RESUMO
SDF-1/CXCL12 is a unique chemotactic factor with multiple functions on various types of precursor cells, all carrying the cognate receptor CXCR4. Whereas individual biological functions of SDF-1/CXCL12 have been well documented, practical applications in medicine are insufficiently studied. This is explained by the complex multifunctional biology of SDF-1 with systemic and local effects, critical dependence of SDF-1 activity on aminoterminal proteolytic processing and limited knowledge of applicable modulators of its activity. We here present new insights into modulation of SDF-1 activity in vitro and in vivo by a macromolecular compound, chlorite-oxidized oxyamylose (COAM). COAM prevented the proteolytic inactivation of SDF-1 by two inflammation-associated proteases: matrix metalloproteinase-9/MMP-9 and dipeptidylpeptidase IV/DPPIV/CD26. The inhibition of proteolytic inactivation was functionally measured by receptor-mediated effects, including intracellular calcium mobilization, ERK1/2 phosphorylation, receptor internalization and chemotaxis of CXCR4-positive cells. Protection of SDF-1/CXCL12 against proteolysis was dependent on electrostatic COAM-SDF-1 interactions. By in vivo experiments in mice, we showed that the combination of COAM with SDF-1 delivered through physiological fibrin hydrogel had beneficial effect for the healing of skin wounds. Collectively, we show that COAM protects SDF-1 from proteolytic inactivation, maintaining SDF-1 biological activities. Thus, protection from proteolysis by COAM represents a therapeutic strategy to prolong SDF-1 bioavailability for wound healing applications.
Assuntos
Quimiocina CXCL12 , Dipeptidil Peptidase 4 , Receptores CXCR4 , Pele , Cicatrização , Quimiocina CXCL12/metabolismo , Animais , Cicatrização/efeitos dos fármacos , Camundongos , Humanos , Dipeptidil Peptidase 4/metabolismo , Pele/metabolismo , Pele/efeitos dos fármacos , Pele/patologia , Receptores CXCR4/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteólise/efeitos dos fármacos , Camundongos Endogâmicos C57BLRESUMO
Inflammatory bowel disease (IBD) is a chronic disorder characterized by recurrent gastrointestinal inflammation, lacking a precise aetiology and definitive cure. The gut microbiome is vital in preventing and treating IBD due to its various physiological functions. In the interplay between the gut microbiome and human health, extracellular vesicles secreted by gut bacteria (BEVs) are key mediators. Herein, we explore the role of Roseburia intestinalis (R)-derived EVs (R-EVs) as potent anti-inflammatory mediators in treating dextran sulfate sodium-induced colitis. R was selected as an optimal BEV producer for IBD treatment through ANCOM analysis. R-EVs with a 76 nm diameter were isolated from R using a tangential flow filtration system. Orally administered R-EVs effectively accumulated in inflamed colonic tissues and increased the abundance of Bifidobacterium on microbial changes, inhibiting colonic inflammation and prompting intestinal recovery. Due to the presence of Ile-Pro-Ile in the vesicular structure, R-EVs reduced the DPP4 activity in inflamed colonic tissue and increased the active GLP-1, thereby downregulating the NFκB and STAT3 via the PI3K pathway. Our results shed light on the impact of BEVs on intestinal recovery and gut microbiome alteration in treating IBD.
Assuntos
Colite , Vesículas Extracelulares , Microbioma Gastrointestinal , Vesículas Extracelulares/metabolismo , Animais , Colite/metabolismo , Colite/microbiologia , Colite/terapia , Camundongos , Inflamação/metabolismo , Sulfato de Dextrana , Humanos , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/terapia , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Camundongos Endogâmicos C57BL , Masculino , Dipeptidil Peptidase 4/metabolismo , NF-kappa B/metabolismo , Clostridiales/metabolismoRESUMO
BACKGROUND: Owing to its unique location and multifaceted metabolic functions, epicardial adipose tissue (EAT) is gradually emerging as a new metabolic target for coronary artery disease risk stratification. Microvascular obstruction (MVO) has been recognized as an independent risk factor for unfavorable prognosis in acute myocardial infarction patients. However, the concrete role of EAT in the pathogenesis of MVO formation in individuals with ST-segment elevation myocardial infarction (STEMI) remains unclear. The objective of the study is to evaluate the correlation between EAT accumulation and MVO formation measured by cardiac magnetic resonance (CMR) in STEMI patients and clarify the underlying mechanisms involved in this relationship. METHODS: Firstly, we utilized CMR technique to explore the association of EAT distribution and quantity with MVO formation in patients with STEMI. Then we utilized a mouse model with EAT depletion to explore how EAT affected MVO formation under the circumstances of myocardial ischemia/reperfusion (I/R) injury. We further investigated the immunomodulatory effect of EAT on macrophages through co-culture experiments. Finally, we searched for new therapeutic strategies targeting EAT to prevent MVO formation. RESULTS: The increase of left atrioventricular EAT mass index was independently associated with MVO formation. We also found that increased circulating levels of DPP4 and high DPP4 activity seemed to be associated with EAT increase. EAT accumulation acted as a pro-inflammatory mediator boosting the transition of macrophages towards inflammatory phenotype in myocardial I/R injury through secreting inflammatory EVs. Furthermore, our study declared the potential therapeutic effects of GLP-1 receptor agonist and GLP-1/GLP-2 receptor dual agonist for MVO prevention were at least partially ascribed to its impact on EAT modulation. CONCLUSIONS: Our work for the first time demonstrated that excessive accumulation of EAT promoted MVO formation by promoting the polarization state of cardiac macrophages towards an inflammatory phenotype. Furthermore, this study identified a very promising therapeutic strategy, GLP-1/GLP-2 receptor dual agonist, targeting EAT for MVO prevention following myocardial I/R injury.
