Dipeptidyl peptidases in atherosclerosis: expression and role in macrophage differentiation, activation and apoptosis.

Atherosclerosis is a chronic inflammatory disorder of the arterial wall leading to coronary artery disease, stroke, and peripheral arterial disease. Along with the discovery of dipeptidyl peptidase 4 (DPP4) as a therapeutic target in type 2 diabetes, a role for DPP4 in atherosclerosis is emerging. However, until now the expression and role of other DPPs such as DPP8 and DPP9 in atherosclerosis is completely unknown.

Method comparison of dipeptidyl peptidase IV activity assays and their application in biological samples containing reversible inhibitors.

Background: Dipeptidyl peptidase IV (DPPIV, DPP4) is a serine protease that releases N-terminal dipeptides. It is a validated drug target for type 2 diabetes and DPPIV inhibitors are currently evaluated for other therapeutic applications. Various assays are used for DPPIV activity measurements in biological samples.

Dipeptidyl peptidase IV inhibition improves cardiorenal function in overpacing-induced heart failure.

Aims: Recent studies indicate that brain natriuretic peptide (BNP(1-32)) may be truncated into BNP(3-32) by dipeptidyl peptidase IV (DPP4) and that BNP(3-32) has reduced biological activities compared with BNP(1-32). We investigated if DPP4 contributes to the cardiorenal alterations and to the attenuated response to BNP seen in heart failure.

Methods And Results: Haemodynamic and renal assessment was performed in 12 pigs at baseline, 4 weeks after pacing-induced heart failure, and during BNP infusion.

Expression and spatial heterogeneity of dipeptidyl peptidases in endothelial cells of conduct vessels and capillaries.

Dipeptidyl peptidase IV (DPPIV)/CD26 is by far the most extensively studied member of the prolyl oligopeptidase family of serine proteases. The discovery of the related enzymes DPP8 and DPP9 necessitates a (re-)evaluation of the DPPIV-like enzymatic activity in cells and organs. In this study, we aimed (1) to investigate the expression of the individual dipeptidyl peptidases in different types of endothelial cells (ECs) and (2) to reconsider published data in relation to our findings.

The role of tryptophan catabolism along the kynurenine pathway in acute ischemic stroke.

Post-stroke inflammation may induce upregulation of the kynurenine (KYN) pathway for tryptophan (TRP) oxidation, resulting in neuroprotective (kynurenic acid, KA) and neurotoxic metabolites (3-hydroxyanthranillic acid, 3-HAA). We investigated whether activity of the kynurenine pathway in acute ischemic stroke is related to initial stroke severity, long-term stroke outcome and the ischemia-induced inflammatory response. Plasma concentrations of TRP and its metabolites were measured in 149 stroke patients at admission, at 24 h, at 72 h and at day 7 after stroke onset.

Dipeptidyl peptidase 9 (DPP9) from bovine testes: identification and characterization as the short form by mass spectrometry.

The dipeptidyl peptidases (DPP) 8 and 9 belong to the DPP4 activity and/or structure homologues (DASH). Recently, a DPP9-like protein was purified from bovine testes. The aim of the present study was to prove its identity and to investigate the characteristics of this natural enzyme.

Inhibition of CD26/DPP IV attenuates ischemia/reperfusion injury in orthotopic mouse lung transplants: the pivotal role of vasoactive intestinal peptide.

The T cell activation Ag CD26/dipeptidylpeptidase IV (DPP IV) combines co-stimulatory and enzymatic properties. Catalytically, it functions as an exopeptidase, modulating biological activity of key chemokines and peptides. Here we investigated the effect of organ-specific inhibition of DPP IV catalytic activity on ischemia/reperfusion injury after extended ischemia in the mouse model of orthotopic single lung transplantation.

The effect of organ-specific CD26/DPP IV enzymatic activity inhibitor-preconditioning on acute pulmonary allograft rejection.

