immunol ; 12: 597399, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33796097

RESUMO

There exists increasing evidence that people with preceding medical conditions, such as diabetes and cancer, have a higher risk of infection with SARS-CoV-2 and are more vulnerable to severe disease. To get insights into the possible role of the immune system upon COVID-19 infection, 2811 genes of the gene ontology term "immune system process GO: 0002376" were selected for coexpression analysis of the human targets of SARS-CoV-2 (HT-SARS-CoV-2) ACE2, TMPRSS2, and FURIN in tissue samples from patients with cancer and diabetes mellitus. The network between HT-SARS-CoV-2 and immune system process genes was analyzed based on functional protein associations using STRING. In addition, STITCH was employed to determine druggable targets. DPP4 was the only immune system process gene, which was coexpressed with the three HT-SARS-CoV-2 genes, while eight other immune genes were at least coexpressed with two HT-SARS-CoV-2 genes. STRING analysis between immune and HT-SARS-CoV-2 genes plotted 19 associations of which there were eight common networking genes in mixed healthy (323) and pan-cancer (11003) tissues in addition to normal (87), cancer (90), and diabetic (128) pancreatic tissues. Using this approach, three commonly applicable druggable connections between HT-SARS-CoV-2 and immune system process genes were identified. These include positive associations of ACE2-DPP4 and TMPRSS2-SRC as well as a negative association of FURIN with ADAM17. Furthermore, 16 drugs were extracted from STITCH (score <0.8) with 32 target genes. Thus, an immunological network associated with HT-SARS-CoV-2 using bioinformatics tools was identified leading to novel therapeutic opportunities for COVID-19.


Assuntos
Diabetes Mellitus/metabolismo , Neoplasias/metabolismo , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/química , Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/genética , COVID-19/imunologia , COVID-19/metabolismo , Bases de Dados Genéticas , Diabetes Mellitus/genética , Diabetes Mellitus/imunologia , Diabetes Mellitus/virologia , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Furina/genética , Furina/metabolismo , Regulação da Expressão Gênica/imunologia , Ontologia Genética , Estudo de Associação Genômica Ampla , Genômica , Humanos , Linfócitos/imunologia , Linfócitos/metabolismo , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/virologia , Pâncreas/imunologia , Pâncreas/metabolismo , Pâncreas/virologia , Mapas de Interação de Proteínas/genética , Mapas de Interação de Proteínas/imunologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo
18.
Oncol Rep ; 45(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33649840

RESUMO

Radioactive iodine (RAI, 131I) therapy is the main treatment for thyroid carcinoma (TC). Long noncoding RNA (lncRNA)/microRNA (miR) competing endogenous RNA (ceRNA) networks have aroused great interest for their roles in gene expression. The present study aimed to investigate the effect of lncRNA SNHG7 on the growth and 131I resistance of TC. Differentially expressed lncRNAs in TC and paracancerous tissues were analyzed. The binding of miR­9­5p with small nucleolar RNA host gene 7 (SNHG7) and dipeptidyl­peptidase 4 (DPP4) was identified. Gain­ and loss­of­function analyses of SNHG7 and miR­9­5p were performed to determine their effects on the growth and 131I resistance of TC cells. The activity of the PI3K/Akt pathway was evaluated. Consequently, upregulated SNHG7 was revealed in TC tissues and correlated with 131I resistance. Silencing of SNHG7 or overexpressing miR­9­5p inhibited the growth and 131I resistance of TC cells. SNHG7 acted as a ceRNA of miR­9­5p to enhance DPP4 expression. Overexpressed SNHG7 increased DPP4 expression and activated the PI3K/Akt signaling pathway by sponging miR­9­5p. The in vitro results were reproduced in vivo. In summary, the present study provided evidence that the SNHG7/miR­9­5p/DPP4 ceRNA network could promote the growth and 131I resistance of TC cells via PI3K/Akt activation. The present study may offer novel options for TC treatment.


