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PubMed1980

Restoration of E-rosette formation by bestatin in patients with bladder cancer.

Incubation of peripheral blood lymphocytes from patients with bladder cancer in bestatin (specific inhibitor of aminopeptidase B and leucine aminopeptidase) solution resulted in a significant increase in the proportion of E-rosette-forming lymphocytes. The increase in the proportion of E-rosette-forming lymphocytes was abolished after reincubation with 100% autochthonous serum. The fraction of E-rosette-forming lymphocytes from patients with bladder cancer which had restored receptors for sheep erythrocytes (SRBC) by incubation with bestatin also expressed receptors for the Fc portion of IgG and IgM. The proportion of EAC-forming lymphocytes remained unchanged after the incubation with bestatin. When 600 mg of bestatin was administered for 1 day to patients with bladder cancer, restorative effect on the proportion of E-rosette forming lymphocytes was also demonstrated. The proportion of EAC-forming lymphocytes, however, did not change significantly.

Adjuvants, Immunologic↗

PubMed1978

New microbial secondary metabolites under preclinical development for cancer treatment.

Limitless numbers of various genetic structures have been formed in chromosomes and plasmids and numerous bioactive compounds are produced by microorganisms. Therefore, it may be said that compounds useful in treatment of cancer will be found more and more in microbial secondary metabolites and more effective antitumor antibiotics and their derivatives, or more effective products producing immune resistance to cancer, will be discovered. In these studies, as discussed in this paper, the most urgent problem is to establish a rational screening principle or system to select compounds worth clinical examination. This is particularly important in the analog area. Bleomycin is an analog of phleomycin chosen because of lower renal toxicity. It has become an antitumor agent of significant value. Macromycin is a new structure which has been found to bind with animal cells and inhibit growth. Neothramycin is a new benzodiazepine antibiotic which has lower toxicity than other structures studied in this class and is active against L1210, Yoshida sarcoma, and Sarcoma 180. Aclacinomycin A is an analog of adriamycin chosen for clinical study based on its low cardiac toxicity and high distribution in mouse lung and spleen. Coriolins are another new structural class. Diketocoriolin B has activity in L1210 leukemia and has been shown to inhibit Na-K-ATPase. Bestatin is a compound which inhibits aminopeptidase B and leucine aminopeptidase has been shown to increase delayed hypersensitivity. Bestatin also increases the effects of other antitumor agents such as adriamycin, and bleomycin.

Animals↗

PubMed1993

Inhibition of aminopeptidases by N-aminoacyl-O-4-nitrobenzoyl hydroxamates.

10 N-aminoacyl-O-4-nitrobenzoyl hydroxamates were investigated as potential inhibitors of aminopeptidases. While the metal-depending enzymes aminopeptidase M, aminopeptidase P and leucine aminopeptidase were inhibited reversibly by the compounds, the thiol enzyme cathepsin H was inhibited efficiently in time-dependent reactions according to its substrate specificity. N-phenylalanyl-O-4-nitrobenzoyl hydroxamate was shown to be most effective, exhibiting a second-order-rate constant of inhibition of 31,766 M-1 s-1.

Amino Acid Sequence↗

PubMed2004

Proteasome and peptidase function in MHC-class-I-mediated antigen presentation.

MHC-class-I-presented peptides are predominantly generated by the proteasome system. IFN-gamma strongly influences the processing efficiency by inducing immunoproteasome formation and proteasome activator PA28 synthesis. Depending on the protein substrate, the presence of immunoproteasomes and PA28 influence epitope liberation either positively or negatively. Abundantly occurring defective ribosomal products are a major source for proteasome-dependent antigen processing; however, antigen presentation is relatively inefficient. This is in part due to the existence of a panel of cytosolic aminopeptidases, such as bleomycin hydrolase (BH), puromycin-sensitive aminopeptidase (PSA) and thimet oligoendopeptidase (TOP), that can destroy epitopes or their precursors. Other aminopeptidases, such as leucine aminopeptidase (LAP) and endoplasmic reticulum aminopeptidase 1 (ERAP 1), can trim epitope precursors from the amino terminus to their correct size for MHC class I binding to enhance antigen presentation. Recent evidence suggests that tripeptidyl peptidase II (TPPII), a large peptidase with exo-and endo-proteolytic activities, is also involved in antigen processing and may generate a specific set of MHC class I epitopes.