Assuntos
Tecido Adiposo , Modelos Animais de Doenças , Receptor do Peptídeo Semelhante ao Glucagon 1 , Macrófagos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão Miocárdica , Pericárdio , Infarto do Miocárdio com Supradesnível do Segmento ST , Animais , Pericárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Masculino , Macrófagos/metabolismo , Macrófagos/patologia , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Infarto do Miocárdio com Supradesnível do Segmento ST/metabolismo , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Humanos , Feminino , Pessoa de Meia-Idade , Fenótipo , Dipeptidil Peptidase 4/metabolismo , Idoso , Técnicas de Cocultura , Adiposidade , Circulação Coronária , Transdução de Sinais , Microcirculação , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Vasos Coronários/diagnóstico por imagem , Incretinas/farmacologia , Microvasos/metabolismo , Microvasos/patologia , Células Cultivadas , Camundongos , Tecido Adiposo EpicárdicoRESUMO
Adiponectin is a circulating hormone secreted by adipose tissue that exerts, unlike other adipokines such as leptin, anti-inflammatory, anti-atherosclerotic and other protective effects on health. Adiponectin receptor agonists are being tested in clinical trials and are expected to show benefits in many diseases. In a recent article, LW Chen's group used monocyte chemoattractant protein-1 (MCP-1/CCL2) to improve plasma levels of adiponectin, suggesting the involvement of dipeptidyl peptidase 4 (DPP4/CD26) in the mechanism. Here, we discuss the significance of the role of DPP4, favoring the increase in DPP4-positive interstitial progenitor cells, a finding that fits with the greater stemness and persistence of other DPP4/CD26-positive cells.
Assuntos
Adipogenia , Tecido Adiposo , Dipeptidil Peptidase 4 , Dipeptidil Peptidase 4/metabolismo , Dipeptidil Peptidase 4/genética , Adipogenia/genética , Adipogenia/efeitos dos fármacos , Humanos , Tecido Adiposo/metabolismo , Animais , Adiponectina/metabolismo , Adiponectina/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Células Estromais/metabolismo , Adipócitos/metabolismo , Adipócitos/efeitos dos fármacosRESUMO
Baltic herring is the main catch in the Baltic Sea; however, its usage could be improved due to the low processing rate. Previously we have shown that whole Baltic herring hydrolysates (BHH) and herring byproducts hydrolysates (BHBH) by commercial enzymes consisted of bioactive peptides and had moderate bioactivity in in vitro dipeptidyl peptidase (DPP)-4 assay. In this study, we identified the hydrolysate peptides by LC-MS/MS and predicted the potential bioactive DPP-4 inhibitory peptides using in silico tools. Based on abundance, peptide length and stability, 86 peptides from BHBH and 80 peptides from BHH were proposed to be novel DPP-4 inhibitory peptides. BHH was fed to a mice intervention of a high-fat, high-fructose diet to validate the bioactivity. The results of the glucose tolerance and insulin tolerance improved. Plasma DPP-4 activities, C-peptide levels, and HOMA-IR scores significantly decreased, while plasma glucagon-like peptide-1 content increased. In conclusion, BHH is an inexpensive and sustainable source of functional antidiabetic ingredients.
