Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of N-[(R,S)-2-benzyl-3[(S)-(2-amino-4-methylthio)butyldithiol]-1-oxopropyl]-L-phenylalanine benzyl ester (RB101), a dual inhibitor of the enkephalin-degrading enzymes, neutral endopeptidase and aminopeptidase N, was assessed in anaesthetised rats on the C-fibre reflex elicited by electrical stimulation within the sural nerve territory and recorded from the ipsilateral biceps femoris muscle. The temporal evolution of the pharmacological response was monitored by the repeated application of a constant stimulus intensity, namely three times threshold (3 T). In addition, recruitment curves were built by varying the stimulus intensity from 0 to 7 T. RB101 (7.5, 15 and 30 mg kg(-1), i.v.) induced a dose-dependent, naloxone-reversible depression of the reflex, which lasted around 60 min with the highest dose. The ED(50) was calculated as 16.9 mg kg(-1). Analyses of the recruitment curves revealed: (1) a significant increase of threshold; (2) a significant depression of the reflex in the ascending part of the curve; and (3) a lack of major depressive effects on the responses elicited by the strongest stimuli (corresponding to the plateau of the curve). The increase in the nociceptive threshold by enkephalin-degrading enzyme inhibitors, confirms previous data obtained from behavioural tests. In addition, the present study revealed an efficacy of these compounds over a wide range of stimulus intensities, albeit excluding the highest.
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PMID:Depressant effect on a C-fibre reflex in the rat, of RB101, a dual inhibitor of enkephalin-degrading enzymes. 1207 85

Cell surface aminopeptidases play an important role in biological processes through degradation of small peptides. There are many bioactive peptides in ascites and these peptides are involved in carcinoma cell dissemination and infiltration. In human mesothelial cells dipeptidyl peptidase IV (DPPIV) shows the highest expression mostly in four cell surface aminopeptidases: aminopeptidase A, neutral endopeptidase 24-11, aminopeptidase N and DPPIV. Since mesothelial cells are always in contact with ascites, we examined the influence of malignant ascites on DPPIV. DPPIV enzyme activity in mesothelial cells was enhanced by the addition of ascites obtained from ovarian carcinoma patients in a time- and concentration-dependent manner, and flow cytometry and immunocytochemistry also revealed an increased expression of DPPIV on the cell surface of mesothelial cells. The <3-kD fraction of malignant ascites increased the DPPIV enzyme activity to the same level as the total ascites. Northern hybridization demonstrated that DPPIV mRNA was increased 3-fold by the addition of the <3-kD malignant ascites. In conclusion, DPPIV is highly expressed in human mesothelial cells and was regulated by ascites.
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PMID:Increased expression of dipeptidyl peptidase IV in human mesothelial cells by malignant ascites from ovarian carcinoma patients. 1223 51

Adrenal gland as a major source of enkephalins on the periphery can be affected by a rare adrenal gland tumor, adrenal pheochromocytoma. It has been demonstrated that this tumor might be associated with altered concentration of enkephalin-like peptides. The effect of these peptides can be either prolonged or abbreviated by two neutrophil membrane bound enzymes; aminopeptidase N (APN) and neutral endopeptidase (NEP). We assumed that altered enkephalin level in pheochromocytoma patients (but not in patients with non-functional adenomas or tumors of different origin) might result in differently regulated APN and/or NEP activity. We measured APN and NEP activity on surface of neutrophils, level of lipid peroxidation (LPO) in plasma and enkephalin concentration in plasma in patients with pheochromocytomas, non-functional adenomas, malignant renal tumors and healthy controls. Catheholamines and vanyllmandelic acid (VMA) were measured in 24-h urine of pheochromocytoma patients. NEP and APN activity on neutrophils from all pheochromocytoma patients was significantly increased as compared with healthy controls, non-functional adenomas and malignant renal tumors. In all pheochromocytoma patients NEP activity was reduced almost to the control level after surgery. At the same time APN activity was in some patients up- and in others down-regulated. In comparison, elevated levels of cateholamines and VMA were found after multiple determinations in 6 out of 10 pheochromocytoma patients. Although preliminary, this study has shown specifically and consistently up-regulated NEP activity on neutrophils from pheochromocytoma patients, and uniformly decreased NEP activity in these patients after adrenalectomy.
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PMID:Enkephalin degradating enzymes in pheochromocytoma patients. 1246 78

Using purified enzyme preparations, we investigated the actions of angiotensin-converting enzyme, aminopeptidase N, and endopeptidase 24.11 on corticotropin-releasing factor (CRF). The effects of inhibition of these enzymes on CRF action in rat anterior pituitary cultures were also determined. Finally, specific inhibitors were used to evaluate ectopeptidase action on the regional brain metabolism of CRF. K(m) values for CRF were 165, 90, and 42 microM for angiotensin-converting enzyme, aminopeptidase N, and endopeptidase 24.11, respectively. A CRF metabolite profile for each enzyme was determined. In pituitary cultures, inhibition of endopeptidase 24.11 and aminopeptidase N potentiated CRF-stimulated release of adrenocorticotropic hormone (ACTH). In rat pituitary and hypothalamus membrane preparations, specific inhibitor experiments indicated that CRF hydrolysis involved members of the neutral endopeptidase and aminopeptidase enzyme families. In cortex membranes, similar peptidase inhibition was without effect. These data support the hypothesis that ectopeptidases play a major role in CRF metabolism and biological function.
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PMID:Action of three ectopeptidases on corticotropin-releasing factor: metabolism and functional aspects. 1249 37