Aminopeptidases↗

PubMed2000

Effects of sodium glycocholate and protease inhibitors on permeability of TRH and insulin across rabbit trachea.

The permeabilities of thyrotropin-releasing hormone (TRH) and insulin as model peptides were examined to characterize the tracheal epithelial barrier in in vitro experiments using excised rabbit trachea. TRH was not metabolized during 150 min duration of tracheal permeation and the apparent permeability coefficient (Papp) for TRH was about 3 x 10(-7) cm/s. The tracheal permeability of TRH was increased about three times by 10 mM glycocholate as a permeation enhancer. Insulin showed a slight degradation during 150 min duration of tracheal permeation, the Papp for insulin was 7 x 10(-9) cm/s. The tracheal permeability of insulin was significantly increased by 10 mM glycocholate, 1 mM bestatin (aminopeptidase B and leucine aminopeptidase inhibitor), and 10,000 KIU/ml aprotinin (trypsin and chymotrypsin inhibitor). The peptidase activities of rabbit tracheal epithelium were found to be the following; di-peptidyl-aminopeptidase IV (DPP IV) > Leu-aminopeptidase > cathepsin-B > trypsin. These activities were significantly lower than those of jejunal mucosal tissues. These results suggest that the tracheal absorption of peptide drugs through the respiratory tract may contribute to the systemic delivery of these drugs following the pulmonary administration of these drugs by intratracheal insufflation and instillation.

Animals↗

PubMed1978

Small molecular microbial products enhancing immune response.

Plasmids are involved in the biosynthesis of many microbial secondary metabolites, and compounds which have various chemical structures are produced by microorganisms. Therefore, it is possible to find microbial products which have no antimicrobial activities but pharmacological activities. Aminopeptidases, alkaline phosphatase and esterase have been found to appear on the cell surface and their strong inhibitors have been confirmed to enhance or decrease immune response. These inhibitors have a very low toxicity without cytotoxic action. Bestatin, which inhibited aminopeptidase B and leucine aminopeptidase, enhanced delayed-type hypersensitivity in a wide range of its low dosis (0.1-100 micrometer/mouse) and produced an immune resistance to the second inoculation of the same tumor cells. It showed a synergistic action with antitumor agents in treatment of experimental tumors. Treatment with bestatin alone exhibited a strong therapeutic effect on slowly growing solid tumors.

Aminopeptidases↗

PubMed2004

Role of aminopeptidases in the blood pressure regulation.

In addition to the neural and autoregulatory factors, blood pressure (BP) is regulated by humoral factors including vasoactive peptides. When evaluating the peptide actions, degradation by proteases should be also considered in addition to the generation of peptides and their receptors. This review describes the roles of aminopeptidase A, placental leucine aminopeptidase and kininase I, which are enzymes responsible for hydrolyzing angiotensin II (AngII), vasopressin (AVP) and bradykinin (BK), respectively, in BP regulation. Especially, we focus on the association of the proteases with preeclampsia, hypertensive disorder peculiar to pregnancy, since one of the representative organs that are rich in theses proteases is placenta. Although the physiological roles of the placental proteases have not been fully understood, several lines of evidence suggest that the proteases are involved in the maintenance of pregnancy homeostasis including fetal and maternal BP regulation through the metabolism of bioactive peptides at the interface between mother and fetus.

Amino Acid Sequence↗

PubMed2003

Changes in the levels of neuropeptides and their metabolizing enzymes in the brain regions of nucleus basalis magnocellularis-lesioned rats.

The regulation mechanism of the interrelation between neuropeptides and their metabolizing enzymes in in vivo tissues is still not clear. In the present report, we attempted to measure the levels of neuropeptides and their enzymes in the frontal cortex, hippocampus, and striatum of the rat that had been bilaterally lesioned by the infusion of ibotenic acid or amyloid beta-peptide 25 - 35 (Abeta25 - 35) into the nucleus basalis magnocellularis. In the drug-treated rats, at two weeks after the infusion, the decrease of somatostatin-like immunoreactivity (SS-LI) and the increase of cholecystokinin-8S-LI were found in some brain regions relative to vehicle-treated rats. The immunoreactivities of endopeptidase 24.15 and puromycin-sensitive aminopeptidase and the leucine aminopeptidase- and aminopeptidase B-like enzyme activities did not change in the three brain regions, suggesting that the levels of those peptide-degrading enzymes do not correlate with the changes of the neuropeptide levels. The decrease of subtilisin-like proprotein convertase (SPC)-like enzyme activity was found in the hippocampus of the Abeta25 - 35-treated rats. The SS mRNA level decreased in the hippocampus in parallel with decreases in the SS-LI level and SPC-like enzyme activity. The present data indicate that some of the neuropeptide-processing enzymes may contribute to the control of neuropeptide levels.