Assuntos
Dipeptidil Peptidase 4 , Inibidores da Dipeptidil Peptidase IV , Obesidade , Animais , Dipeptidil Peptidase 4/metabolismo , Camundongos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Obesidade/metabolismo , Masculino , Peptídeos , Dieta Hiperlipídica , Peixes , Hidrolisados de Proteína/farmacologia , Hidrolisados de Proteína/química , Modelos Animais de Doenças , Espectrometria de Massas em Tandem , Hipoglicemiantes/farmacologia , Simulação por Computador , Camundongos Endogâmicos C57BL , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Resistência à InsulinaRESUMO
Dipeptidyl peptidase 4 (DPP4) plays a key role in glucose metabolism, which has been a close target for diabetes pathology and treatment. It is significant for the evaluation of cellular DPP4 activity in various biological systems. Fluorescence imaging technology is currently a popular method for detecting enzymes in living cells due to its advantages of high selectivity, high sensitivity, high spatiotemporal resolution, and real-time visualization. Herein, a near-infrared (NIR)-emissive probe NEDP with a large Stokes shift (153 nm) was developed for the assay of DPP4 activity. Upon addition of DPP4, NEDP can emit a significant turn-on NIR fluorescence signal (673 nm) with high sensitivity and specificity. Moreover, NEDP can successfully be used for imaging of intracellular DPP4, confirming the regulation of DPP4 expression in hyperglucose and its treatment in living cells. Most importantly, NEDP can not only monitor the changes of DPP4 in vivo but also show that DPP4 in diabetes is mainly up-regulated in the liver, and the level of DPP4 is positively correlated with the pathological damage of the liver. In addition, NEDP can identify the serum of diabetic patients from healthy people through the fluorescence response to DPP4. These results demonstrated that the designed probe NEDP provides a prospective visual tool to explore the relationship between DPP4 and diabetes and would be applied for detecting serum of diabetes in the clinic.
Assuntos
Diabetes Mellitus Experimental , Dipeptidil Peptidase 4 , Corantes Fluorescentes , Fígado , Dipeptidil Peptidase 4/metabolismo , Dipeptidil Peptidase 4/sangue , Animais , Humanos , Camundongos , Fígado/metabolismo , Fígado/patologia , Corantes Fluorescentes/química , Diabetes Mellitus Experimental/metabolismo , Imagem Óptica , Raios Infravermelhos , MasculinoRESUMO
BACKGROUND: The gut microbiota controls broad aspects of human metabolism and feeding behavior, but the basis for this control remains largely unclear. Given the key role of human dipeptidyl peptidase 4 (DPP4) in host metabolism, we investigate whether microbiota DPP4-like counterparts perform the same function. RESULTS: We identify novel functional homologs of human DPP4 in several bacterial species inhabiting the human gut, and specific associations between Parabacteroides and Porphyromonas DPP4-like genes and type 2 diabetes (T2D). We also find that the DPP4-like enzyme from the gut symbiont Parabacteroides merdae mimics the proteolytic activity of the human enzyme on peptide YY, neuropeptide Y, gastric inhibitory polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) hormones in vitro. Importantly, administration of E. coli overexpressing the P. merdae DPP4-like enzyme to lipopolysaccharide-treated mice with impaired gut barrier function reduces active GIP and GLP-1 levels, which is attributed to increased DPP4 activity in the portal circulation and the cecal content. Finally, we observe that linagliptin, saxagliptin, sitagliptin, and vildagliptin, antidiabetic drugs with DPP4 inhibitory activity, differentially inhibit the activity of the DPP4-like enzyme from P. merdae. CONCLUSIONS: Our findings confirm that proteolytic enzymes produced by the gut microbiota are likely to contribute to the glucose metabolic dysfunction that underlies T2D by inactivating incretins, which might inspire the development of improved antidiabetic therapies.
Assuntos
Diabetes Mellitus Tipo 2 , Dipeptidil Peptidase 4 , Microbioma Gastrointestinal , Incretinas , Diabetes Mellitus Tipo 2/microbiologia , Diabetes Mellitus Tipo 2/metabolismo , Dipeptidil Peptidase 4/metabolismo , Animais , Humanos , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Incretinas/metabolismo , Polipeptídeo Inibidor Gástrico/metabolismo , MasculinoRESUMO
Dipeptidyl peptidase-4 (DPP-4) inhibitors belong to a prominent group of pharmaceutical agents that are used in the governance of type 2 diabetes mellitus (T2DM). They exert their antidiabetic effects by inhibiting the incretin hormones like glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide which, play a pivotal role in the regulation of blood glucose homoeostasis in our body. DPP-4 inhibitors have emerged as an important class of oral antidiabetic drugs for the treatment of T2DM. Surprisingly, only a few 2D-QSAR studies have been reported on DPP-4 inhibitors. Here, fragment-based QSAR (Laplacian-modified Bayesian modelling and Recursive partitioning (RP) approaches have been utilized on a dataset of 108 DPP-4 inhibitors to achieve a deeper understanding of the association among their molecular structures. The Bayesian analysis demonstrated satisfactory ROC values for the training as well as the test sets. Meanwhile, the RP analysis resulted in decision tree 3 with 2 leaves (Tree 3: 2 leaves). This present study is an effort to get an insight into the pivotal fragments modulating DPP-4 inhibition.
