Gemigliptin, a potent selective dipeptidyl peptidase 4 inhibitor, protects endothelial progenitor cells by oxidative stress via caspase-3 dependent pathway
Ontology highlight
ABSTRACT:
SUBMITTER: Lee M
PROVIDER: S-EPMC10914559 | biostudies-literature | 2024 Mar
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BACKGROUND AND PURPOSE: Current methods used to treat critical limb ischaemia (CLI) are hampered by a lack of effective strategies, therefore, therapeutic vasculogenesis may open up a new field for the treatment of CLI. In this study we investigated the ability of the DPP-4 inhibitor, sitagliptin, originally used as a hypoglycaemic agent, to induce vasculogenesis in vivo. EXPERIMENTAL APPROACH: Sitagliptin were administered daily to C57CL/B6 mice and eGFP transgenic mouse bone marrow-transplanted ICR mice that had undergone hindlimb ischaemic surgery. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neovasculogenesis and circulating levels of endothelial progenitor cells (EPCs) respectively. Cell surface markers of EPCs and endothelial NOS (eNOS) in vessels were studied. KEY RESULTS: Sitagliptin elevated plasma glucagon-like peptide-1 (GLP-1) levels in mice subjected to ischaemia, decreased plasma dipeptidyl peptidase-4 (DPP-4) concentration, and augmented ischaemia-induced increases in stromal cell-derived factor-1 (SDF-1) in a dose-dependent manner. Blood flow in the ischaemic limb was significantly improved in mice treated with sitagliptin. Circulating levels of EPCs were also increased after sitagliptin treatment. Sitagliptin also enhanced the expression of CD 34 and eNOS in ischaemic muscle. In addition, sitagliptin promoted EPC mobilization and homing to ischaemic tissue in eGFP transgenic mouse bone marrow-transplanted ICR mice. CONCLUSION AND IMPLICATIONS: Circulating EPC levels and neovasculogenesis were augmented by the DPP-4 inhibitor, sitagliptin and this effect was dependent on an eNOS-related pathway in a mouse model of hindlimb ischaemia. The results indicate that oral administration of sitagliptin has therapeutic potential as an inducer of vasculogenesis.
| S-EPMC3514763 | biostudies-literature
Project description:BackgroundDipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the treatment of patients with type 2 diabetes and have proven protective effects on diabetic kidney disease (DKD). Whether DPP-4 inhibitors have renoprotective effects on insulin-deficient type 1 diabetes has not been comprehensively examined. The aim of this study was to determine whether gemigliptin, a new DPP-4 inhibitor, has renoprotective effects in streptozotocin (STZ)-induced type 1 diabetic mice.MethodsDiabetes was induced by intraperitoneal administration of a single dose of STZ. Mice with diabetes were treated without or with gemigliptin (300 mg/kg) for 8 weeks. Morphological changes of the glomerular basement membrane (GBM) were observed by electron microscopy and periodic-acid Schiff staining. In addition, we measured blood glucose and urinary albumin excretion and evaluated fibrotic markers using immunohistochemical staining, quantitative reverse transcription polymerase chain reaction analysis, and Western blot analysis.ResultsGemigliptin did not reduce the blood glucose levels of STZ-treated mice. In gemigliptin-treated mice with STZ, a significant reduction in urinary albumin excretion and GBM thickness was observed. Immunohistological examination revealed that gemigliptin attenuated renal fibrosis induced by STZ and decreased extracellular matrix protein levels, including those of type I collagen and fibronectin, and Smad3 phosphorylation. In cultured rat renal cells, gemigliptin inhibited transforming growth factor β-stimulated type I collagen and fibronectin mRNA and protein levels via down-regulation of Smad3 phosphorylation.ConclusionOur data demonstrate that gemigliptin has renoprotective effects on DKD, regardless of its glucose-lowering effect, suggesting that it could be used to prevent DKD, including in patients with type 1 diabetes.
| S-EPMC4929225 | biostudies-literature
Project description:Effect of expression of dipeptidyl peptidase-IV (DPP-IV) in U373 cell line on uncontrolled cell proliferation and aberrant interactions with the brain extracellular matrix.
