Wound healing process and dipeptidyl peptidase IV

Cijeljenje rane dinamičan je proces koji se odvija u više međuovisnih faza koje uključuju reguliranu interakciju među različitim vrstama stanica, izvanstaničnog matriksa, proteaza i njihovih supstrata. Rastući znanstveni dokazi naglašavaju važnost proteaza u regulaciji ključnih procesa cijeljenja rane. Dipeptidil-peptidaza IV (DPP IV/CD26, EC 3.4.14.5), glavni je član obitelji DPP IV proteina. Riječ je o ubikvitarnom multifunkcionalnom transmembranskom glikoproteinu koji je prisutan i u topljivom obliku, a djeluje kao proteolitička i kostimulacijska molekula te vezni protein. Izražena je na površini različitih vrsta stanica, uključujući epitelne, endotelne stanice i limfocite. Pokazano je da ima značajnu ulogu u različitim fiziološkim i patološkim procesima. DPP IV/CD26 je u velikoj mjeri istraživana zbog svoje sposobnosti održavanja homeostaze glukoze. Štoviše, budući na utvrđene pozitivne učinke inhibicije DPP IV/CD26 u cijeljenju kroničnih dijabetičkih ulkusa, kao i uključenosti u drugim patološkim procesima, ova je molekula od rastućeg znanstvenog interesa u cilju razjašnjavanja mehanizama njezinog djelovanja. Poznato je da DPP IV/CD26 sudjeluje u regulaciji stanične adhezije, migracije i apoptoze stanica kao i angiogenezi te razgradnji ekstracelularnog matriksa, ključnim procesima u cijeljenju rana. Prethodne studije pokazale su da DPP IV/CD26 ima posebno važnu ulogu u regeneraciji kože, gdje je utvrđeno da može posredovati upalne procese i utjecati na epitelizaciju ranjenog tkiva. Stoga je cilj ovog preglednog rada sažeti ključna otkrića u procesima cijeljenja rana te prikazati nove spoznaje o ulozi DPP IV/CD26 u procesima regeneracije tkiva.Wound healing is a dynamic process occurring in multiple interdependent stages that include a regulated interaction between different cell types, extracellular matrix, proteases and their substrates. Increasing scientific evidence emphasizes the importance of proteases playing crucial roles in the regulation of processes of wound healing. Dipeptidyl peptidase IV (DPP IV/CD26, EC 3.4.14.5), the main member of the DPP IV family of proteins, is a ubiquitous multifunctional transmembrane as well as soluble glycoprotein, acting as a proteolytic and costimulation molecule, and binding protein. It is expressed on the surface different cell types, including epithelial, endothelial cells and lymphocytes. It has been shown to play a significant role in different physiological as well as pathological processes. DPP IV/ CD26 was largely investigated given its ability to maintain glucose homeostasis. Moreover, since positive effects of DPP IV/CD26 inhibition in healing of chronic diabetic foot ulcers as well as other pathologies have been shown, growing efforts are made in order to elucidate its mechanisms of action. It is known that DPP IV/CD26 is involved in the regulation of cell adhesion, migration, apoptosis, angiogenesis and extracellular matrix degradation, which are all key processes in wound healing. Previous studies indicated that DPP IV/CD26 plays a particularly relevant role in skin regeneration where it was found to mediate inflammatory processes and influence epithelialization of wounds. Therefore, the aim of this review was to summarize crucial findings regarding wound healing as well as new insights about the involvement of DPP IV/CD26 in tissue regeneration

Relevance of DPP IV/CD26 among the Gut-brain Axis during Experimental Colitis

Inflammatory bowel diseases (IBD) represent a group of chronic conditions of the gastrointestinal tract of unknown etiology. Latest knowledge accentuates the bidirectional connection between the central and enteric nervous systems. An important role of peptidases has been proposed in maintaining the homeostasis in the gut. One of them is dipeptidil-peptidase IV (DPP IV/CD26), a multifunctional glycoprotein found in both soluble and membrane-bound form in living organisms. In order to evaluate the relevance of DPP IV/CD26 among the gut-brain axis, a TNBS (Crohn-like) model of colitis has been induced in CD26 deficient and wild type mice. Results of this study showed that CD26 deficient mice show specificity in histological damage compared to wild type mice. A decreased DPP IV/CD26 activity was found in serum, colon and brain in wild type mice with colitis, while CD26 protein expression was increased in colon of those mice. DPP IV/CD26-like activity was decreased only in colon of CD26 deficient mice. Changes occurring during inflammatory processes in colon reflected on investigated parameters in brain. Therefore, our results indicate the importance of the gut-brain axis in the pathogenesis of IBD. (doi: 10.5562/cca1813