Assuntos
Teorema de Bayes , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Hipoglicemiantes , Relação Quantitativa Estrutura-Atividade , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Estrutura Molecular , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , HumanosRESUMO
Bioactive peptides derived from food are promising health-promoting ingredients that can be used in functional foods and nutraceutical formulations. In addition to the potency towards the selected therapeutic target, the bioavailability of bioactive peptides is a major factor regarding clinical efficacy. We have previously shown that a low molecular weight peptide fraction (LMWPF) from poultry by-product hydrolysates possesses angiotensin-1-converting enzyme (ACE-1) and dipeptidyl-peptidase 4 (DPP4) inhibitory activities. The present study aimed to investigate the bioavailability of the bioactive peptides in the LMWPF. Prior to the investigation of bioavailability, a dipeptide YA was identified from this fraction as a dual inhibitor of ACE-1 and DPP4. Gastrointestinal (GI) stability and intestinal absorption of the bioactive peptides (i.e., YA as well as two previously reported bioactive dipeptides (VL and IY)) in the LMWPF were evaluated using the INFOGEST static in vitro digestion model and intestinal Caco-2 cell monolayer, respectively. Analysis of peptides after in vitro digestion confirmed that the dipeptides were resistant to the simulated GI conditions. After 4 hours of incubation, the concentration of the peptide from the apical side of the Caco-2 cell monolayer showed a significant decrease. However, the corresponding absorbed peptides were not detected on the basolateral side, suggesting that the peptides were not transported across the intestinal monolayer but rather taken up or metabolized by the Caco2 cells. Furthermore, when analyzing the gene expression of the Caco-2 cells upon peptide stimulation, a down-regulation of peptide transporters, the transcription factor CDX2, and the tight junction protein-1 (TJP1) was observed, suggesting the specific effects of the peptides on the Caco-2 cells. The study demonstrated that bioactive dipeptides found in the LMWPF were stable through in vitro GI digestion; however, the overall bioavailability may be hindered by inadequate uptake across the intestinal barrier.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Dipeptidil Peptidase 4 , Inibidores da Dipeptidil Peptidase IV , Absorção Intestinal , Hidrolisados de Proteína , Animais , Humanos , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Disponibilidade Biológica , Células CACO-2 , Digestão , Dipeptídeos/química , Dipeptídeos/metabolismo , Dipeptídeos/farmacocinética , Dipeptídeos/farmacologia , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Inibidores da Dipeptidil Peptidase IV/farmacologia , Trato Gastrointestinal/metabolismo , Absorção Intestinal/efeitos dos fármacos , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/farmacocinética , Peptídeos/farmacologia , Peptidil Dipeptidase A/metabolismo , Aves Domésticas , Hidrolisados de Proteína/química , Hidrolisados de Proteína/farmacologiaRESUMO
We evaluated the impact of early recovery of mucosal-associated invariant T cells (MAIT) and gamma-delta (γδ) T cells, especially Vδ2+ T cells, on the clinical outcomes of 76 patients who underwent allogeneic hematopoietic cell transplantation (allo-HCT). MAIT cells were identified at day 20-30 post-transplant using flow cytometry and defined as CD3+ TCRVα7.2+CD161+. Two subsets of Vδ2+ T cells were analyzed according to the expression of CD26. The cytotoxicity profile of MAIT and Vδ2+ T cells was analyzed according to the intracellular expression of perforin and granzyme B, and intracellular IFN-γ was evaluated after in vitro activation. CD26+Vδ2+ T cells displayed higher intracellular levels of IFN-γ, whereas CD26- Vδ2+ T were found to be more cytotoxic. Moreover, MAIT cell frequency was correlated with the frequency of Vδ2+ T cells with a better correlation observed with Vδ2+CD26+ than with the Vδ2+CD26- T cell subset. By using the composite endpoint graft-versus-host disease (GvHD)-free, relapse-free survival (GRFS) as the primary endpoint, we found that patients with a higher MAIT cell frequency at day 20-30 after allo-HCT had a significantly increased GRFS and a better overall survival (OS) and disease-free survival (DFS). Moreover, patients with a low CD69 expression by MAIT cells had an increased cumulative incidence of grade 2-4 acute GvHD (aGvHD). These results suggest that MAIT cell reconstitution may provide mitigating effects early after allo-HCT depending on their activation markers and functional status. Patients with a high frequency of Vδ2+CD26+ T cells had a significantly higher GRFS, OS and DFS, but there was no impact on cumulative incidence of grade 2-4 aGVHD, non-relapse mortality and relapse. These results revealed that the impact of Vδ2+ T cells on the success of allo-HCT may vary according to the frequency of the CD26+ subset.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Células T Invariantes Associadas à Mucosa , Transplante Homólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/etiologia , Células T Invariantes Associadas à Mucosa/imunologia , Adulto Jovem , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adolescente , Idoso , Resultado do Tratamento , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Dipeptidil Peptidase 4/metabolismo , Citotoxicidade ImunológicaRESUMO
Glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and glucagon are three naturally occurring peptide hormones that mediate glucoregulation. Several agonists representing appropriately modified native ligands have been developed to maximize metabolic benefits with reduced side-effects and many have entered the clinic as type 2 diabetes and obesity therapeutics. In this work, we describe strategies for improving the stability of the peptide ligands by making them refractory to dipeptidyl peptidase-4 catalyzed hydrolysis and inactivation. We describe a series of alkylations with variations in size, shape, charge, polarity, and stereochemistry that are able to engender full activity at the receptor(s) while simultaneously resisting enzyme-mediated degradation. Utilizing this strategy, we offer a novel method of modulating receptor activity and fine-tuning pharmacology without a change in peptide sequence.