Aminopeptidases↗

PubMed1999

Distinct proteolytic processes generate the C and N termini of MHC class I-binding peptides.

Most of the MHC class I peptides presented to the immune system are generated during the course of protein breakdown by the proteasome. However, the precise role of the proteasome, e.g., whether this particle or some other protease generates the carboxyl (C) and amino (N) termini of the presented 8- to 10-residue peptides, is not clear. Here, we show that presentation on Db of ASNENMETM, a peptide from influenza nucleoprotein, and on Kb of FAPGNYPAL, a peptide from Sendai virus nucleoprotein, was blocked by the proteasome inhibitor, lactacystin. Using plasmid minigene constructs encoding oligopeptides of various lengths, we found that presentation of ASNENMETM from C-terminally extended peptides that contain this antigenic peptide plus three or five additional amino acids and presentation of FAPGNYPAL from a peptide containing FAPGNYPAL plus one additional C-terminal residue required the proteasome. In contrast, the proteasome inhibitor did not reduce presentation of cytosolically expressed ASNENMETM or FAPGNYPAL or N-terminally extended versions of these peptides, suggesting involvement of aminopeptidase(s) in trimming these N-extended variants. Accordingly, when the N termini of these 3N-extended peptides were blocked by acetylation, they were resistant to hydrolysis by cellular aminopeptidases and pure leucine aminopeptidase. Moreover, if introduced into the cytosol, Ag presentation of these peptides occurred to a much lesser extent than from their nonacetylated counterparts. Thus, the proteasome is essential for the generation of ASNENMETM and FAPGNYPAL peptides from the full-length nucleoproteins. Although it generates the C termini of these presented peptides, distinct aminopeptidase(s) can trim the N termini of these presented peptides to their proper size.

Aminopeptidases↗

PubMed1991

[Peptidase activity and toxicity of strains of Pseudomonas aeruginosa].

Pseudomonas aeruginosa is a microorganism of the terrestrial and aquatic environment which may cause pulmonary, urinary and corneal infections. The pathogenesis of Pseudomonas-induced diseases seems to be linked to the production of extracellular substances such as exotoxins, hemolysins, leukocidins and hydrolytic enzymes, including various peptidases. Anyway there is not a clear view on the role other proteases have in the mechanism of pathogenesis, and even if their activity may always be associated to the toxicity of the microorganism. We have therefore determined the activity of a number of eso- and endopeptidases in 17 strains of P. aeruginosa isolated from patients with urinary pathologies. Four of these peptidase activities, namely elastase, neutral protease, aminopeptidase I and leucine aminopeptidase show a positive correlation with three parameters selected as indices of toxicity, i.e. the mucoid appearance, the gentamicin resistance and the adhesivity of colonies.

Aminopeptidases↗

PubMed1986

[Biochemical diagnosis of duodenitis].

The activities of enteropeptidase, alanine aminopeptidase, sucrase, and leucine aminopeptidase were determined in mucosa biopsies taken from three defined places of the duodenum and in duodenal juice. We examined 23 adults with a histological proven normal mucosa and 10 patients suffering from duodenitis grade I. Using multivariate evaluation of all the four enzyme activities of the three mucosa sites, we could differentiate duodenitis from normal mucosa with an efficiency of 88%.

Adult↗

PubMed1977

Enzyme inhibitors in relation to cancer therapy.

In the last 11 years the authors have succeeded in isolating nearly 40 enzyme inhibitors of small molecular size from microbial origins. These inhibitors proved to be not only useful tools in analyses of homeostasis of living organisms but also promising agents for cancer chemotherapy. Leupeptin was originally isolated as an inhibitor against serine or thiol proteases such as trypsin, plasmin, papain and cathepsin B. And soon it was demonstrated that leupeptin suppressed chemical carcinogenesis in rats. Pepstatin has an extremely strong activity to inhibit pepsin and cathepsin D. It also inhibits ascites accumulation caused by neoplastic diseases. Bestatin is a specific inhibitor against aminopeptidase B and leucine aminopeptidase. The enzymes are located on the surface membrane in various kinds of cells including lymphocytes. Bestatin was shown to enhance not only blastogenesis of lymphocytes in vitro but also establishment of delayed-type hypersensitivity in vivo. Combined use of bestatin and other antitumor agents gave promising results in animal experiments. Studies on enzyme inhibitors have provided us a new approach to cancer chemotherapy.

