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Dissertation
The role of glucose-derived compounds in liver diseases
Doctor of Philosophy (Ph.D.), Drexel University
Jun 2012
DOI:
https://doi.org/10.17918/00010318
Abstract
Liver cirrhosis and hepatocellular carcinoma (HCC) account for hundreds of thousands of deaths annually. Elucidating common mechanisms in the development of liver cirrhosis, regardless of the etiology of liver disease, as well as developing new therapies for patients with metastatic HCC remains a challenge. Previously, it was demonstrated that the N-glycosylation pattern on anti-Gal IgG molecules changes as liver fibrosis (scarring of the liver) progresses to end stage liver fibrosis also called cirrhosis. Whether these changes in N-glycans affect the effector functions of the antibodies possibly mediating liver pathogenesis has never been addressed. Anti-Gal antibodies are naturally produced by humans in response to the [alpha]-Gal epitope present on the Enterobacteria that colonize the gastrointestinal tract. Using rabbit erythrocytes as a source of the [alpha]-Gal epitope, we examined the ability of serum containing anti-Gal antibodies from patients with early or late liver fibrosis to induce complement-dependent hemoglobin release. Our results indicate that activation of complement by anti-Gal antibodies from patients with liver fibrosis is dependent on the stage of the liver fibrosis. Thus, these data might indicate a possible role for anti-Gal antibodies at mediating liver fibrosis progression to cirrhosis. Additionally, we investigated the anti-cancerous effects of 3-deoxyglucosone (3DG) and methylglyoxal (MG), two glucose metabolites, on HCC cell lines. In vitro and in vivo studies have reported conflicting anti-cancerous activities of MG. However, in spite of the controversy, we wanted to reevaluate whether MG had anti-cancerous activities on HCC. In addition, we investigated whether 3DG had an anti-cancerous modality, as this had not been studied previously. Our studies show that both 3DG and MG impair the migration, invasion, and adhesion of HCC cell lines. Furthermore, 3DG and MG inhibited HCC cell invasion in a p53-dependent manner regardless of whether the cells expressed mutant or wild-type p53. p53 is a tumor suppressor protein and dysregulation in this signaling pathway has been implicated in 30% of HCC cases. Therefore our results suggest that 3DG and MG could be potential therapeutics in p53-expressing HCC. Taken together, our data demonstrates a role for glucose-derived compounds in both the development and therapeutics of liver disease.
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Details
- Title
- The role of glucose-derived compounds in liver diseases
- Creators
- Lorena Loarca
- Contributors
- Carol Artlett (Advisor) - Drexel University, Drexel University (1970-)Richard F. Rest (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991021889062204721