Assuntos
Dipeptidil Peptidase 4/genética , Radioisótopos do Iodo/farmacologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/radioterapia , Animais , Processos de Crescimento Celular/efeitos da radiação , Dipeptidil Peptidase 4/metabolismo , Ativação Enzimática , Feminino , Redes Reguladoras de Genes , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/metabolismo , Tolerância a Radiação , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia
19.
Molecules ; 26(4)2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33672038

RESUMO

Our previous study found that desmethylxanthohumol (1) inhibited α-glucosidase in vitro. Recently, further investigations revealed that dehydrocyclodesmethylxanthohumol (2) and its dimer analogue rottlerone (3) exhibited more potent α-glucosidase inhibitory activity than 1. The aim of this study was to synthesize a series of rottlerone analogues and evaluate their α-glucosidase and DPP-4 dual inhibitory activity. The results showed that compounds 4d and 5d irreversibly and potently inhibited α-glucosidase (IC50 = 0.22 and 0.12 µM) and moderately inhibited DPP-4 (IC50 = 23.59 and 26.19 µM), respectively. In addition, compounds 4d and 5d significantly promoted glucose consumption, with the activity of 5d at 0.2 µM being comparable to that of metformin at a concentration of 1 mM.


Assuntos
Inibidores da Dipeptidil Peptidase IV/farmacologia , Flavonoides/síntese química , Flavonoides/farmacologia , Glucose/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Propiofenonas/síntese química , Propiofenonas/farmacologia , Dipeptidil Peptidase 4/metabolismo , Flavonoides/química , Células Hep G2 , Humanos , Cinética , Propiofenonas/química , alfa-Glucosidases/metabolismo
20.
Clin Transl Gastroenterol ; 12(3): e00320, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33704099

RESUMO

INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) is a membrane-bound glycoprotein that acts as a receptor but also exists in a soluble form. It has been recognized as a mediator of inflammation and considered a biomarker in inflammatory bowel disease (IBD). METHODS: We evaluated a prospectively recruited cohort, consisting of 101 patients with IBD, using validated clinical indexes; 22 patients with ulcerative colitis (UC) underwent endoscopic evaluation. Fecal DPP-4 (fDPP-4) levels were analyzed and correlated with clinical scores, Mayo endoscopic score (in UC patients), serum DPP-4, C-reactive protein, and fecal calprotectin. Immunohistochemical staining for DPP-4 in intestinal biopsies was also performed. RESULTS: When compared with remitters, median fDPP-4 levels were higher in patients with ileal Crohn's disease (CD) (7,584 [1,464-7,816] vs 2,104 [630-2,676] ng/mL, P = 0.015) and lower in patients with UC exhibiting clinical activity (1,213 [559-1,682] vs 7,814 [2,555-7,985] ng/mL, P < 0.001). Patients with UC presenting endoscopic activity also had lower levels than remitters (939 [559-1,420] vs 7,544 [4,531-7,940] ng/mL, P = 0.006). Fecal DPP-4 discriminated clinical activity from remission with areas under the curve of 0.76 (95% confidence interval [CI] 0.58-0.94, P = 0.015) and 0.80 (95% CI 0.68-0.93, P < 0.001) in CD and UC, respectively; it allowed to differentiate endoscopic activity in patients with UC, with areas under the curve of 0.84 (95% CI 0.63-1.00, P = 0.009). Immunohistochemical analysis revealed higher DPP-4 apical expression in UC remitters, but no statistically significant differences were revealed between patients with ileal CD. DISCUSSION: Our results suggest that fDPP-4 can be used as a biomarker of IBD activity, particularly in UC. The expression profiles in intestinal tissue might represent a functional compartmentalization of DPP-4 expression.


Assuntos
Colite Ulcerativa/diagnóstico , Doença de Crohn/diagnóstico , Dipeptidil Peptidase 4/análise , Adulto , Biomarcadores/análise , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Colite Ulcerativa/imunologia , Colo/diagnóstico por imagem , Colo/imunologia , Doença de Crohn/imunologia , Dipeptidil Peptidase 4/metabolismo , Endoscopia Gastrointestinal , Fezes/química , Feminino , Humanos , Íleo/diagnóstico por imagem , Íleo/imunologia , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/imunologia , Complexo Antígeno L1 Leucocitário/análise , Complexo Antígeno L1 Leucocitário/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transdução de Sinais/imunologia , Adulto Jovem
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