Assuntos
Peptídeo 1 Semelhante ao Glucagon , Humanos , Peptídeo 1 Semelhante ao Glucagon/química , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Desenho de Fármacos , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Peptídeos/química , Polipeptídeo Inibidor Gástrico/química , Polipeptídeo Inibidor Gástrico/metabolismo , Alquilação , Glucagon/química , Glucagon/metabolismo , Animais , Ligantes , Hidrólise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismoRESUMO
The inhibition of dipeptidyl- peptidase 4 (DPP-4) is an essential therapy for controlling hyperglycemia in patients with type 2 diabetes (T2DM). However, the role of DPP-4 in cancer is not yet clear, with some studies suggesting that it may either promote or suppress tumors. This makes it crucial to have personalized treatment for diabetic women with cancer to effectively manage their diabetes whilst and preventing cancer mortality. To address this issue, we conducted an integrative in-silico analysis and systematic review of the literature to comprehensively examine the relationship between DPP-4 expression and the effects of its inhibitors on prevalent female malignancies. We specifically chose studies that examined the effects of DPP-4 expression and DPP-4 inhibition (DPP-4i) on prevalent cancers in women, such as breast cancer (BC), ovarian cancer (OV), cervical cancer (CC), and endometrial cancer (EC). These studies comprised those conducted both in vivo and in vitro. The review of the literature indicated that DPP-4i may worsen aggressive traits such as metastasis, Epithelial-to-mesenchymal transition (EMT), and chemotherapy resistance in BC cells. However, cohort studies on diabetic and BC patients did not confirm these findings. In vitro studies indicate that on OV, DPP-4 upregulation has been shown to prevent metastasis, while CCappears to be influenced by DPP-4 expression in terms of cell migration. sitagliptin, a pharmaceutical inhibitor of DPP-4, had a significant impact on reducing adhesion in CC cells in vitro. Overexpression of DPP-4 increased cell migration and proliferation in CC and EC cells, and hence the application of sitagliptin is expected to prevent this effect. On the other hand, the result of in-silico data confirmed that a significant correlation exists between DPP-4 expression and immune cell infiltration in breast, ovarian, cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) as well as downregulated in these cancers compared to their normal tissue samples. Furthermore, a significant (p < 0.05) effect on OS of BC and CESC patients has been reported due to the elevation of DPP-4 methylation on a specific CPG Island. These findings could aid in creating specialized treatments for diabetic women with specific malignancies, but caution should be exercised when considering the patient's medical history and cancer type.