The discovery that the endogenous morphine-like peptides named enkephalins are inactivated by two metallopeptidases, neutral endopeptidase and aminopeptidase N, which can be blocked by dual inhibitors, represents a promising way to develop 'physiological' analgesics devoid of the side effects of morphine. A new series of dual aminophosphinic inhibitors of the two enkephalin-catabolizing enzymes has been recently designed. In this study, one of these inhibitors, RB3007, was tested in various assays commonly used to select analgesics (mouse hot-plate test, rat tail-flick test, writhing and formalin tests in mice, and paw pressure test in rats), and the extracellular levels of the endogenous enkephalins in the ventrolateral periaqueductal grey have been measured by microdialysis after systemic administration of RB3007. In the mouse hot-plate test, the dual inhibitor induced long-lasting (2 h) antinociceptive effects with a maximum of 35% analgesia 60 min after i.v. or i.p. administration. These antinociceptive responses were antagonized by prior injection of naloxone (0.1 mg/kg, s.c.). Similar long lasting effects were observed in the other animal models used. Very interestingly, injection of RB3007 (50 mg/kg, i.p.) significantly increased (82%) the extracellular levels of Met-enkephalin with a peak 60 min after i.p. injection. This increase parallels the antinociceptive responses observed. In addition, strong facilitatory effects of subanalgesic doses of the CCK(2) receptor antagonist, PD-134,308 or the synthetic opioid agonist, methadone on RB3007-induced antinociceptive responses were observed. These findings may constitute promising data for future development of a new class of analgesics that could be of major interest in a number of severe and persistent pain syndromes.
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PMID:Pain management by a new series of dual inhibitors of enkephalin degrading enzymes: long lasting antinociceptive properties and potentiation by CCK2 antagonist or methadone. 1285 23

The cell surface aminopeptidase N (APN/CD13), overexpressed in tumor cells, plays a critical role in angiogenesis. However, potent, selective, and, particularly, noncytotoxic inhibitors ot this protein are lacking, and the present work was undertaken with the aim of developing a new generation of noncytotoxic inhibitors that bind to APN/CD13. In this context, we have synthesized a series of novel flavone-8-acetic acid derivatives. Among the herein described and evaluated compounds, the 2',3-dinitroflavone-8-acetic acid (19b) proved to be the most efficient and exhibited an IC(50) of 25 microM which is 2.5 times higher than that of bestatin (1), the natural known inhibitor of APN/CD13. However, in contrast to bestatin (1), the dinitroflavone 19b did not induce any cytotoxicity to cultured human model cells. The presence of other substituents such as NO(2) or OCH(3) groups at the 3'- or 4'-position of the B phenyl group, or the existence of steric constraints (compounds 24 and 29), did not improve selectivity and potency. The flavone 19b affinity for APN/CD13 is not recovered with other proteases such as matrix metalloproteinase-9 (MMP-9), angiotensin converting enzyme (ACE/CD143), neutral endopeptidase (NEP/CD10), gamma-glutamyl transpeptidase (CD224), or the serine proteases dipeptidyl peptidase IV (DPPIV/CD26) or cathepsin G.
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PMID:Synthesis and biological evaluation of novel flavone-8-acetic acid derivatives as reversible inhibitors of aminopeptidase N/CD13. 1293 Jan 51

Keratinocytes actively participate in immune response and inflammation by secreting cytokines and chemokines. Membrane-bound peptidases serve as negative loop in controlling concentration of peptide signalling molecules. Recently, they have also been proposed as additional mechanism of cell-to-cell interaction and as signalling molecules. In this study, we examined expression of two membrane-bound peptidases: aminopeptidase N (APN; EC 3.4.11.2; CD13) and neutral endopeptidase (NEP; EC 3.4.24.11; CD10) on nonstimulated cultured human keratinocytes obtained from healthy skin. Membrane expression of CD13 and CD10 was analysed by FACS and fluorescent microscope. Functional properties of CD13 and CD10 were examined by testing their enzymatic activity towards selective substrates. The data were compared to those obtained on cultured nonstimulated human skin fibroblasts expressing both CD13/APN and CD10/NEP. Approximately one-third (i.e. 31.7+/-2.8%; n=3) of cultured keratinocyte express CD13 as compared to fibroblasts which are 100% CD13(+) (n=3). Density of CD13 on keratinocytes is several times lower than on fibroblasts. Membrane CD13 expression on keratinocytes was associated with significant enzyme activity, which on the basis of substrate (L-Ala-betaNA) and inhibitor (bestatin, actinonin) selectivity could be ascribed to aminopeptidase N. Kinetic parameter V(max) revealed lower APN activity expressed on keratinocytes than on fibroblasts (V(max)=1.49+/-0.08 microM/60 min/5 x 10(4) cells for keratinocytes, n=3 versus V(max)=4.09+/-0.76 microM/60 min/5 x 10(4) cells for fibroblasts, n=3). Likewise, K(m) value of APN on keratinocytes was lower as compared to fibroblasts (K(m)=0.307+/-0.090 mM for keratinocytes, n=3 versus K(m)=0.766+/-0.065 mM for fibroblasts, n=3). CD13 demonstrated on cultured keratinocytes, is at least partly due to its constitutive expression since it was also found on freshly prepared epidermal skin cells. Inhibitors of APN, actinonin, bestatin and substance-P, as well as the APN blocking antibody WM-15, decreased keratinocytes growth. In contrast to membrane CD13 associated with APN enzyme activity, neither membrane CD10, nor its enzyme (NEP) activity could be found on the same keratinocyte samples. In conclusion, functional CD13, associated with APN activity, was found on about one third of cultured, non-stimulated keratinocytes, whereas no CD10/NEP was found on the same keratinocyte samples. Role of APN in regulation of keratinocyte growth is suggested, as its inhibition resulted in decreased keratinocyte growth.
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PMID:Expression of CD13/aminopeptidase N and CD10/neutral endopeptidase on cultured human keratinocytes. 1475 68

