scholarly journals Systemic levels of neuropeptide Y and dipeptidyl peptidase activity in patients with Ewing sarcoma-Associations with tumor phenotype and survival

Cancer ◽  
2014 ◽  
Vol 121 (5) ◽  
pp. 697-707 ◽  
Author(s):  
Jason U. Tilan ◽  
Mark Krailo ◽  
Donald A. Barkauskas ◽  
Susana Galli ◽  
Haifa Mtaweh ◽  
...  
Keyword(s):  
Neuropeptide Y ◽  
Ewing Sarcoma ◽  
Dipeptidyl Peptidase ◽  
Peptidase Activity ◽  
Tumor Phenotype

Estrogen modulates the contribution of neuropeptide Y to baseline hindlimb blood flow control in female Sprague-Dawley rats

2010 ◽  
Vol 298 (5) ◽  
pp. R1351-R1357 ◽  
Author(s):  
Dwayne N. Jackson ◽  
Christopher G. Ellis ◽  
J. Kevin Shoemaker
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Flow Control ◽  
Neuropeptide Y ◽  
Female Rats ◽  
Vastus Lateralis Muscle ◽  
Peptidase Activity ◽  
Vascular Conductance ◽  
Ovx Rats ◽  
Blood Flow Control

The purpose of this study was to determine the role of estrogen in neuropeptide Y (NPY) and Y1 receptor (Y1R)-mediated vascular responses in female rats. Based on earlier work from our laboratory that female rats lacked an NPY contribution to hindlimb vascular conductance relative to males, we tested the hypothesis that estrogen modulates Y1R-mediated hindlimb blood flow control. Thus it was expected that ovariectomy would: 1) increase skeletal muscle Y1R expression, 2) decrease skeletal muscle Y2 receptor (Y2R) expression, 3) decrease peptidase activity, and/or 4) increase overall skeletal muscle NPY concentration. Separate groups of control (CTL), ovariectomized (OVX), and OVX + 17β-estradiol replacement (OVX + E2; 21-day pellet) rats were studied. Animals were anesthetized and given localized hindlimb delivery of BIBP-3226 (Y1R antagonist), while femoral artery blood flow and blood pressure were recorded. Tissue samples from the white and red vastus lateralis muscle were extracted to examine Y1R and Y2R expression, peptidase activity, and NPY concentration. We found that Y1R blockade resulted in increased baseline hindlimb blood flow and vascular conductance in OVX rats, whereas no change was noted in CTL or OVX + E2 groups ( P < 0.05). This enhanced functional effect in the OVX group aligned with greater skeletal muscle Y1R expression in white vastus muscle and a substantial increase in NPY concentration in both white and red vastus muscle compared with CTL and OVX + E2 groups. There was no change in Y2R expression or peptidase activity among the groups. These data support the hypothesis that estrogen blunts Y1R activation in the rat hindlimb through an effect on Y1R expression and NPY concentration.

scholarly journals Influence of dipeptidyl peptidase IV on enzymatic properties of adenosine deaminase.

2006 ◽  
Vol 53 (3) ◽  
pp. 539-546 ◽  
Author(s):  
Svetlana Sharoyan ◽  
Alvard Antonyan ◽  
Sona Mardanyan ◽  
Giulio Lupidi ◽  
Gloria Cristalli
Keyword(s):  
Adenosine Deaminase ◽  
Immune Cell ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Soluble Form ◽  
Kidney Cortex ◽  
Peptidase Activity ◽  
Extracellular Medium ◽  
Ph Profile ◽  
Enzyme Preparations

The importance of ADA (adenosine deaminase) in the immune system and the role of its interaction with an ADA-binding cell membrane protein dipeptidyl peptidase IV (DPPIV), identical to the activated immune cell antigen, CD26, has attracted the interest of researchers for many years. To investigate the specific properties in the structure-function relationship of the ADA/DPPIV-CD26 complex, its soluble form, identical to large ADA (LADA), was isolated from human blood serum, human pleural fluid and bovine kidney cortex. The kinetic constants (Km and Vmax) of LADA and of small ADA (SADA), purified from bovine lung and spleen, were compared using adenosine (Ado) and 2'-deoxyadenosine (2'-dAdo) as substrates. The Michaelis constant, Km, evidences a higher affinity of both substrates (in particular of more toxic 2'-dAdo) for LADA and proves the modulation of toxic nucleoside neutralization in the extracellular medium due to complex formation between ADA and DPPIV-CD26. The values of Vmax are significantly higher for SADA, but the efficiency, Vmax/Km, in LADA-catalyzed 2'-dAdo deamination is higher than that in Ado deamination. The interaction of all enzyme preparations with derivatives of adenosine and erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) was studied. 1-DeazaEHNA and 3-deazaEHNA demonstrate stronger inhibiting activity towards LADA, the DPPIV-CD26-bound form of ADA. The observed differences between the properties of the two ADA isoforms may be considered as a consequence of SADA binding with DPPIV-CD26. Both SADA and LADA indicated a similar pH-profile of adenosine deamination reaction with the optimum at pHs 6.5-7.5, while the pH-profile of dipeptidyl peptidase activity of the ADA/DPPIV-CD26 complex appeared in a more alkaline region.

