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1.
Food Chem ; 369: 130888, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34474286

RESUMO

Food proteins and their constituent peptides impart huge health benefits besides their nutritional attributes. Sorghum bicolor protein hydrolysates (SPH) and derived bioactive peptides generated by simulated gastrointestinal digestion were studied for DPP-4 inhibitory properties using in vitro and in situ assays. Identified peptides, LSICGEESFGTGSDHIR (PEP1), SLGESLLQEDVEAHK (PEP2) and QLRDIVDK (PEP4) displayed potent DPP-4 inhibition with IC50 values of 73.5, 82.5 and 8.55 µM respectively. DPP-4 inhibition mechanism by the peptides was investigated by DPP4-peptide inhibition kinetics, molecular docking and microscale thermophoresis binding studies. The peptides bound to DPP-4 with micromolar affinities and PEP4 showed significantly increased affinity. The mixed type enzyme inhibition by peptides suggested that the peptides either block the active site of DPP-4 or changes the enzyme conformation via a secondary binding site. Overall, the results demonstrate that sorghum seeds are an adequate source of peptides with DPP-4 inhibitory properties that could be used in functional food formulations.


Assuntos
Inibidores da Dipeptidil Peptidase IV , Sorghum , Dipeptidil Peptidase 4 , Simulação de Acoplamento Molecular , Peptídeos
2.
Mater Sci Eng C Mater Biol Appl ; 130: 112472, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34702509

RESUMO

Cancer-derived exosomes or their specific components hold great promise for early diagnosis and precise staging of cancers. This work aimed to construct a novel enzyme-activatable fluorescent substrate for real-time detection and in situ imaging of a key exosomal surface protein CD26 in various biological systems, as well as to reveal the relevance of exosomal CD26 to the tumorigenesis. For these purposes, a group of Gly-Pro amides deriving from several near-infrared fluorophores were designed on the basis of the unique prolyl-cleaving dipeptidease activity of CD26, while molecular docking simulations were applied to assess the possibility of the designed amides as CD26 specific substrates. Following virtual screening and experimental validation, it was observed that GP-ACM displayed the best combination of high sensitivity and excellent specificity to CD26. The sensing and imaging ability of GP-ACM towards CD26 were examined in a range of biological systems, such as living cells, in situ tissues, and the exosomes secreted from cancer cells. Under physiological conditions, GP-ACM can be readily hydrolyzed by CD26 to release the fluorescent product ACM. The fluorescent product emits strong near-infrared fluorescence signals around 660 nm, which can be easily captured by the devices equipped with a fluorescence detector. GP-ACM prolyl-cleaving reaction shows excellent specificity and rapid response towards CD26, while its fluorescent product ACM displays good chemical stability and outstanding photostability. With the help of GP-ACM, CD26 in living cells, tissues and the tumor-secreted exosomes can be real-time monitored and in-situ imaged, while further investigations reveal that the exosomal CD26 activities are abnormally elevated with the progression of colon tumor. Collectively, the present study offers a practical optical assay for real-time monitoring CD26 activities in multiple complex biological systems including the exosomes secreted by tumor cells. The simplicity and effectiveness of this assay hold great potential for facilitating fundamental researches and clinical diagnosis of exosomal CD26 associated diseases.


Assuntos
Neoplasias Colorretais , Exossomos , Neoplasias Colorretais/diagnóstico por imagem , Dipeptidil Peptidase 4 , Corantes Fluorescentes , Humanos , Simulação de Acoplamento Molecular
3.
J Gen Virol ; 102(10)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34704923

RESUMO

The highly pathogenic Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a severe respiratory virus. Recent reports indicate additional central nervous system (CNS) involvement. In this study, human DPP4 transgenic mice were infected with MERS-CoV, and viral antigens were first detected in the midbrain-hindbrain 4 days post-infection, suggesting the virus may enter the brainstem via peripheral nerves. Neurons and astrocytes throughout the brain were infected, followed by damage of the blood brain barrier (BBB), as well as microglial activation and inflammatory cell infiltration, which may be caused by complement activation based on the observation of deposition of complement activation product C3 and high expression of C3a receptor (C3aR) and C5a receptor (C5aR1) in neurons and glial cells. It may be concluded that these effects were mediated by complement activation in the brain, because of their reduction resulted from the treatment with mouse C5aR1-specific mAb. Such mAb significantly reduced nucleoprotein expression, suppressed microglial activation and decreased activation of caspase-3 in neurons and p38 phosphorylation in the brain. Collectively, these results suggest that MERS-CoV infection of CNS triggers complement activation, leading to inflammation-mediated damage of brain tissue, and regulating of complement activation could be a promising intervention and adjunctive treatment for CNS injury by MERS-CoV and other coronaviruses.


