1,721,791 research outputs found
In-vitro study on the cytotoxic effects and mechanisms of action of arsenic trioxide on human neuroblastoma cells
No full textpublished_or_final_versionabstractPaediatrics and Adolescent MedicineMasterMaster of Philosoph
The immunomodulatory effect of Brazilian green propolis and its uniquecompound Artepillin C
No full textpublished_or_final_versionPaediatrics and Adolescent MedicineDoctoralDoctor of Philosoph
The immunomodulatory effects of purified {221}-glucans and {221}-glucan containing herbs
No full textpublished_or_final_versionabstractPaediatrics and Adolescent MedicineDoctoralDoctor of Philosoph
The role of platelet-derived molecules: PDGF and serotonin in the regulation of megakaryopoiesis
No full textInvestigations on platelet-derived growth factor (PDGF) and serotonin (5-HT), molecules stored in platelet granules, imply their potential effects in regulating megakaryopoiesis, which also intimates the existence of an autocrine and/or paracrine loop constructed by megakaryocytes/platelets and their granular constituents. In addition, numerous reports indicate that melatonin, a derivative from serotonin effectively enhances platelet counts in patients with thrombocytopenia. However, their exact roles on human megakaryocytes and the underlying mechanisms remain unknown.
Present studies showed that PDGF, like thrombopoietin (TPO), significantly promoted platelet recovery and the formation of bone marrow colony-forming unit-megakaryocyte (CFU-MK) in an irradiated-mouse model. An increased number of hematopoietic stem/progenitor cells and a reduction of apoptosis were found in the bone marrow aspirate. In the M-07e apoptotic model, PDGF had a similar anti-apoptotic effect as TPO on megakaryocytes. Our findings demonstrated that PDGF activated the PI3-k/Akt signaling pathway, while addition of imatinib mesylate reduced p-Akt expression. Our findings suggested that the PDGF-initiated radioprotective effect is likely to be mediated via PDGF receptors (PDGFRs) with subsequent activation of the PI3-k/Akt pathway. We also provide a possible explanation that blockade of PDGFR may reduce thrombopoiesis and play a role in imatinib mesylate-induced thrombocytopenia.
We explored how serotonin regulated megakaryopoiesis and proplatelet formation. Our results indicated that serotonin (5-HT) significantly promoted CFU-MK formation and reduced apoptosis on megakaryocytes through phosphorylation of Akt. These effects were attenuated by addition of ketanserin, a 5-HT2 receptor inhibitor. In addition, serotonin was able to stimulate the F-actin reorganization in megakaryocytes through activating the p-Erk1/2 expression.
Bone marrow mesenchymal stromal cells (MSCs) are important in regulating megakaryopoiesis through stimulating the release of thrombopoietic growth factor, such as TPO. Our studies suggested that when activated by serotonin, bone marrow MSCs were induced to release significant amount of TPO. Furthermore, thousands of membrane-derived microparticles (MPs) arose from MSCs and the TPO RNA/proteins contained within MPs were also considerably increased under serotonin treatment. In summary, our findings demonstrated an important role serotonin played on megakaryopoiesis. This effect was likely mediated via 5HT2 receptors with subsequent activation of Akt and Erk 1/2 phosphorylation, which led to survival of megakaryocytes and proplatelet formation. Serotonin also stimulated TPO released from MSCs in both dissociative and MP-encapsulated form, which indirectly promoted megakaryopoiesis.
The effects of melatonin on megakaryopoiesis were also determined in our studies. Our findings showed that melatonin enhanced proliferation and reduced doxorubicin-induced toxicity on MKs. We further demonstrated the mechanism for melatonin-mediated protection on MKs maybe via repair of G2/M phase cell cycle arrest and inhibition of cell apoptosis on MK cells.