We investigated the expression pattern of neprilysin (CD10), aminopeptidase N (CD13) and angiotensin-I converting enzyme (CD143) in hepatocellular carcinomas (HCC), and their putative roles in hepatocarcinogenesis. Tissue samples were obtained from 31 patients with HCC. Tissue samples obtained from non-neoplastic liver, fetal livers and focal nodular hyperplasias (FNH) were used by comparison. Transcription and expression of CD10, CD13, and CD143 were studied by quantitative RT-PCR, Western blotting, and immunohistochemistry. Cell proliferation assays were performed with the C3A hepatoma cell line. The mRNA and protein of each of CD10, CD13 and CD143 were differentially expressed in HCCs. CD10 was decreased in HCCs as compared to non-neoplastic liver tissue, while CD13 and CD143 were mildly increased. In fetal liver and FNHs, the expression of CD10 was less intense than in the surrounding non-tumorous liver. The expression patterns of CD13 and CD143 in fetal livers and FNHs were similar to HCCs and were predominantly localized in bile canaliculi (CD13) and endothelial cells (CD143). CD10 and CD13 mRNAs were expressed by C3A cells and blocking either CD10 or CD13 ectopeptidase activity retarded cell growth significantly in vitro. We demonstrate that ectopeptidases are differentially expressed in HCCs and may have influence on tumor biology. Overall, expression of CD10 in non-neoplastic and neoplastic hepatocytes appears to correlate inversely with their state of proliferation or differentiation. CD13 shows a characteristic canalicular distribution pattern and may be important for cell polarization and bile compartmentalization in HCCs, while CD143 may influence angiogenesis.
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PMID:Ectopeptidases are differentially expressed in hepatocellular carcinomas. 1476 32

Opioid peptides have been reported to have important functions in human reproduction. Indeed, very high concentrations of enkephalins and their degrading enzymes have been reported in human semen. In the present paper, we compare the activity of two enkephalin-degrading enzymes, aminopeptidase N and neutral endopeptidase 24.11, in different fractions of semen from normozoospermic, fertile men and from subfertile patients with different abnormalities revealed by spermiogram analysis (asthenozoospermia, necrozoospermia, and teratozoospermia). High levels of activity of aminopeptidase N were found in the soluble and particulate sperm fractions of semen from patients presenting asthenozoospermia with necrozoospermia. In contrast, lower aminopeptidase N activity was measured in the soluble sperm fraction of asthenozoospermic semen. The percentage of dead spermatozoa was positively correlated with aminopeptidase N activity in both soluble and particulate sperm fractions. In contrast, the percentage of immobile spermatozoa was negatively correlated with aminopeptidase activity in soluble and particulate sperm, and in prostasome fractions. Levels of activity of neutral endopeptidase were found to be unaltered among the different conditions. In summary, the results of the present study indicate that alterations in the activity of aminopeptidase N may be one of the molecular components that contribute to male human subfertility.
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PMID:Enkephalin-degrading enzymes in normal and subfertile human semen. 1529 3

Willow herb (Epilobium angustifolium L.) extracts showed inhibitory activity against the metallopeptidases: neutral endopeptidase (NEP), angiotensin-converting enzyme (ACE), and aminopeptidase N (APN). A bioassay-guided fractionation led to the isolation of several flavonoids and phenolic acids and an ellagitannin. The dimeric macrocyclic ellagitannin oenothein B inhibited the neutral endopeptidases in a dose-dependent manner with IC50 = 20 microM. Other polyphenols showed weaker activity but their synergistic activity cannot be excluded. Taking into account the role of these peptidases in prostate diseases, the results may partly support and explain the use of Epilobium extracts in folk medicine.
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PMID:Compounds from Epilobium angustifolium inhibit the specific metallopeptidases ACE, NEP and APN. 1549 Mar 19


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