BackgroundBillions of cells undergo apoptosis each day in the average normal adult. The ability to readily assess the degree of apoptosis in human diseases is hampered by the lack of sensitive and specific serum biomarkers of apoptosis. Fortilin is a novel prosurvival molecule that protects cells against various noxious stimuli. While fortilin is secreted into the extracellular space under certain conditions, the relationship between the serum concentration of fortilin and the presence and extent of apoptosis in vivo remains unknown.Methods & resultsUsing a newly developed fortilin ELISA system, we show here that fortilin exists in the normal human and mouse circulation. We further demonstrate that fortilin serum levels are significantly elevated in patients with solid cancer, in response to anti-cancer chemo- or radiation therapy. The elevation of fortilin serum levels is more robust and sensitive than that of such previously-reported serum biomarkers of apoptosis as fragmented cytokeratin-18, cytochrome c, and nucleosomal DNA. In addition, targeted apoptotic liver damage induced by Jo2 anti-Fas (CD95) antibody consistently and significantly increased serum fortilin levels in C57BL/6J mice. Finally, when challenged by anti-human-Fas IgM antibody, Jurkat leukemic T cells apoptosed and released fortilin into the medium before plasma membrane integrity was compromised.ConclusionsTaken together, these data suggest that serum fortilin levels reflect the degree and extent of apoptosis occurring in vivo.General significanceFortilin is a viable serum biomarker of in vivo apoptosis and can be utilized to noninvasively assess the status of in vivo apoptosis in humans.
2-Hydroxy-ethyl methacrylate (HEMA) is a major monomer released from resin-base dental restorative materials. HEMA is cytotoxic to pulp cells and leads to apoptosis. This study examined the effect of Translationally Controlled Tumor Protein (TCTP) against apoptosis from HEMA. TCTP from banana prawn (Penaeus merguiensis) was cloned and the protein was purified. It significantly increased the number of viable of HEMA-treated cells compared to HEMA-treated cells alone. Flow cytometry indicated the addition of TCTP at 10 μg/ml to 8 and 10 mM HEMA decreased the apoptotic cells from 20 to 10%. The proliferative property and anti-apoptotic activity against HEMA was concentration dependent. It was interesting that the added TCTP was not detected inside the cells and the native human TCTP was decreased after treated with HEMA and TCTP (20 μg/ml) + HEMA(10 mM) for 24 h. These results provided preliminary information, which may contribute to the development of less toxic dental materials.
Dental materials that can promote cell proliferation and function is required for regenerative pulp therapy. Resin modified glass ionomer cement (RMGIC), a broadly used liner or restorative material, can cause apoptosis to pulp cells mainly due to HEMA (2-hydroxyethyl methacrylate), the released residual monomer. Recent studies found that chitosan and albumin could promote release of protein in GIC while translationally controlled tumor protein (TCTP) has an anti-apoptotic activity against HEMA. The aim of this study was to examine the effect of chitosan and albumin modified RMGIC (Exp-RMGIC) supplemented with TCTP on pulp cell viability and mineralization. Exp-RMGIC+TCTP was composed of RMGIC powder incorporated with 15 % of chitosan, 5 % albumin and supplemented with TCTP mixed with the same liquid components of RMGIC. The effect of each specimen on pulp cells was examined using the Transwell plate. From the MTT assay, Exp-RMGIC+TCTP had the highest percentages of viable cells (P < 0.05) at both 24 and 74 h. Flow cytometry revealed that, after 24 h, Exp-RMGIC+TCTP gave the lowest percentages of apoptotic cells compared to other groups. There was no difference in alkaline phosphatase (ALP) activity among different formula of the specimens, while cells cultured in media with TCTP had higher ALP activity. Von Kossa staining revealed that RMGIC+TCTP, and Exp-RMGIC+TCTP had higher percentages of calcium deposit area compared to those without TCTP. It was concluded that Exp-RMGIC supplemented with TCTP had less cytotoxicity than RMGIC and can protect cells from apoptosis better than RMGIC supplemented with TCTP.
Apoptosis plays a critical role in many diseases including cancer and infectious diseases. The assessment of apoptosis occurring in the human body would allow clinicians to diagnose and treat these conditions. However, there is no sensitive and specific serum biomarker of apoptosis reported. Fortilin is a nuclear‐cytosolic shuttle protein with multifunctional implicated in various cellular functions. Since it is a potent anti‐apoptotic molecule and can be secreted into extracellular space via exosomes, we hypothesized that fortilin could be a viable serum biomarker of apoptosis occurring in vivo. Serum fortilin was quantified using ELISA in pre‐ and post‐treatment sera of patients with solid malignancies who were undergoing chemo‐ or radiation therapy, which trigger apoptosis in cancer tissue. The result showed that serum fortilin level was significantly elevated in patients who received anticancer therapy and more sensitive than cytochrome c, nucleosomal DNA, and fragmented cytokeratin‐18 biomarkers. Strikingly, serum fortilin level was elevated in the mouse model of apoptosis‐induced liver damage where Jo2 anti‐Fas antibody was administered to induce Fas‐mediated hepatocyte apoptosis. Moreover, fortilin was released from apoptosing Jurkat cell before plasma membrane integrity was compromised in a well‐defined Fas‐induced apoptosis. In conclusion, serum fortilin is a viable apoptosis biomarker which is secreted from apoptosing cells into the circulation, reflecting the degree of apoptosis occurring in vivo.
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