Assuntos
Encéfalo/patologia , Proteínas do Sistema Complemento/imunologia , Infecções por Coronavirus/patologia , Dipeptidil Peptidase 4/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Animais , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/patologia , Encéfalo/irrigação sanguínea , Encéfalo/imunologia , Encéfalo/virologia , Ativação do Complemento/efeitos dos fármacos , Inativadores do Complemento/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Humanos , Inflamação , Camundongos , Camundongos Transgênicos , Microglia/imunologia , Microglia/patologia
4.
Nat Commun ; 12(1): 6242, 2021 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-34716325

RESUMO

Despite recent advances in understanding skin scarring, mechanisms triggering hypertrophic scar formation are still poorly understood. In the present study, we investigate mature human hypertrophic scars and developing scars in mice at single cell resolution. Compared to normal skin, we find significant differences in gene expression in most cell types present in scar tissue. Fibroblasts show the most prominent alterations in gene expression, displaying a distinct fibrotic signature. By comparing genes upregulated in murine fibroblasts during scar development with genes highly expressed in mature human hypertrophic scars, we identify a group of serine proteases, tentatively involved in scar formation. Two of them, dipeptidyl-peptidase 4 (DPP4) and urokinase (PLAU), are further analyzed in functional assays, revealing a role in TGFß1-mediated myofibroblast differentiation and over-production of components of the extracellular matrix in vitro. Topical treatment with inhibitors of DPP4 and PLAU during scar formation in vivo shows anti-fibrotic activity and improvement of scar quality, most prominently after application of the PLAU inhibitor BC-11. In this study, we delineate the genetic landscape of hypertrophic scars and present insights into mechanisms involved in hypertrophic scar formation. Our data suggest the use of serine protease inhibitors for the treatment of skin fibrosis.


Assuntos
Cicatriz/patologia , Dipeptidil Peptidase 4/genética , Proteínas de Membrana/genética , Animais , Diferenciação Celular/efeitos dos fármacos , Cicatriz/metabolismo , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Feminino , Expressão Gênica , Humanos , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos BALB C , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/fisiologia , Análise de Célula Única , Fosfato de Sitagliptina/farmacologia , Fator de Crescimento Transformador beta1/farmacologia
6.
Nat Commun ; 12(1): 5498, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535662

RESUMO

Rapid identification of host genes essential for virus replication may expedite the generation of therapeutic interventions. Genetic screens are often performed in transformed cell lines that poorly represent viral target cells in vivo, leading to discoveries that may not be translated to the clinic. Intestinal organoids are increasingly used to model human disease and are amenable to genetic engineering. To discern which host factors are reliable anti-coronavirus therapeutic targets, we generate mutant clonal IOs for 19 host genes previously implicated in coronavirus biology. We verify ACE2 and DPP4 as entry receptors for SARS-CoV/SARS-CoV-2 and MERS-CoV respectively. SARS-CoV-2 replication in IOs does not require the endosomal Cathepsin B/L proteases, but specifically depends on the cell surface protease TMPRSS2. Other TMPRSS family members were not essential. The newly emerging coronavirus variant B.1.1.7, as well as SARS-CoV and MERS-CoV similarly depended on TMPRSS2. These findings underscore the relevance of non-transformed human models for coronavirus research, identify TMPRSS2 as an attractive pan-coronavirus therapeutic target, and demonstrate that an organoid knockout biobank is a valuable tool to investigate the biology of current and future emerging coronaviruses.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , Bancos de Espécimes Biológicos , Sistemas CRISPR-Cas , Coronavirus , Dipeptidil Peptidase 4/genética , Organoides/metabolismo , Serina Endopeptidases/genética , COVID-19 , Linhagem Celular , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio , SARS-CoV-2 , Transcriptoma , Replicação Viral
7.
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
8.
BMC Health Serv Res ; 21(1): 807, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34384428

RESUMO

BACKGROUND: Medicine purchasing in Chinese public hospitals is decided by the hospital Pharmacy Management Committee (PMC), that is complex, subjective and requires efficient approaches to ensure transparency and consistency for the factors being considered. This study aimed to use the Evidence and Value: Impact on Decision Making (EVIDEM) framework to assess medicine in these hospitals. In this study anti-diabetic drugs DPP-4 inhibitors, which work by inhibiting the activation of the Dipeptidyl Peptidase 4 (DPP-4) inhibitors, were appraised. METHODS: Following EVIDEM methodology (EVIDEM-10th), we convened an appraisal group and asked each individual to express their perspectives by assigning weights to each criterion. A systematic literature search for information of each criterion of five DPP-4 inhibitors was completed. Then the appraisal group scored for each criterion of the five DPP-4 inhibitors. The estimated value of the five DPP-4 inhibitors was obtained by Multi-Criteria Decision Analysis (MCDA) which combined individual weighting of each criterion with individual scoring for each intervention in each criterion. RESULTS: By assigning weights, the most important criterion was the quality of evidence (4.01±0.52), and that the comparative cost consequences-non-medical cost was the least important criterion (2.87±1.03). Criteria included disease severity, size of the affected population, comparative effectiveness, type of therapeutic/preventive benefit and cost of intervention, all of which were assigned the same weight of 3.58. After MCDA, the overall value orders for each DPP-4 inhibitor included Sitagliptin (0.45), Linagliptin (0.44), Vildagliptin (0.43), Alogliptin (0.42) and Saxagliptin (0.40). CONCLUSIONS: Based on EVIDEM framework and MCDA, we found that overall value of five DPP-4 inhibitors was similar. It is feasible to use the EVIDEM framework and MCDA in purchasing medicine for Chinese public hospitals.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , China , Tomada de Decisões , Técnicas de Apoio para a Decisão , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4 , Hospitais Públicos , Humanos
9.
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
10.
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
12.
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
13.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200325