Assuntos
Neoplasias da Mama , Dipeptidil Peptidase 4 , Inibidores da Dipeptidil Peptidase IV , Transição Epitelial-Mesenquimal , Humanos , Feminino , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Dipeptidil Peptidase 4/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicaçõesRESUMO
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent glocal cause of chronic hepatic disease, with incidence rates that continue to rise steadily. Treatment options for affected patients are currently limited to dietary changes and exercise interventions, with no drugs having been licensed for the treatment of this disease. There is thus a pressing need for the development of novel therapeutic strategies. Work from our group suggests that the primary bioactive ingredient in green tea, epigallocatechin gallate (EGCG), may help reduce liver fat content and protect against hepatic injury through the inhibition of dipeptidyl peptidase 4 (DPP4) expression and activity. The study investigated the potential pathways by which EGCG may improve NAFLD, identified the sites of interaction between EGCG and DPP4, and proposed novel clinical treatment strategies. METHODS: A clinical randomized controlled trial was conducted to investigate the potential efficacy of EGCG in NAFLD patients. The study compared relevant indices before and after EGCG administration. Animal models of NAFLD were constructed using male C57BL/6J mice fed a high-fat diet to observe the ameliorative effects of EGCG on the livers of the model mice and to investigate the potential pathways by which EGCG alleviates NAFLD. The interaction mechanism between EGCG and DPP4 was investigated using oleic acid and palmitic acid-treated HepG2 cell lines. Plasmids in which different sites had been disrupted were used to identify the effective interaction sites. RESULTS: ECGC was found to suppress the accumulation of lipids, inhibit inflammation, remediate dysregulated lipid metabolism, and improve the pathogenesis of NAFLD via the inhibition of the expression and activity of DPP4. CONCLUSIONS: The study results indicate that EGCG has a positive impact on improving NAFLD. These results highlight promising new opportunities to safely and effectively treat NAFLD in the clinic. STUDY ID NUMBER: ChiCTR2300076741; https://www.chictr.org.cn/.
Assuntos
Catequina , Dipeptidil Peptidase 4 , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , Catequina/análogos & derivados , Catequina/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Masculino , Humanos , Camundongos , Dipeptidil Peptidase 4/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Dieta Hiperlipídica/efeitos adversos , Pessoa de Meia-Idade , Feminino , Modelos Animais de Doenças , Adulto , Células Hep G2RESUMO
Astragalus kurdicus Boiss. roots are used in folk medicine for antidiabetic purposes. Different Astragalus plant metabolites have a notable potential for antidiabetic activity through varying mechanisms. Herein, this study is designed to assess the antidiabetic activity of Astragalus kurdicus total (AKM: methanol extract, yield: 14.53 %) and sub-extracts (AKB: n-butanol, AKC: chloroform, AKW: water, AKH: hexane extracts), utilizing a range of diabetes-related inâ vitro methodologies, and to investigate the chemical composition of the plant. The highest astragaloside and saponin content was seen in AKB extract. Among the measured saponins, the abundance of Astragalosideâ IV (27.41â µg/mg in AKM) was the highest in high-performance thin-layer chromatography (HPTLC) analysis. Furthermore, flavonoid-rich AKC was found to be mostly responsible for the high antioxidant activity. According to the results of the activity tests, AKW was the most active extract in protein tyrosine phosphatase 1â B (PTP1B), dipeptidyl peptidaseâ IV (DPP4), and α-amylase inhibition tests (percent inhibitions are: 87.17 %, 82.4 %, and 91.49 % respectively, at 1â mg/mL). AKM and AKW demonstrated the highest efficacy in stimulating the growth of prebiotic microorganisms and preventing the formation of advanced glycation end products (AGEs). Thus, for the first time, the antidiabetic activity of A. kurdicus was evaluated from various perspectives.
Assuntos
Astrágalo , Hipoglicemiantes , Extratos Vegetais , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Astrágalo/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/isolamento & purificação , Saponinas/farmacologia , Saponinas/química , Saponinas/isolamento & purificação , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/isolamento & purificação , Humanos , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo , Triterpenos/química , Triterpenos/farmacologia , Triterpenos/isolamento & purificação , Dipeptidil Peptidase 4/metabolismo , Dipeptidil Peptidase 4/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificaçãoRESUMO
Dipeptidyl peptidase-IV (DPPIV) inhibitory peptides are a class of antihyperglycemic drugs used in the treatment of type 2 diabetes mellitus, a metabolic disorder resulting from reduced levels of the incretin hormone GLP-1. Given that DPPIV degrades incretin, a key regulator of blood sugar levels, various antidiabetic medications that inhibit DPPIV, such as vildagliptin, sitagliptin, and linagliptin, are employed. However, the potential side effects of these drugs remain a matter of debate. Therefore, we aimed to investigate food-derived peptides from Cannabis sativa (hemp) seeds. Our developed bioinformatics pipeline was used to identify the putative hydrolyzed peptidome of three highly abundant proteins: albumin, edestin, and vicilin. These proteins were subjected to in silico digestion by different proteases (trypsin, chymotrypsin, and pepsin) and then screened for DPPIV inhibitory peptides using IDPPIV-SCM. To assess potential adverse effects, several prediction tools, namely, TOXINpred, AllerCatPro, and HemoPred, were employed to evaluate toxicity, allergenicity, and hemolytic effects, respectively. COPID was used to determine the amino acid composition. Molecular docking was performed using GalaxyPepDock and HPEPDOCK, 3D visualizations were conducted using the UCSF Chimera program, and MD simulations were carried out with AMBER20 MD software. Based on the predictive outcomes, FNVDTE from edestin and EAQPST from vicilin emerged as promising candidates for DPPIV inhibitors. We anticipate that our findings may pave the way for the development of alternative DPPIV inhibitors.