Diabetes, Dipeptidyl Peptidase iv and Wound Healing: from Basic Science to Therapeutic Possibilities

Hyperglycemia, often accompanied with various complications such as chronic ulcers, represents a major socio-economic health problem. Dipeptidyl peptidase IV or CD26 molecule (DPP IV/CD26), is an omnipresent transmembrane protein with significant involvements in different physiological and pathological processes. It has been recognized as a therapeutic option in the treatment of hyperglycemia, especially in patients suffering from type 2 diabetes, given its capability to regulate the biological activity of incretins, which are major regulators of glucose homeostasis. Furthermore, DPP IV/CD26 has been indicated to be involved in the regulation of inflammatory processes as well as cell proliferation and angiogenesis. New scientific evidence shows that inhibition of DPP IV/CD26 leads to a more efficacious healing of chronic ulcers in diabetic patients as well as in mice models of wounded tissue restoration. However, the role of DPP IV/CD26 in the process of wound healing in hyperglycemia is not entirely known. Our aim was to summarize most important findings on the involvement of DPP IV/CD26 in the regulation of glycemia as well as tissue regeneration and reparation. This work reviews basic biochemical

Wound Healing Process, Diabetes and Implications of Dipeptidyl Peptidase IV (DPP IV/CD26

Dipeptidyl Peptidase IV or molecule CD26 (DPP IV/CD26) is a multifunctional protein, identified as a therapeutic target for type 2 diabetes, due to its ability to degrade incretins, insulin secretagogues. Delayed wound healing is a significant complication in diabetic patients that represents a major socio-economic health problem. It has been proposed that DPP IV/CD26 inhibition accelerates healing of chronic diabetic ulcers in those patients, through the induction of a histological pattern consistent with enhanced angiogenesis. Studies on mice models of diabetesdisturbed wound healing also suggested that the inhibition of DPP IV enzymatic activity may improve tissue regeneration processes. However, further research is needed to elucidate the role of DPP IV/CD26 in diabetic wound healing. The objective of this work was to discuss recent findings on the implications of DPP IV/CD26 in tissue regeneration and reparation in diabetic environmen

Is Dipeptidyl Peptidase IV (DPP IV) Associated with Inflammation Present in Human Spondyloarthritides and Rheumatoid Arthritis?

Dipeptidyl peptidase IV (DPP IV) is a serine peptidase which has been suggested to play a role in the pathogenesis of rheumatoid arthritis, but its mediator actions have not been well investigated in patients with spondyloarthritides. The purpose of this study was to investigate clinical relevance of changes in serum DPP IV activity and concentration in these diseases. Serum DPP IV activity was significantly decreased in patients with spondyloarthritides and rheumatoid arthritis compared to the control group, while DPP IV concentration was increased. Among spondyloarthritides patients, DPP IV concentration was decreased in patients with reactive arthritis. No difference was observed in DPP IV activity or concentration between spondyloarthritides and rheumatoid arthritis, as well as between patients with clinically active disease and those in remission. Our results suggest that DPP IV could not be used as a specific serum marker, but could be potentially used as a non-specific inflammatory marker. (doi: 10.5562/cca1863

Involvement of DPP IV/CD26 in cutaneous wound healing process in mice

Dipeptidyl peptidase IV (DPP IV/CD26) is a widely distributed multifunctional protein that plays a significant role in different physiological as well as pathological processes having a broad spectrum of bioactive substrates and immunomodulative properties. It has potential influence on different processes crucial for wound healing, including cell adhesion, migration, apoptosis and extracellular matrix degradation. However, despite its known enzymatic and immunomodulative functions, limited data characterize the role of DPP IV/CD26 in cutaneous wound healing mechanisms. The aim of this study was to investigate the process of wound healing in conditions of CD26 deficiency in order to obtain better insights on the role of DPP IV/CD26 in cutaneous regeneration. Experimental wounds were made on the dorsal part of CD26 deficient (CD26-/-) and wild-type mice (C57BL/6). The process of cutaneous wound healing was monitored on defined time-schedule post wounding by macroscopic, microscopic, and biochemical analyses. Obtained results revealed a better rate of wound closure, revascularization and cell proliferation in CD26-/- mice, with enhanced local expression of hypoxia-inducible factor 1α and vascular endothelial growth factor. CD26 deficiency induced prompt macrophage recruitment at the site of skin damage but did not influence mobilization of T-cells in comparison to wild- type mice. CD26-/- mice have significantly higher values of IP-10 in serum and control skins compared to wild-type mice but values in wounds did not differ significantly on days 2, 4 and 7 of wound healing. DPP IV/CD26 activity was found to be decreased 4 days post-wounding in serum and 2, 4 and 7 days post-wounding in wounds of wild-type animals compared to control skins. These findings contribute to better understanding of wound healing mechanisms and could give a support in finding new therapeutic approaches for wound healing and tissue regeneration