Aminopeptidases↗

PubMedDate not supplied

Adenomyosis: study in a Jewish female population.

In a series of 920 hysterectomies, performed during a three-year period at the Gynecological Clinic of Hasharon Hospital, adenomyosis weas found in 89 cases, an incidence of 9.06%. Although this result is in accordance with that reported by other authors, we found a marked difference between the incidence of adenomyosis in the two Jewish female groups under study: the Ashkenazic women (natives of European countries or U.S.A.), and the Sephardic women (natives of Near East countries, Yemen or North Africa); 69.66% of the adenomyosis cases were in the former group as against only 30.34% in the latter. A preoperative diagnosis of adenomyosis was made in 19.10% of the cases. This comparatively high percentage appears to be due to the routine examination of the serum activity of cystine aminopeptidase (CAP) and leucine aminopeptidase (LAP), performed in all patients before operation. Increased values of these enzymes indicate the presence of uterine or ovarian tumoral processes. It is suggested that the diagnosis of adenomyosis must be considered in cases of uterine bleeding, dysmenorrhea and increased CAP and LAP values discovered in multiparous women of around 50 years of age, even when the bimanual examination does not reveal any other pathologic condition.

Adult↗

PubMed1976

Organ specificity of angiotensin II and Des-aspartyl angiotensin II in the conscious rat.

Des-Asp angiotensin II (des-Asp AII) is a naturally occurring heptapeptide metabolite of angiotensin II (AII) which is formed by the enzymatic action of aminopeptidase A. Angiotensin II and des-Asp AII were infused into unanesthetized rats while direct mean arterial pressure, serum aldosterone and serum corticosterone were measured. Both AII and des-Asp AII caused a dose-related increase in serum aldosterone with a significant increase occurring with a dose as low as 1 ng/min. This effect was blocked by pretreatment with 1-Sar-8-Ala-angiotensin II, a competitive inhibitor of AII; however, the inhibitor was more effective in blocking the effects of AII (101%) than of des-Asp AII (82%). Both angiotensins induced a dose-related increase in serum corticosterone and mean arterial pressure. Des-Asp AII was however only 1/10 as potent as AII in elevating mean arterial pressure. 1-Sar-8-Ala-AII was also effective in inhibiting the pressor effects of AII and des-Asp AII. These data illustrate a high degree of organ specificity or selectivity for des-Asp AII and a low specificity for AII. Aminopeptidase A and leucine aminopeptidase were identified in the adrenal cortex and medulla in large amounts. Des-Asp AII may thus be formed from AII locally in the adrenal gland prior to exerting its action at that site.

Adrenal Cortex↗

PubMed1991

Bestatin, an aminopeptidase inhibitor with a multi-pharmacological function.

Bestatin, the dipeptide N-((2S, 3R)-3-amino-2-hydroxy-4-phenyl butanyl) L-leucine is a leucine aminopeptidase and aminopeptidase-B inhibitor. It exerts a direct stimulating effect on lymphocytes (and monocytes) via its fixation on cell surface leucine-aminopeptidase, and an indirect effect on monocytes (and lymphocytes) via aminopeptidase B inhibition of tuftsin catabolism. Thus it is an immuno-modifier as shown by the Japanese and also our groups: a) immuno-modifier, especially stimulator, in normal young mice; b) immunorestorator and spontaneous tumor preventive agent in aged mice; c) immunorestorator in the elderly and in cancer patients and HIV infected subjects. It stimulates granulocytopoiesis and thrombocytopoiesis in vitro, and can restore them in vivo in myelo-hypoplastic man. The anti-aminopeptidase action of Bestatin also protects enkephalins against their catabolism, which encouraged us, with good preliminary results, to study its analgesic action and search for a preventive effect on "desaddicted" toxicomaniac relapses.

Aminopeptidases↗

PubMed1977

Biomedical responses of rats to chronic exposure to dietary cadmium fed in ad libitum and equalized regimes.