Assuntos
Cannabis , Dipeptidil Peptidase 4 , Inibidores da Dipeptidil Peptidase IV , Hipoglicemiantes , Peptídeos , Sementes , Humanos , Cannabis/química , Biologia Computacional/métodos , Dipeptidil Peptidase 4/metabolismo , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hidrólise , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Simulação de Acoplamento Molecular , Peptídeos/química , Proteínas de Plantas/química , Proteínas de Armazenamento de Sementes/química , Sementes/químicaRESUMO
The role of the gut microbiota and its interplay with host metabolic health, particularly in the context of type 2 diabetes mellitus (T2DM) management, is garnering increasing attention. Dipeptidyl peptidase 4 (DPP4) inhibitors, commonly known as gliptins, constitute a class of drugs extensively used in T2DM treatment. However, their potential interactions with gut microbiota remain poorly understood. In this study, we employed computational methodologies to investigate the binding affinities of various gliptins to DPP4-like homologs produced by intestinal bacteria. The 3D structures of DPP4 homologs from gut microbiota species, including Segatella copri, Phocaeicola vulgatus, Bacteroides uniformis, Parabacteroides merdae, and Alistipes sp., were predicted using computational modeling techniques. Subsequently, molecular dynamics simulations were conducted for 200 ns to ensure the stability of the predicted structures. Stable structures were then utilized to predict the binding interactions with known gliptins through molecular docking algorithms. Our results revealed binding similarities of gliptins toward bacterial DPP4 homologs compared to human DPP4. Specifically, certain gliptins exhibited similar binding scores to bacterial DPP4 homologs as they did with human DPP4, suggesting a potential interaction of these drugs with gut microbiota. These findings could help in understanding the interplay between gliptins and gut microbiota DPP4 homologs, considering the intricate relationship between the host metabolism and microbial communities in the gut.
Assuntos
Diabetes Mellitus Tipo 2 , Dipeptidil Peptidase 4 , Inibidores da Dipeptidil Peptidase IV , Microbioma Gastrointestinal , Humanos , Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Sítios de Ligação , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação ProteicaRESUMO
Cancer-associated fibroblasts (CAFs) are a heterogeneous population of fibroblasts with various features in the cancer stroma and have been reported to influence cancer progression through cell-cell interactions in various types of malignancies, including lung adenocarcinoma (LUAD). Dipeptidyl peptidase 4 (DPP4) is a transmembrane protein with serine protease activity and is involved in the progression of tumors, metabolic diseases, and autoimmune diseases. In the present study, we focused on the role of DPP4-positive CAFs in LUAD. Immunohistochemistry revealed that 38 of 89 LUAD patients showed DPP4 expression in the fibrous stroma, and patients harboring DPP4-positive CAFs were more often male, had a higher Brinkman index, and had a higher Ki-67 labeling index of tumor cells than those with DPP4-negative CAFs. DPP4-positivity was associated with the expression of other CAF markers, α-SMA, periostin, and podoplanin, as well as a cellular senescence marker, p16. In the in vitro study, conditioned media collected from pulmonary fibroblast (OUS-11, HPF, and HPF-C)-induced overexpression of DPP4 significantly promoted the proliferation of LUAD cells (A549 and PC-9) and increased the expression levels of MCP-1, IL-8, IL-6, and GCSF in the media compared to those in controls. In addition, OUS-11 overexpression in DPP4 overexpression increased periostin expression. In conclusion, DPP4-positive CAFs could promote lung adenocarcinoma cell growth by producing soluble factors, and DPP4 inhibition may inhibit cancer progression.
Assuntos
Adenocarcinoma de Pulmão , Fibroblastos Associados a Câncer , Proliferação de Células , Dipeptidil Peptidase 4 , Neoplasias Pulmonares , Humanos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Dipeptidil Peptidase 4/metabolismo , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/enzimologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/enzimologia , Masculino , Proliferação de Células/fisiologia , Feminino , Pessoa de Meia-Idade , Idoso , Microambiente TumoralRESUMO
A novel pangolin-origin MERS-like coronavirus (CoV), MjHKU4r-CoV-1, was recently identified. It is closely related to bat HKU4-CoV, and is infectious in human organs and transgenic mice. MjHKU4r-CoV-1 uses the dipeptidyl peptidase 4 (DPP4 or CD26) receptor for virus entry and has a broad host tropism. However, the molecular mechanism of its receptor binding and determinants of host range are not yet clear. Herein, we determine the structure of the MjHKU4r-CoV-1 spike (S) protein receptor-binding domain (RBD) complexed with human CD26 (hCD26) to reveal the basis for its receptor binding. Measuring binding capacity toward multiple animal receptors for MjHKU4r-CoV-1, mutagenesis analyses, and homology modeling highlight that residue sites 291, 292, 294, 295, 336, and 344 of CD26 are the crucial host range determinants for MjHKU4r-CoV-1. These results broaden our understanding of this potentially high-risk virus and will help us prepare for possible outbreaks in the future.