RESUMO

The SARS-CoV-2 infection determines the COVID-19 syndrome characterized, in the worst cases, by severe respiratory distress, pulmonary and cardiac fibrosis, inflammatory cytokine release, and immunosuppression. This condition has led to the death of about 2.15% of the total infected world population so far. Among survivors, the presence of the so-called persistent post-COVID-19 syndrome (PPCS) is a common finding. In COVID-19 survivors, PPCS presents one or more symptoms: fatigue, dyspnea, memory loss, sleep disorders, and difficulty concentrating. In this study, a cohort of 117 COVID-19 survivors (post-COVID-19) and 144 non-infected volunteers (COVID-19-free) was analyzed using pyrosequencing of defined CpG islands previously identified as suitable for biological age determination. The results show a consistent biological age increase in the post-COVID-19 population, determining a DeltaAge acceleration of 10.45 ± 7.29 years (+5.25 years above the range of normality) compared with 3.68 ± 8.17 years for the COVID-19-free population (p < 0.0001). A significant telomere shortening parallels this finding in the post-COVID-19 cohort compared with COVID-19-free subjects (p < 0.0001). Additionally, ACE2 expression was decreased in post-COVID-19 patients, compared with the COVID-19-free population, while DPP-4 did not change. In light of these observations, we hypothesize that some epigenetic alterations are associated with the post-COVID-19 condition, particularly in younger patients (< 60 years).


Assuntos
Envelhecimento/genética , COVID-19/genética , COVID-19/fisiopatologia , Ilhas de CpG , Encurtamento do Telômero , Telômero/metabolismo , Adulto , Idoso , Enzima de Conversão de Angiotensina 2/sangue , Biomarcadores , COVID-19/complicações , COVID-19/etiologia , Metilação de DNA , Dipeptidil Peptidase 4/sangue , Epigenômica , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Interações entre Hospedeiro e Microrganismos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sobreviventes
14.
Nat Commun ; 12(1): 4384, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34282151

RESUMO

Skin and lung fibrosis in systemic sclerosis (SSc) is driven by myofibroblasts, alpha-smooth muscle actin expressing cells. The number of myofibroblasts in SSc skin correlates with the modified Rodnan skin score, the most widely used clinical measure of skin disease severity. Murine fibrosis models indicate that myofibroblasts can arise from a variety of different cell types, but their origin in SSc skin has remained uncertain. Utilizing single cell RNA-sequencing, we define different dermal fibroblast populations and transcriptome changes, comparing SSc to healthy dermal fibroblasts. Here, we show that SSc dermal myofibroblasts arise in two steps from an SFRP2hi/DPP4-expressing progenitor fibroblast population. In the first step, SSc fibroblasts show globally upregulated expression of transcriptome markers, such as PRSS23 and THBS1. A subset of these cells shows markers indicating that they are proliferating. Only a fraction of SFRP2hi SSc fibroblasts differentiate into myofibroblasts, as shown by expression of additional markers, SFRP4 and FNDC1. Bioinformatics analysis of the SSc fibroblast transcriptomes implicated upstream transcription factors, including FOSL2, RUNX1, STAT1, FOXP1, IRF7 and CREB3L1, as well as SMAD3, driving SSc myofibroblast differentiation.


