Time filter

Source Type

Sunderic M.,University of Belgrade | Malenkovic V.,Clinical Medical Center Bezanijska Kosa | Nedic O.,University of Belgrade
Experimental and Molecular Pathology

The intention of this work was to systematically study the presence of insulin-like growth factor-binding protein 1 and 2 (IGFBP-1 and IGFBP-2) complexes with alpha-2-macroglobulin (α2M) in the circulation of patients with various types of cancer. Serum samples were collected from patients diagnosed with cancer and divided into eight groups according to the tumor type: liver, pancreas, colon, lung, prostate, breast, cervix and ovary. Results obtained for each cancer group were compared with results obtained for the age and gender-matched controls. Electrophoretic separation and densitometric evaluation of immunoreactive protein bands were performed. According to our results, IGFBP-1/α2M and IGFBP-2/α2M complexes did not exhibit the same presence in different tumors and were also not uniformly related to the amount of monomer forms. Variations in relative quantities of IGFBP-1 monomers and complexes in different tumor types were much more pronounced than those of IGFBP-2. The amount of IGFBP-2 monomer increased in sera from all studied patients compared to controls, whereas the amount of IGFBP-2/α2M complexes most often decreased, being significantly reduced in patients with pancreas, colon, breast or ovary tumor. Although there is still no confirmation of the physiological role of IGFBP-2/α2M complexes, their decreased concentration in the circulation provides greater amount of free IGFBP-2. © 2015 Elsevier Inc. Source

Nedic O.,University of Belgrade | Miljus G.,University of Belgrade | Malenkovic V.,Clinical Medical Center Bezanijska Kosa
Journal of Medical Biochemistry

Background: Insulin and insulin-like growth factor (IGF) activities are disturbed during critical illness. Time-course changes in the concentrations of insulin, IGF-I and IGFbinding proteins (IGFBPs) were monitored in this study and their correlation with interleukin (IL)-6 was assessed in patients subjected to total gastrectomy and specific nutritional regime. Methods: Patients were fed post-operatively according to the following scheme: parenteral nutrition on day 1, enteral nutrition combined with parenteral form from day 2 to 7, peroral nutrition from day 8 and full oral nutrition from day 14. Blood samples were taken periodically and the levels of IL-6, insulin, IGF-I and IGFBP-1 to -4 were determined. Results: On day 1 post-operatively, the concentration of IL- 6 reached its maximum and decreased afterwards. The concentration of insulin increased until day 3 and then started to fall. The concentration of IGF-I, already low preoperatively, continued to decrease. The concentration of IGFBP-1 peaked on day 1 post-operatively, whereas the concentration of IGFBP-3 decreased on that day. The concentration of IL-6 correlated positively with the concentration of IGFBP-1 and negatively with IGFBP-3. On day 14, the concentrations of IL-6, insulin and IGFBP-1 returned to or were close to their basal levels, whereas the concentrations of IGF-I and IGFBP-3 remained reduced. Conclusions: 14-day post-operative recovery, which included specific nutritional support, was suitable to restore insulin concentration and re-establish IGFBP-1 regulation primarily by nutrition. Very low IGF-I level on day 14 after surgery and IGFBP-3 concentration still lower than before surgery indicated that the catabolic condition was not compensated. © by Olgica Nedić 2016. Source

Sunderic M.,University of Belgrade | Dukanovic B.,Clinical Medical Center Bezanijska Kosa | Malenkovic V.,Clinical Medical Center Bezanijska Kosa | Nedic O.,University of Belgrade
Experimental and Molecular Pathology

The components of the insulin-like growth factor (IGF) system and molecules with which they interact are associated with the neoplastic transformation of cells in colorectal cancer. The IGF-binding protein-2 (IGFBP-2) plays a significant role in mitotic stimulation of the cancer cells and its concentration is significantly elevated in tumor states. Little is known about IGFBP-2 at the molecular level and the purpose of this study was to examine the interactions between IGFBP-2 and some other proteins, the fragmentation pattern and posttranslational modifications that might have occurred due to a disease. Results have shown that the amount of monomer IGFBP-2 was 20-30% greater in patients with cancer and the amount of fragmented IGFBP-2 was doubled compared to healthy people, whereas the portion of IGFBP-2 in complex with α2 macroglobulin (α2M) was 2.5 times lower in cancer patients. According to this distribution, IGFBP-2 was not only increasingly synthetized in patients with cancer, but also the amount involved in complexes with α2M was reduced favoring the existence of binary IGFBP-2/IGF complexes, free to leave the circulation. Both IGFBP-2 and α2M were significantly more oxidized in patients with colon cancer than in healthy individuals and α2M was additionally sialylated. It can be speculated that the formation of IGFBP-2/α2M complexes is part of the control mechanism involved in the regulation of IGFBP-2 and, consequently, IGF availability. It also seems that posttranslational modifications are more important factors in determining the amount of IGFBP-2/α2M complexes than the actual quantity of these two proteins. © 2013 Elsevier Inc. Source