Forty 100 g male rats were fed, in groups of eight, either 0, 5, or 25 ppm cadmium in a purified diet for 14 wk. Three groups were fed each of the levels of cadmium on an ad libitum basis. Two other groups were fed either 0 or 5 ppm cadmium in amounts that were equalized to that consumed by the 25 ppm group fed ad libitum. Cadmium ingestion decreased daily diet consumption, weight gain, and terminal body weight. These parameters were not significantly different in rats whose diet consumption was equalized. Packed cell volume and serum iron as well as serum zinc were decreased in the rats fed 25 ppm cadmium. These effects were not related to diet intake. No major differences were observed in serum ceruloplasmin, glucose, protein, leucine aminopeptidase activity, or copper in any of the groups. Blood urea nitrogen and renal leucine aminopeptidase activity were decreased by cadmium ingestion in the rats fed ad libitum only. In contrast, serum alkaline phosphatase activity was elevated by cadmium in the equalized-intake groups only. Cadmium and zinc concentrations were elevated and the iron concentration was decreased in the kidney, liver, and intestinal mucosa of the cadmium-fed rats irrespective of level of diet consumption. The increased uptake of cadmium in these tissues was coincident with the increased content of the cadmium-binding protein, metallothionein, in the cytosol fraction. The results indicate that some parameters of chronic cadmium toxicity are associated with diet consumption whereas others are not.

Animals↗

PubMed1982

Intestinal metaplasia of the stomach as a precancerous stage.

Intestinal metaplasia is defined as the appearance of intestinal epithelium in the stomach. Intestinal metaplasia is frequently found in populations with a high incidence of gastric cancer. Macroscopic demonstration of sucrase and trehalase with Tes-tape in many resected stomachs yielded new information for understanding the nature of intestinal metaplasia. Intestinal metaplasia can be classified into two types, complete and incomplete. The former is associated with the presence of sucrase, trehalase, leucine aminopeptidase, alkaline phosphatase, goblet cells and Paneth cells, and the latter with that of sucrase, leucine aminopeptidase and goblet cells, but not trehalase or Paneth cells. Goblet cells in the complete type of intestinal metaplasia contain sialomucin, as does the small intestine, while those in the incomplete type contain sulphomucin and sialomucin, as does the large intestine. Well-differentiated adenocarcinoma is closely related to intestinal metaplasia, especially the incomplete type. Atypical epithelium of intestinal metaplasia has been proposed as a more proximate stage of gastric cancer. Intestinal metaplasia can be diagnosed by staining with dye under endoscopic observation. A reduced level of pepsinogen I in the blood reflects the presence of severe intestinal metaplasia, which is understood to be a sign of high risk of gastric cancer. Intestinal metaplasia is supposed to be produced by components of food. Mutagens/carcinogens such as N-methyl-N'-nitro-soguanidine and N-propyl-N'-nitro-N-nitrosoguanidine can produce intestinal metaplasia in the glandular stomach of rats and gastric cancers. The formation of intestinal metaplasia precedes the appearance of adenocarcinoma in the glandular stomach. Intestinal metaplasia, which is a kind of host reaction to environmental agents, may result either from genetic change - change in DNA structure - or from epigenetic change - change in the differentiation mechanism. Preventive measures could be developed to suppress the development of intestinal metaplasia and to suppress the process of conversion of metaplastic cells to cancer cells.

Cell Differentiation↗

PubMed1991

A comparative study of [Leu1]Tuftsin and tuftsin, a natural phagocytosis-stimulating peptide.

1. [Leu1]tuftsin was reported to have greater phagocytosis-stimulating activity than tuftsin (Thr-Lys-Pro-Arg). 2. However, a study on inactivation of tuftsin by polymorphonuclear leukocytes (PMNs) demonstrated that leucine aminopeptidase, an ecto-enzyme, located on PMN surface was responsible for this mechanism. 3. Since leucine aminopeptidase is known to cleave Leu more easily than Thr at the N-terminal position of peptides, this suggested to us that [Leu1]tuftsin might then be inactivated by PMNs more easily than tuftsin, and thus this analog might be less active than tuftsin. 4. In addition, many tuftsin preparations used in earlier studies were not fully active, as high-performance liquid chromatography was not available to separate out many contaminating diastereomers. 5. In view of this, we have synthesized and purified [Leu1]tuftsin and compared its phagocytosis-stimulating activity with tuftsin. 6. Our results indicate that [Leu1]tuftsin is not as active as tuftsin in stimulating phagocytosis.

Amino Acid Sequence↗