Assuntos
Fibroblastos/metabolismo , Proteínas de Membrana/metabolismo , Miofibroblastos/metabolismo , Escleroderma Sistêmico/metabolismo , Pele/patologia , Transcriptoma , Animais , Diferenciação Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Dipeptidil Peptidase 4 , Fibrose , Fatores de Transcrição Forkhead , Fator Regulador 7 de Interferon , Proteínas de Membrana/genética , Camundongos , Proteínas do Tecido Nervoso , Proteínas Proto-Oncogênicas , Fibrose Pulmonar/patologia , Proteínas Repressoras , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Serina Endopeptidases/metabolismo , Dermatopatias/patologia , Proteína Smad3
15.
Diabetes Obes Metab ; 23(10): 2402-2408, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34227216

RESUMO

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) may have favourable neurohumoral and metabolic effects in patients with chronic liver disease. However, studies examining SGLT2i in this population have been limited to patients with non-alcoholic fatty liver disease and have focused on surrogate biomarkers. Our aim was to evaluate whether SGLT2i can reduce the incidence of ascites and death over a period of 36 months in patients with cirrhosis and diabetes mellitus. Using electronic health data from Veterans Affairs hospitals in the United States, we conducted a propensity score matched intention-to-treat analysis among veterans on metformin who subsequently received either SGLT2i or dipeptidyl peptidase-4 inhibitors. Among 423 matched pairs (in total, 846 patients), we found no significant difference in the risk for ascites (hazard ratio 0.68 for SGLT2i, 95% confidence interval 0.37-1.25; p = .22) but did find that SGLT2i users had a reduced risk for death (adjusted hazard ratio 0.33, 95% confidence interval 0.11-0.99; p < .05). In comparison with dipeptidyl peptidase-4 inhibitors, SGLT2i may improve survival for patients with cirrhosis who require additional pharmacotherapy for diabetes mellitus beyond metformin, but confirmatory studies are necessary.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Metformina , Inibidores do Transportador 2 de Sódio-Glicose , Veteranos , Ascite/tratamento farmacológico , Ascite/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Dipeptidil Peptidase 4 , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/epidemiologia , Metformina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Estados Unidos/epidemiologia
16.
Endocrinol Metab (Seoul) ; 36(4): 904-908, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34311543

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic remains an unbeaten enemy. Unfortunately, no targeted treatment option is available. Patients with type 2 diabetes mellitus (T2DM) have increased odds for severe or fatal disease, as demonstrated in recent observational studies. There is an ongoing discussion regarding the impact of different antidiabetic drug classes on outcomes of interest among affected subjects. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been placed at the epicenter, since the DPP-4 enzyme seems to be implicated in the disease pathogenesis. Herein we present an updated meta-analysis of observational studies addressing the risk of COVID-19 death among patients with T2DM on prior DPP-4 inhibitor treatment. We pooled data from 10 observational studies, showing that DPP-4 inhibitors produce a non-significant decrease in the risk for COVID-19-related death. However, when administered in the inpatient setting, DPP-4 inhibitors decrease the risk for COVID-19-related death by 50%. Ongoing randomized controlled trials will shed further light.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/mortalidade , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/mortalidade , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Estudos Observacionais como Assunto/métodos , COVID-19/sangue , Diabetes Mellitus Tipo 2/sangue , Dipeptidil Peptidase 4/sangue , Inibidores da Dipeptidil Peptidase IV/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Mortalidade/tendências
17.
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
18.
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
20.
J Biol Chem ; 297(2): 100963, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34265307

RESUMO

The amyloid cascade hypothesis, which proposes a prominent role for full-length amyloid ß peptides in Alzheimer's disease, is currently being questioned. In addition to full-length amyloid ß peptide, several N-terminally truncated fragments of amyloid ß peptide could well contribute to Alzheimer's disease setting and/or progression. Among them, pyroGlu3-amyloid ß peptide appears to be one of the main components of early anatomical lesions in Alzheimer's disease-affected brains. Little is known about the proteolytic activities that could account for the N-terminal truncations of full-length amyloid ß, but they appear as the rate-limiting enzymes yielding the Glu3-amyloid ß peptide sequence that undergoes subsequent cyclization by glutaminyl cyclase, thereby yielding pyroGlu3-amyloid ß. Here, we investigated the contribution of dipeptidyl peptidase 4 in Glu3-amyloid ß peptide formation and the functional influence of its genetic depletion or pharmacological blockade on spine maturation as well as on pyroGlu3-amyloid ß peptide and amyloid ß 42-positive plaques and amyloid ß 42 load in the triple transgenic Alzheimer's disease mouse model. Furthermore, we examined whether reduction of dipeptidyl peptidase 4 could rescue learning and memory deficits displayed by these mice. Our data establish that dipeptidyl peptidase 4 reduction alleviates anatomical, biochemical, and behavioral Alzheimer's disease-related defects. Furthermore, we demonstrate that dipeptidyl peptidase 4 activity is increased early in sporadic Alzheimer's disease brains. Thus, our data demonstrate that dipeptidyl peptidase 4 participates in pyroGlu3-amyloid ß peptide formation and that targeting this peptidase could be considered as an alternative strategy to interfere with Alzheimer's disease progression.


Assuntos
Doença de Alzheimer , Animais , Encéfalo/metabolismo , Dipeptidil Peptidase 4 , Modelos Animais de Doenças , Humanos , Camundongos , Placa Amiloide
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