Miljus G.,University of Belgrade | Malenkovic V.,Clinical Medical Center Bezanijska Kosa | Nedic O.,University of Belgrade

Insulin-like growth factor (IGF) binding protein 3 (IGFBP-3) is the most abundant IGFBP in the circulation and its main role is to regulate the amount of free, receptor-reactive IGFs that are involved in a broad range of metabolic and mitogenic activities. IGFBP-3 interacts with several other biomolecules forming complexes that might have IGF-dependent or independent functions. Transferrin (Tf) forms complexes with IGFBP-3, but the physiological significance of this interaction remains unclear. Tf is an iron-transporting protein, and is able to carry other metal ions as well. IGFBP-3, on the other hand, possesses one metal-binding domain. As both proteins have the ability to bind metals, the formation of the IGFBP-3-Tf complexes may be expected to influence the metabolism of metal ions and/or mitogenic/metabolic roles in which IGFBP-3 is involved. The aim of this study was to quantify the amount of complexes in the circulation, to investigate the importance of a specific metal ion for their formation and isolation, and to search for the possible physiological place of the IGFBP-3-Tf complexes. The effects of the following ions were analyzed: Fe3+, Cu2+, Ni2+, Mg 2+ and Zn2+. Results have shown that the amount of IGFBP-3 involved in the complex formation with Tf in healthy persons was 5.4 ± 1.02 nM and iron ions were substantial for their formation and isolation without employment of harsh conditions. The amount of IGFBP-3-Tf complexes was further determined in persons with iron over-load, patients with iron-deficiency anemia and patients with colorectal carcinoma-associated anemia. The amount of complexes was in direct correlation with the concentrations of iron and IGFBP-3. In the case of the colorectal carcinoma-associated anemia, the amount of complexes was inversely correlated with the concentration of ferritin. IGFBP-3, thus, appears to be a member of a network of iron-binding proteins that participates in cell signaling that involves iron-associated response. © 2013 The Royal Society of Chemistry. Source

Nedic O.,University of Belgrade | Robajac D.,University of Belgrade | Sunderic M.,University of Belgrade | Miljus G.,University of Belgrade | And 2 more authors.
Free Radical Biology and Medicine

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide and also the one with the highest mortality rate. Tumor growth is assisted by various growth factors, and insulin-like growth factors (IGFs) are among the most important. A majority of the IGFs are bound to IGF-binding proteins (IGFBPs) and their release is dependent on the rate of IGFBP proteolysis. The action of free IGFs is exerted and controlled by binding to cell membrane receptors (IGF-Rs). The objective of this work was to connect two determinants of the CRC pathology: oxidation as a process that underlies tumor development and the members of the IGF system that control it. Carbonyl groups (CO) on IGFBP-2, IGFBP-3, IGF-1R, and IGF-2R were determined in samples obtained from patients with CRC, and IGF-binding properties of these proteins were analyzed. According to our results, IGFBP-2 and IGFBP-3 in serum had increased content of CO groups due to CRC. Oxidation of IGFBP-2 increased its affinity for IGF molecules, whereas oxidation of IGFBP-3 reduced it. As for receptors, only intact CO-IGF-2R was detected on solubilized colon membranes, whereas CO-IGF-1R was degraded into fragments. Oxidative changes in the IGF axis may be regarded as part of the mechanism of its action. IGFs bound to IGFBP-3 remain in the circulation, whereas those bound to IGFBP-2 freely reach target tissues. Therefore, oxidation supports IGF distribution toward tissues and, consequently, promotes tumor growth. © 2013 Elsevier Inc. All rights reserved. Source

Discover hidden collaborations