Background: Systemic inhibition of serum CD26/dipeptidylpeptidase (DPP IV) enzymatic activity abrogated acute rejection of pulmonary allografts, whereas organ-specific inhibition ameliorated ischemia/reperfusion injury in syngeneic transplants. Here, we analyze the effect of allograft-specific inhibitor preconditioning on acute rejection in the presence of cyclosporine-based immunosuppressive therapy.

Methods: Orthotopic left single lung transplantation (Tx) in rats (LBNF1 to LEWIS).

Cytokine changes and tryptophan metabolites in medication-naïve and medication-free schizophrenic patients.

Cytokine imbalances especially between T helper type (Th) 1 and Th2 and tryptophan breakdown were reported to be involved in the pathophysiology of schizophrenia. The hyperactive inflammatory response system could induce enhanced tryptophan breakdown. This study aimed to investigate the relationship between cytokine changes, tryptophan breakdown parameter changes and clinical parameters in patients with schizophrenia in comparison with normal controls.

Primary graft dysfunction in lung transplantation: the role of CD26/dipeptidylpeptidase IV and vasoactive intestinal peptide.

Background: Enzymatic activity inhibition of CD26/dipeptidylpeptidase IV (CD26/DPP IV) attenuated short-term post-Tx (transplantation) ischemia-reperfusion injury after 18-hr-ischemia. Here, we investigated the effect of intragraft CD26/DPP IV catalytic inhibition on primary graft dysfunction during 7 day post-Tx, following extended ischemia.

Methods: A syngeneic rat (LEW [Lewis abstract]) orthotopic lung Tx model was used, grafts exposed to 18 hr cold ischemia before Tx.

Dipeptidyl-peptidase IV and B-type natriuretic peptide. From bench to bedside.

B-type natriuretic peptide (BNP) has emerged as a reliable biomarker in patients with congestive heart failure. The mature, biologically active B-type natriuretic peptide, BNP(1-32), is cleaved by corin from the 108 amino acid proBNP. However, in vivo as well as in vitro data demonstrated that this BNP(1-32) might be an ideal substrate for the endogenous aminopeptidase, dipeptidyl-peptidase IV (DPP IV).

Enzyme activity and immunohistochemical localization of dipeptidyl peptidase 8 and 9 in male reproductive tissues.

The mRNA expression pattern of dipeptidyl peptidase (DPP) 8 and DPP9, two DPP4 homologs, was studied previously and showed a broad tissue distribution. In this study, protein expression and activity of DPP8 and DPP9 were investigated in male reproductive tissues of different mammals. Based on specific DPP activities and inhibition profiles, the proline-selective DPP activity in the bovine and rat testis could predominantly be attributed to DPP8/9 and not to DPP4.

Neurotoxic and neuroprotective metabolites of kynurenine in patients with renal cell carcinoma treated with interferon-alpha: course and relationship with psychiatric status.

Aims: Immunotherapy with interferon-alpha (IFN-alpha) is associated with psychiatric side-effects, including depression. One of the putative pathways underlying these psychiatric side-effects involves tryptophan (TRP) metabolism. Cytokines including IFN-alpha induce the enzyme indoleamine 2,3-dioxygenase (IDO), which converts TRP to kynurenine (KYN), leading to a shortage of serotonin (5-HT).

In vivo profiling of DPP4 inhibitors reveals alterations in collagen metabolism and accumulation of an amyloid peptide in rat plasma.

Dipeptidyl peptidase 4 (DPP4) inhibitors represent a novel class of oral anti-hyperglycemic agents. The complete pharmacological profile of these protease inhibitors remains unclear. In order to gain deeper insight into the in vivo effects caused by DPP4 inhibition, two different DPP4 inhibitors (vildagliptin and AB192) were analyzed using differential peptide display.

DPP4 inhibitors for diabetes--what next?

With vildagliptin and sitagliptin on the market for the treatment of type 2 diabetes, dipeptidyl peptidase 4 (DPP4, EC 3.4.14.