scholarly journals High neuropeptide Y release associates with Ewing sarcoma bone dissemination -in vivomodel of site-specific metastases

Oncotarget ◽  
2015 ◽  
Vol 6 (9) ◽  
pp. 7151-7165 ◽  
Author(s):  
Sung-Hyeok Hong ◽  
Jason U. Tilan ◽  
Susana Galli ◽  
Ewa Izycka-Swieszewska ◽  
Taylor Polk ◽  
...  
Keyword(s):  
Neuropeptide Y ◽  
Ewing Sarcoma ◽  
Site Specific ◽  
Neuropeptide Y Release

Abstract PR15: Hypoxia, polyploidy, neuropeptide Y, and Ewing sarcoma bone metastases: Is there a link?

2018 ◽  
Author(s):  
Akanksha Mahajan ◽  
Sung-Hyeok Hong ◽  
Susana Galli ◽  
Congyi Lu ◽  
Shiya Zhu ◽  
...  
Keyword(s):  
Neuropeptide Y ◽  
Bone Metastases ◽  
Ewing Sarcoma

Inhibitors of Fibroblast Activation Protein (FAP) Inhibit Primary Myeloma Growth and Osteoclastogenesis Ex Vivo and In Vivo.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 813-813
Author(s):  
Angela Pennisi ◽  
Xin Li ◽  
Dana Gaddy ◽  
Nisreen Akel ◽  
Nazneen Aziz ◽  
...  
Keyword(s):  
Cell Growth ◽  
Cell Surface ◽  
Cell Survival ◽  
Dipeptidyl Peptidase ◽  
Fibroblast Activation Protein ◽  
Peptidase Activity ◽  
Dependent Manner ◽  
Pretreatment Level ◽  
Fibroblast Activation

Abstract Fibroblast activation protein (FAP), a cell surface serine protease with both dipeptidyl peptidase and collagenase activity, is selectively expressed by tumor stroma and involved in tumor metastasis. We have reported that FAP is upregulated in myelomatous bone and is overexpressed in osteoclasts after coculture with myeloma (MM) cells. FAP is not expressed by MM cells and FAP siRNA reduced MM cell survival in cocultures (Ge et al., BJH 2006). The aim of the study was to investigate the effect of FAP inhibitors, PT-100 and PT-630 on MM cell growth and osteoclastogenesis using coculture system and the SCID-hu model for primary MM. PT-630 inhibits cell surface dipeptidyl peptidase activity while PT-100 also inhibits intracellular activity of these enzymes. MM cells from 6 patients were cocultured with osteoclasts and treated twice a day with PT-100 and PT-630 (0.1–100 μM) for 5–7 days. Whereas PT-100 effectively inhibited MM cell growth in all tested doses by 38%–62% (p<0.002 vs. 100 μM), PT-630 inhibited MM cell growth in a dose dependent manner reaching 45% growth inhibition with 100 μM (p<0.02). These compounds had no direct effect on MM cell survival. Moreover, recombinant FAP had no impact on MM cells cultured alone, suggesting that FAP-induced MM cell survival depends on close contact between MM cells and osteoclasts. The anti-MM effect of PT-100 in cocultures was mediated through downregulation of phosphorylated p38 in MM cells as detected by Phospho MAPK array and confirmed by Western blot. MMP-2 and MMP-9 have been associated with FAP activity. The level of MMP-2 but not MMP-9 was reduced in coculture conditioned media by 44±7% (p<0.04) following treatment with PT-100 while PT-630 had no significant effect on production of these matrix metalloproteinases. To test effect on osteoclastogenesis, osteoclast precursors were incubated with RANKL and M-CSF in the absence and presence of PT-100 (1 μM) and PT-630 (10 μM) for 5–7 days. PT-100 and PT-630 inhibited formation of multinucleated osteoclasts by 78±6% (p<0.001) and 56±6% (p<0.003), respectively. Culture of osteoclasts on dentine slices in the presence of PT-100 and PT-630 reduced resorption pit area by 92% (p<0.01) and 69% (p<0.04), respectively. The anti-osteoclastogenic effects were mediated through inhibition of phosphorylated p38 MAPK in osteoclastic cultures in a dose related manner. In vivo, SCID-hu mice engrafted with MM cells from 4 patients were orally treated for 4–5 weeks with PT-100 (20 mg/day) and PT-630 (200 mg/day). These agents inhibited MM growth in 2 experiments, delayed growth in one experiment and had no effect on MM in an additional experiment. Overall, final hIg levels in hosts treated with vehicle, PT-100 and PT-630 were 355±170, 183±78 and 76±27 mg/ml, respectively. Bone mineral density (BMD) of the myelomatous bone was increased in responding hosts (3% vs. -32% change from pretreatment level in control) and had reduced severity of bone loss in myelomatous bone of nonresponding hosts (−15% vs. −28% change from pretreatment level in control), suggesting that, as shown in vitro, these agents directly affect bone cell function in vivo. We conclude that FAP is critically involved in MM osteolysis and tumor growth and thus approaches to inhibit FAP activity in myelomatous bone may help control MM and its associated bone disease.

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