Degradation of thymopentin by human lymphocytes: evidence for aminopeptidase activity

Amoscato, Andrew A.; Balasubramaniam, A.; Alexander, J. Wesley; Bebcock, George F.

doi:10.1016/0167-4838(88)90190-2

Cited by 22 publications

(12 citation statements)

References 34 publications

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“…Thymopentin is a small molecule pentapeptide and stable during the formulating process in vitro [18]. Previous study showed that the pentapeptide was rapidly degraded in plasma [36], and degraded in vitro by human lymphocytes into two main fragments; the tetrapeptide (TP 4, thymocartin) Lys-Asp-Val-Tyr and the tripeptide (TP 3, thymotrinan) Asp-Val-Tyr [2]. The degradation products, both TP4 and TP3, are shown to exert similar immunomodulatory activities to TP5 affecting both humoral and cellular responses [13,27].…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, toxicity of nasal cilia and immunomodulating effects in Sprague–Dawley rats following intranasal delivery of thymopentin with or without absorption enhancers

et al. 2006

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Thymopentin (TP 5), a synthetic pentapeptide, has been used in clinic as a modulator for immnuodeficiencies through intramuscular administration. The objectives of this study was to investigate the pharmacokinetics using normal rats and toxicity of nasal cilia as well as immunomodulating effects using immunosuppression rats after intranasal delivery of thymopentin with or without an absorption enhancer. The absorption extent of fluorescein isothiocyanate (FITC) labeled TP 5 via nasal delivery at a single dose is significantly improved by incorporating sodium deoxycholate, Brij 35 and chitosan, respectively. FITC-TP 5 can also be absorbed to such an extent ranging from 15 to 28% after intranasal administration of FITC-TP 5 alone, FITC-TP 5 with sodium caprylate, or with bacitracin, respectively. After seven consecutive days multiple dosing, TP 5 formulation with sodium deoxycholate or Brij 35 caused apparently injury to nasal cilia, indicating these two enhancers would not be appropriate for nasal delivery. Results from superoxide dismutase activity, maleic dialdehyde, T-lymphocyte subsets (CD3+, CD4+, CD8+ and CD4+/CD8+ ratio) analyses suggest that all the selected enhancers improve the modulating effects of TP 5 in the immunosuppression rats. On an overall evaluation, intranasal TP 5 alone, TP 5 with chitosan, or TP 5 with bacitracin formulation may be suitable for the future clinical application.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, toxicity of nasal cilia and immunomodulating effects in Sprague–Dawley rats following intranasal delivery of thymopentin with or without absorption enhancers

et al. 2006

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“…It has been shown recently that a dimeric developmen tal^ regulated mouse T cell activating mole cule (THAM) was in fact aminopeptidase N [6], A specific monoclonal antibody against this protein activated mouse T lymphocytes to proliferate [21] and bestatin.an inhibitor of aminopeptidase N activity, also stimulated mouse and human T and B cell responses in vivo [37] and in vitro [38]. Therefore, it is possible that the mechanism by which bestatin and anti-THAM antibody stimulate im mune responses or activate T cell involves inhibition of cell surface aminopeptidase N. The most likely role of this enzyme is to cleave biologically active peptides as already reported for thymopentin, the active moiety of thymopoietin [39]. A number of cytokines including IL-1, TNF, IL-6.…”

Section: Discussionmentioning

confidence: 99%

Characterization and Control of Expression of Cell Surface Aminopeptidase N Activity in Human Mesangial Glomerular Cells

Stefanović¹,

Vlahović²,

Ardaillou³

et al. 1992

Cell Physiol Biochem

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Intact human glomerular mesangial cells in culture hydrolyzed synthetic substrates of aminopeptidase N. Mesangial cell aminopeptidase N is an ectoenzyme as demonstrated by the extracellular location of the product, the inhibition of enzyme activity by the diazonium salt of sulfanilic acid, a nonpenetrating agent, the similar activities measured with intact and sonicated cells and the localization of the immunoreactive antigen by immunofluorescence on the cell surface. A broad substrate specificity was documented with various p-nitroanilide substrates in the following order of affinity: Ala, Leu > Lys, Arg > Pro, Gly and Val. Using Ala p-nitroanilide as substrate, apparent K_m and V_max values of 0.86 ± 0.70 mM and 3.54 ± 0.13 nmol min^–1 mg^–1, respectively were obtained. Enzyme activity was inhibited by bestatin and 1, 10-phenanthroline. Inhibition by 1 10-phenanthroline was noncompetitive. Cell surface aminopeptidase N activity increased in the presence of phorbolmyristate acetate (PMA). This effect was time-dependent, requiring a lag time of 12 h. It was also concentration-dependent with a threshold at 1 ng/ml and a maximum stimulation (2.2 times basal value) at 10 ng/ml. The effect of PMA was prevented by cycloheximide, an inhibitor of protein synthesis, and actinomycin D, an inhibitor of RNA synthesis. It was also suppressed by H7, an inhibitor of protein kinase C activity. The presence of aminopeptidase N in cultured glomerular mesangial cells and control of its expression by mitogens suggest that this enzyme may play a role in glomerular cell proliferation.

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“…The dried precipitates were dissolved in 0.5 mL of 1 M acetic acid and the undissolved particles were removed by centrifugation. The peptide analysis was carried out following the protocol for the studies of TP5 (Tuthill et al, 2000) and Tα1 Amoscato et al, 1988) using HPLC. The plasma half-lives of target peptides were calculated via a logarithmlinear regression analysis of the peptide concentrations.…”

Section: The Plasma Half-life Determinationmentioning

confidence: 99%

Expression of thymosin α1-thymopentin fusion peptide in Pichia pastoris and its characterization

Gao

Zhang

et al. 2008

Arch. Pharm. Res.

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Thymopentin plays an important role in improving imbalanced immune systems of patients, however, it has a limited half-life in plasma. To get more stable and active thymopentin analogs, a fusion thymosin alpha1-thymopentin (Talpha1-TP5) gene was synthesized and cloned into vector pGAPZalphaA. Talpha1-TP5 fusion peptide was expressed in pichia pastoris and purified by metal chelating chromatography and gel filtration chromatography. The circular dichroism spectra (CD) indicated that the secondary structure of Talpha1-TP5 fusion peptide is dominated by a-helix and random coil. In vitro analysis showed that the plasma half-life of Talpha1-TP5 fusion peptide is 140 +/- 14 min, which is longer than that of TP5 (5.6+/-0.7 min) and Talpha1 (127+/-11 min). The in vitro activity assay presented that Talpha1-TP5 fusion peptide has greater activity in promoting proliferation of Kunming mouse splenocytes, and in vivo experiment it showed better activity in promoting the phagocytosis of macrophages and secretion of IL-2 than both Talpha1 and TP5. Our findings suggest that Talpha1-TP5 fusion peptide might be a potential therapeutic agent.

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Degradation of thymopentin by human lymphocytes: evidence for aminopeptidase activity

Cited by 22 publications

References 34 publications

Pharmacokinetics, toxicity of nasal cilia and immunomodulating effects in Sprague–Dawley rats following intranasal delivery of thymopentin with or without absorption enhancers

Pharmacokinetics, toxicity of nasal cilia and immunomodulating effects in Sprague–Dawley rats following intranasal delivery of thymopentin with or without absorption enhancers

Characterization and Control of Expression of Cell Surface Aminopeptidase N Activity in Human Mesangial Glomerular Cells

Expression of thymosin α1-thymopentin fusion peptide in Pichia pastoris and its characterization

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