Assuntos
Dipeptidil Peptidase 4 , Especificidade de Hospedeiro , Ligação Proteica , Receptores Virais , Glicoproteína da Espícula de Coronavírus , Tropismo Viral , Humanos , Animais , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/química , Dipeptidil Peptidase 4/metabolismo , Dipeptidil Peptidase 4/genética , Receptores Virais/metabolismo , Receptores Virais/genética , Receptores Virais/química , Camundongos , Sítios de Ligação , Internalização do Vírus , Modelos Moleculares , Domínios Proteicos , Tropismo ao HospedeiroRESUMO
Improving cancer immunotherapy efficacy hinges on identifying key T-cell populations critical for tumor control and response to Immune Checkpoint Blockade (ICB). We have recently reported that while the co-expression of PD-1 and CD28 is associated with impaired functionality in peripheral blood, it significantly enhances T-cell fitness in the tumor site of non-small cell lung cancer (NSCLC) patients. To uncover the underlying mechanisms, we explored the role of CD26, a key player in T-cell activation through its interaction with adenosine deaminase (ADA), a crucial intra/extracellular enzyme able to neutralize local adenosine (ADO). We found that an autocrine ADA/CD26 axis enhances CD8+PD-1+CD28+ T-cell function, particularly within an immunosuppressive environment marked by CD39 expression. Then, we interrogated the TCGA and OAK datasets to gain insight into the prognostic/predictive potential of our findings. We identified a signature predicting overall survival (OS) in LUAD patients and response to atezolizumab in advanced LUAD cases. These findings suggest promising avenues for therapeutic intervention targeting the ADA/CD26 axis.
Assuntos
Adenosina Desaminase , Antígenos CD28 , Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas , Dipeptidil Peptidase 4 , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Receptor de Morte Celular Programada 1 , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Antígenos CD28/metabolismo , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Dipeptidil Peptidase 4/metabolismo , Dipeptidil Peptidase 4/genética , Adenosina Desaminase/metabolismo , Adenosina Desaminase/genética , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Feminino , Masculino , Apirase/metabolismoRESUMO
Porcine hemagglutinating encephalomyelitis virus (PHEV), a neurotropic betacoronavirus, is prevalent in natural reservoir pigs and infects mice. This raises concerns about host jumping or spillover, but little is known about the cause of occurrence. Here, we revealed that dipeptidyl peptidase 4 (DPP4) is a candidate binding target of PHEV spikes and works as a broad barrier to overcome. Investigations of the host breadth of PHEV confirmed that cells derived from pigs and mice are permissive to virus propagation. Both porcine DPP4 and murine DPP4 have high affinity for the viral spike receptor-binding domain (RBD), independent of their catalytic activity. Loss of DPP4 expression results in limited PHEV infection. Structurally, PHEV spike protein binds to the outer surface of blades IV and V of the DPP4 ß-propeller domain, and the DPP4 residues N229 and N321 (relative to human DPP4 numbering) participate in RBD binding via its linked carbohydrate entities. Removal of these N-glycosylations profoundly enhanced the RBD-DPP4 interaction and viral invasion, suggesting they act as shielding in PHEV infection. Furthermore, we found that glycosylation, rather than structural differences or surface charges, is more responsible for DPP4 recognition and species barrier formation. Overall, our findings shed light on virus-receptor interactions and highlight that PHEV tolerance to DPP4 orthologs is a putative determinant of its cross-species transmission or host range expansion.IMPORTANCEPHEV is a neurotropic betacoronavirus that is circulating worldwide and has raised veterinary and economic concerns. In addition to being a reservoir species of pigs, PHEV can also infect wild-type mice, suggesting a "host jump" event. Understanding cross-species transmission is crucial for disease prevention and control but remains to be addressed. Herein, we show that the multifunctional receptor DPP4 plays a pivotal role in the host tropism of PHEV and identifies the conserved glycosylation sites in DPP4 responsible for this restriction. These findings highlight that the ability of PHEV to utilize DPP4 orthologs potentially affects its natural host expansion.