2011-12-31 | E-MTAB-583 | biostudies-arrayexpress
Project description:Dipeptidyl peptidase-4 inhibitors (DPP4i) are antidiabetic medications that prevent cleavage of incretin hormones by dipeptidyl peptidase-4 (DPP4). DPP4 is ubiquitously expressed, and its hepatic DPP4 expression is upregulated under non-alcoholic steatohepatitis (NASH) conditions. We investigated the effect of DPP4i treatment on NASH pathogenesis, as well as its potential underlying molecular mechanisms. Mice were randomly divided into three groups: Group 1, chow-fed mice treated with vehicle for 20 weeks; Group 2, high-fat, high-fructose, and high-cholesterol Amylin liver NASH (AMLN) diet-fed mice treated with vehicle for 20 weeks; Group 3, AMLN diet-fed mice treated with vehicle for the first 10 weeks, followed by the DPP4i teneligliptin (20 mg/kg/day) for additional 10 weeks. DPP4i administration reduced serum liver enzyme and hepatic triglyceride levels and markedly improved hepatic steatosis and fibrosis in the AMLN diet-induced NASH model. In vivo, NASH alleviation significantly correlated with the suppression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis and downregulated hepatic DPP4 expression. In vitro, DPP4i treatment significantly decreased the markers of TRAIL receptor-mediated lipoapoptosis and suppressed DPP4 expression in palmitate-treated hepatocytes. In conclusion, DPP4i may efficiently attenuate the pathogenesis of AMLN diet-induced NASH in mice by suppressing lipotoxicity-induced apoptosis, possibly by modulating hepatic DPP4 expression.
| S-EPMC7655829 | biostudies-literature
Project description:Controlling oxidative stress through the activation of antioxidant pathways is crucial in bone homeostasis, and impairments of the cellular defense systems involved contribute to the pathogenesis of common skeletal diseases. In this work we focused on the dipeptidyl peptidase 3 (DPP3), a poorly investigated ubiquitous zinc-dependent exopeptidase activating the Keap1-Nrf2 antioxidant pathway. We showed Dpp3 expression in bone and, to understand its role in this compartment, we generated a Dpp3 knockout (KO) mouse model and specifically investigated the skeletal phenotype. Adult Dpp3 KO mice showed a mild growth defect, a significant increase in bone marrow cellularity, and bone loss mainly caused by increased osteoclast activity. Overall, in the mouse model, lack of DPP3 resulted in sustained oxidative stress and in alterations of bone microenvironment favoring the osteoclast compared to the osteoblast lineage. Accordingly, in vitro studies revealed that Dpp3 KO osteoclasts had an inherent increased resorptive activity and ROS production, which on the other hand made them prone to apoptosis. Moreover, absence of DPP3 augmented bone loss after estrogen withdrawal in female mice, further supporting its relevance in the framework of bone pathophysiology. Overall, we show a nonredundant role for DPP3 in the maintenance of bone homeostasis and propose that DPP3 might represent a possible new osteoimmunological player and a marker of human bone loss pathology. © 2019 American Society for Bone and Mineral Research.
| S-EPMC7203631 | biostudies-literature
Project description:IntroductionDipeptidyl peptidase-4 (DPP-4) inhibitors have various cellular effects that are associated with vascular protection. Here, we examined whether vildagliptin protected endothelial function in diabetic rats and explored the involved mechanism.Material and methodsExperimental diabetic rats were obtained by feeding a high-fat diet and administering an intraperitoneal injection of streptozotocin. Rats were randomly divided into four groups: controls (CON), diabetes (DM), diabetes + low dose of vildagliptin (Lvil, 10 mg/kg/day), and diabetes + high dose of vildagliptin (Hvil, 20 mg/kg/day). The metabolic parameters, endothelial function, and whole miRNA expression were measured.ResultsAfter a 12-week treatment, vildagliptin-treated rats showed a significant reduction in blood glucose and blood lipid levels. Moreover, vildagliptin recovered aortic endothelial function in diabetic rats. We identified 31 miRNAs that were differentially expressed in the Hvil group compared with the diabetic group. Importantly, through miRNA target biological function and pathway analysis, we found that vildagliptin activated miR-190-5p to inhibit Ccl2 expression and inhibited miR-134-5p and miR-375-3p to increase Bdnf and Pdk1 expression in the aorta.ConclusionsOur present study indicates that vildagliptin can recover endothelial function in diabetic rats. Anti-inflammatory and anti-apoptosis mechanisms and endothelial moderation may be the intervention targets of vildagliptin to protect the cardiovascular system through miRNA regulation.