Chlorogenic acid ameliorates experimental colitis in mice by suppressing signaling pathways involved in inflammatory response and apoptosis

Chlorogenic acid (ChA) exhibits a multitude of positive health effects, however, the signaling mechanisms by which ChA could influence the inflammatory response in experimental colitis are unknown. To answer this question, we induced colitis in mice by administration of 2.5% dextran sulfate sodium (DSS) in drinking water for seven days. Oral administration of ChA significantly ameliorated clinical symptoms, improved disease activity index and colon shortening induced by DSS. Furthermore, ChA administration resulted in a suppression of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinases 1 and 2 (JNK1/2), Akt and signal transducer and activator of transcription 3 (STAT3) with concomitant upregulation of phosphatase and tensin homolog (PTEN) expression. Immunohistochemical analysis showed a dose- dependent decrease in expression and nuclear translocation of nuclear factor-kappa B (NF-κB) p65 subunit, which was accompanied by suppression of pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) expression. Induction of apoptosis and oxidative stress was attenuated in a dose-dependent manner by suppressing Bax, caspase- 8, caspase-9 and heme oxygenase-1 (HO-1) protein expression in mice administrated with ChA. The results of the current study suggest that ChA could be useful for the treatment of inflammation and attenuating colitis severity by suppressing activation of pro-inflammatory and apoptotic signaling pathways

Chlorogenic acid ameliorates experimental colitis in mice by suppressing signaling pathways involved in inflammatory response and apoptosis

Chlorogenic acid (ChA) exhibits a multitude of positive health effects, however, the signaling mechanisms by which ChA could influence the inflammatory response in experimental colitis are unknown. To answer this question, we induced colitis in mice by administration of 2.5% dextran sulfate sodium (DSS) in drinking water for seven days. Oral administration of ChA significantly ameliorated clinical symptoms, improved disease activity index and colon shortening induced by DSS. Furthermore, ChA administration resulted in a suppression of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinases 1 and 2 (JNK1/2), Akt and signal transducer and activator of transcription 3 (STAT3) with concomitant upregulation of phosphatase and tensin homolog (PTEN) expression. Immunohistochemical analysis showed a dose- dependent decrease in expression and nuclear translocation of nuclear factor-kappa B (NF-κB) p65 subunit, which was accompanied by suppression of pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) expression. Induction of apoptosis and oxidative stress was attenuated in a dose-dependent manner by suppressing Bax, caspase- 8, caspase-9 and heme oxygenase-1 (HO-1) protein expression in mice administrated with ChA. The results of the current study suggest that ChA could be useful for the treatment of inflammation and attenuating colitis severity by suppressing activation of pro-inflammatory and apoptotic signaling pathways

Influence of CD26/dipeptidyl peptidase IV deficiency on immunophenotypic changes during colitis development and resolution.

A lot of evidence for the importance of CD26/dipeptidyl peptidase IV (CD26/DPP IV) in immunoactivation has been reported ; however, its involvement in colitis remains unclear. The aim of this study was to investigate the influence of CD26/DPP IV deficiency on immunophenotypic changes associated with dextran sulfate sodium (DSS)-induced colitis in wild- type (WT) and CD26-deficient mice. Development of clinical symptoms of colitis and animal health status parameters were assessed ; the expression of the nuclear factor (NF)-κB p65 subunit was measured by quantitative real-time PCR, while cell characterization was determined by flow cytometry and immunohistochemical staining. DSS treatment induced loss of body weight and colon length shortening in both mouse strains. An increase of myeloperoxidase activity in CD26-deficient mice was more intensive than in WT mice, in spite of similar histopathological changes. Furthermore, a significant increase in the expression of NF-κB p65 subunit in the colon of CD26-deficient mice was determined. The percentage of splenic CD4+ and CD8+ cells in the acute phase of colitis was significantly decreased in WT mice, while in the same period, an increase in the percentage of splenic CD8+ cells was present in CD26-deficient mice. Development of colitis was accompanied by a significant increase in the percentage of intrahepatic NKT cells in both mouse strains, but their percentage in spleen was increased only in CD26-deficient mice. CD26 deficiency was associated with a heightened response to DSS accompanied by increased expression of NF-κB p65 subunit and distinct changes in leukocyte trafficking. These results provide new insights into the role of CD26/DPP IV during the development of colitis