Faulty serotonin--DHEA interactions in autism: results of the 5-hydroxytryptophan challenge test.

Background: Autism is accompanied by peripheral and central disorders in the metabolism of serotonin (5-HT). The present study examines plasma dehydroepiandrosterone-sulphate (DHEA-S) and the cortisol/DHEA-S ratio following administration of L-5-hydroxytryptophan (5-HTP), the direct precursor of 5-HT, to autistic patients.

Methods: Plasma DHEA-S levels were determined both before and after administration of 5-HTP or placebo, on two consecutive days in a single blind order in 18 male autistic patients and 22 matched healthy controls.

Prolyl oligopeptidase stimulates the aggregation of alpha-synuclein.

Despite its thorough enzymological and biochemical characterization the exact function of prolyl oligopeptidase (PO, E.C. 3.

Inhibitors of dipeptidyl peptidase 8 and dipeptidyl peptidase 9. Part 1: identification of dipeptide derived leads.

Dipeptide derivatives bearing various P2 residues and pyrrolidine derivatives as P1 mimics were evaluated in order to identify lead structures for the development of DPP8 and DPP9 inhibitors. Structure-activity-relationship data obtained in this way led to the preparation of a series of alpha-aminoacyl ((2S, 4S)-4-azido-2-cyanopyrrolidines). These compounds were shown to be nanomolar DPP8/9 inhibitors with modest overall selectivity toward DPP IV and DPP II.

Inhibitors of dipeptidyl peptidase 8 and dipeptidyl peptidase 9. Part 2: isoindoline containing inhibitors.

To obtain selective and potent inhibitors of dipeptidyl peptidases 8 and 9, we synthesized a series of substituted isoindolines as modified analogs of allo-Ile-isoindoline, the reference DPP8/9 inhibitor. The influence of phenyl substituents and different P2 residues on the inhibitors' affinity toward other DPPs and more specifically, their potential to discriminate between DPP8 and DPP9 will be discussed. Within this series compound 8j was shown to be a potent and selective inhibitor of DPP8/9 with low activity toward DPP II.

Purification and characterization of dipeptidyl peptidase IV-like enzymes from bovine testes.

Until now, only recombinant forms of dipeptidyl peptidase (DPP) 8 and 9 have been characterized. We purified non DPPII-non DPPIV enzymes from a natural source. A first DPP8/9-like enzyme was enriched 1160-fold from bovine testes and identified as 'DPP9-like enzyme' by using an anti-DPP9 antibody.

Irreversible inhibition of dipeptidyl peptidase 8 by dipeptide-derived diaryl phosphonates.

Dipeptide-derived compounds, bearing various P2 residues and a diaryl pyrrolidin-2-yl phosphonate at the P1 position, were evaluated as dipeptidyl peptidase 8 (DPP8) inhibitors. With these products, irreversible inhibition of DPP8 was observed. To obtain inhibitors with an improved activity and selectivity profile, a set of selected analogues containing a diaryl isoindolin-1-ylphosphonate at P1 was synthesized and evaluated.

Central serotonergic hypofunction in autism: results of the 5-hydroxy-tryptophan challenge test.

Some studies have suggested that disorders in the central serotonergic function may play a role in the pathophysiology of autistic disorder. In order to assess the central serotonergic turnover in autism, this study examines the cortisol and prolactin responses to administration of L-5-hydroxy-tryptophan (5-HTP), the direct precursor of 5-HT in 18 male, post-pubertal, Caucasian autistic patients (age 13-19 y.; I.

Dipeptidyl peptidase II (DPPII), a review.

An increasing number of biological processes appear to be regulated by Pro-specific N-terminal processing. The proline-specific dipeptidyl peptidases (DPPs) like DPPIV, fibroblast activation protein alpha (FAP), DPPII, DPP8 and DPP9, because of their preference for cleavage after X-Pro in vitro, are likely to be involved in many of these processes. These DPPs are emerging as an important protease family with roles in the regulation of signaling by peptide hormones.