| S-EPMC8425228 | biostudies-literature
Project description:Senescent cells increase in many tissues with age and induce age-related pathologies, including osteoarthritis (OA). Senescent chondrocytes (SnCs) are found in OA cartilage, and the clearance of those chondrocytes prevents OA progression. However, targeting SnCs is challenging due to the absence of a senescent chondrocyte-specific marker. Therefore, we used flow cytometry to screen and select senescent chondrocyte surface markers and cross-validated with published transcriptomic data. Chondrocytes expressing dipeptidyl peptidase-4 (DPP-4), the selected senescent chondrocyte-specific marker, had multiple senescence phenotypes, such as increased senescence-associated-galactosidase, p16, p21, and senescence-associated secretory phenotype expression, and showed OA chondrocyte phenotypes. To examine the effects of DPP-4 inhibition on DPP-4+ SnCs, sitagliptin, a DPP-4 inhibitor, was treated in vitro. As a result, DPP-4 inhibition selectively eliminates DPP-4+ SnCs without affecting DPP-4- chondrocytes. To assess in vivo therapeutic efficacy of targeting DPP-4+ SnCs, three known senolytics (ABT263, 17DMAG, and metformin) and sitagliptin were comparatively verified in a DMM-induced rat OA model. Sitagliptin treatment specifically and effectively eliminated DPP-4+ SnCs, compared to the other three senolytics. Furthermore, Intra-articular sitagliptin injection to the rat OA model increased collagen type II and proteoglycan expression and physical functions and decreased cartilage destruction, subchondral bone plate thickness and MMP13 expression, leading to the amelioration of OA phenotypes. Collectively, OARSI score was lowest in the sitagliptin treatment group. Taken together, we verified DPP-4 as a surface marker for SnCs and suggested that the selective targeting of DPP-4+ chondrocytes could be a promising strategy to prevent OA progression.
| S-EPMC11258469 | biostudies-literature
Project description:ObjectiveVasculoprotective endothelial progenitor cells (EPCs) are regulated by stromal-derived factor-1alpha (SDF-1alpha) and are reduced in type 2 diabetes. Because SDF-1alpha is a substrate of dipeptidyl-peptidase-4 (DPP-4), we investigated whether the DPP-4 inhibitor sitagliptin modulates EPC levels in type 2 diabetic patients.Research design and methodsThis was a controlled, nonrandomized clinical trial comparing 4-week sitagliptin (n = 16) versus no additional treatment (n = 16) in addition to metformin and/or secretagogues in type 2 diabetic patients. We determined circulating EPC levels and plasma concentrations of SDF-1alpha, monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and nitrites/nitrates.ResultsThere was no difference in clinical baseline data between the sitagliptin and control arms. After 4 weeks, as compared with control subjects, patients receiving sitagliptin showed a significant increase in EPCs and SDF-1alpha and a decrease in MCP-1.ConclusionsSitagliptin increases circulating EPCs in type 2 diabetic patients with concomitant upregulation of SDF-1alpha. This ancillary effect of DPP-4 inhibition might have potential favorable cardiovascular implications.
| S-EPMC2890368 | biostudies-literature
Project description:Dipeptidyl peptidase 4 (DPP-4) is a novel adipokine and may be involved in the association between adipose tissue and metabolic syndrome. We investigated DPP-4 and adiponectin levels in the serum, subcutaneous adipose tissue (SAT), and epicardial adipose tissue (EAT), and their relationship with preoperative factors, as well as comparing the DPP-4 levels in SAT and EAT with and without DPP-4 inhibitors. This study included 40 patients (25 men, age 67.5 ± 13.8 years). The serum adipokine, DPP-4, and adiponectin levels in SAT and EAT were measured using ELISA and Western blotting. The DPP-4 and adiponectin levels were significantly higher in the SAT than in the EAT. The serum DPP-4 and DPP-4 activity levels had no correlation with the DPP-4 levels in the SAT and EAT, but the DPP-4 levels in the SAT and EAT had a positive correlation. The DPP-4 levels in the SAT were positively correlated with atherosclerosis, diabetes mellitus, DPP-4-inhibitor use, and fasting blood glucose. The DPP-4 levels in the EAT showed a negative correlation with eGFR and a positive correlation with atrial fibrillation. The DPP-4 activity in the serum had a lower tendency in the group taking DPP-4 inhibitors than in the group not taking them. DPP-4 inhibitors may suppress angiogenesis and adipose-tissue hypertrophy.
| S-EPMC9331841 | biostudies-literature
Project description:The management of patients with type 2 diabetes mellitus (T2DM) is shifting from cardio-centric to weight-centric or, even better, adipose-centric treatments. Considering the downsides of multidrug therapies and the relevance of dipeptidyl peptidase IV (DPP IV) and carbonic anhydrases (CAs II and V) in T2DM and in the weight loss, we report a new class of multitarget ligands targeting the mentioned enzymes. We started from the known α1-AR inhibitor WB-4101, which was progressively modified through a tailored morphing strategy to optimize the potency of DPP IV and CAs while losing the adrenergic activity. The obtained compound 12 shows a satisfactory DPP IV inhibition with a good selectivity CA profile (DPP IV IC50: 0.0490 μM; CA II Ki 0.2615 μM; CA VA Ki 0.0941 μM; CA VB Ki 0.0428 μM). Furthermore, its DPP IV inhibitory activity in Caco-2 and its acceptable pre-ADME/Tox profile indicate it as a lead compound in this novel class of multitarget ligands.
| S-EPMC9937538 | biostudies-literature