The effects of melatonin on megakaryopoiesis were also determined in our studies. Our findings showed that melatonin enhanced proliferation and reduced doxorubicin-induced toxicity on MKs. We further demonstrated the mechanism for melatonin-mediated protection on MKs maybe via repair of G2/M phase cell cycle arrest and inhibition of cell apoptosis on MK cells.published_or_final_versionPaediatrics and Adolescent MedicineDoctoralDoctor of Philosoph
The effect of microtubule targeting chemotherapeutic agents on bone marrow derived mesenchymal stromal cells and its interaction withacute lymphoblastic leukemia blasts
No full textpublished_or_final_versionPaediatrics and Adolescent MedicineMasterMaster of Philosoph
Effects of anoikis stress on human mesenchymal stem cells
No full textpublished_or_final_versionPaediatrics and Adolescent MedicineMasterMaster of Philosoph
Human mesenchymal stromal cells enhance bone marrow metastases of neuroblastoma via SDF-1 related pathways
No full textpublished_or_final_versionPaediatrics and Adolescent MedicineMasterMaster of Philosoph
The role of apoptotic neuroblastoma-derived extracellular vesicles on mesenchymal stem cell and their regulation of T cells
No full textNeuroblastoma is the second most common solid tumour found in paediatrics, even with a combination of therapies including the state of the art anti- disialoganglioside 2 (GD2) immunotherapy, only 50 to 60% of the patients with metastatic disease survived. One of the contributory factors is the unfavourable tumour microenvironement (TME) for the immune cells. Within the TME, mesenchymal stem cells (MSCs) can be found for they can migrate through the blood vessels. They are known for their immunosuppressive function hence they may become a major hindrance to the effective immunotherapy treatment. Nevertheless, studies have shown that MSCs function can be manipulated by the environment. Under certain stimuli, MSCs can convert to a pro-inflammatory phenotype. In neuroblastoma patients who are receiving chemotherapy, an accumulation of apoptotic cells (AC) is expected. The aim of this study was to investigate how apoptotic neuroblastoma cells may affect MSCs T cell modulatory function.
By priming the immortalised MSC (hTMSC) with neuroblastoma-derived apoptotic cells, we found an increase of T cell proliferation and activation. Moreover the T cells were induced to differentiate to pro-inflammatory phenotype. We also found a reduction in regulatory T cells (Treg) differentiation. Moreover these T cells that were co-cultured with AC-primed hTMSC has a greater cancer killing function. We later discovered that this activation of hTMSC may be due to the dying neuroblastoma cells after cisplatin treatment. Not only does cisplatin induce apoptosis in neuroblastoma, we also discovered signs of immunogenic cell death pathway necroptosis - a programmed necrosis cell death occurred.
As immunogenic molecules were not found in the supernatant of the dying neuroblastoma cells, we explored the possible involvement of extracellular vesicles (EVs). EVs-derived from neuroblastoma cell line was highly heterogeneous, we also compared the EVs derived from both cisplatin treated or untreated neuroblastoma cells. We found that each population of EVs had their unique characteristic, interestingly apoptotic neuroblastoma-derived EVs contains the HMGB1 protein which is often associated with pro-immunostimulatory function. The apoptotic microvesicle was the most effective group in inducing the hTMC to decreased Treg differentiation and increase T cell proliferation. To further confirm the importance of HMGB1, we studied the downstream of HMGB1. There was a slight up-regulation of the HMGB1 receptor, RAGE and TLR2 on the hTMSC. This eventually led to an activation of the NF-kB signalling pathway and increased the secretion of pro-inflammatory cytokines IL-6, IL-8 and IL-33.
In conclusion, we proposed that with chemotherapy, abundant ACs will be released. This accumulation of ACs from the TME may alter the immune response. Apoptotic neuroblastoma can release EVs containing immunogenic proteins such as HMGB1 to convert the hTMSC in switching from immunosuppressive to pro-inflammatory phenotype. Our findings suggest a paradigm shift in anti-cancer concept. This is to improve the efficacy of immunotherapy by manipulating the TME towards a more favourable condition for immune surveillance.published_or_final_versionPaediatrics and Adolescent MedicineDoctoralDoctor of Philosoph
Potential interventional modalities on neurodevelopmental and neurodegenerative diseases: in vivo and invitro study
No full textpublished_or_final_versionPaediatrics and Adolescent MedicineDoctoralDoctor of Philosoph
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