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Berberine as a potential therapeutic agent for treating vascular dysfunction in diabetes: targeting AMP-activated protein kinaseWang, Yiqun, 王逸群 January 2010 (has links)
published_or_final_version / Medicine / Doctoral / Doctor of Philosophy
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Defects in early B lymphocyte development in Zmpste24⁻′⁻ miceZhou, Shuangcheng., 周雙宬. January 2009 (has links)
published_or_final_version / Biochemistry / Master / Master of Philosophy
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Vascular effects of vitamin D3 on endothelium-dependent contractions in SHR aortaWong, Sze-ka., 黃思伽. January 2010 (has links)
published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy
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Identification of liver tumour-initiating cells using a chemoresistantanimal modelCastilho, Antonia Genevieve. January 2010 (has links)
published_or_final_version / Pathology / Master / Master of Philosophy
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Phenotype analysis of Pdss2 conditional knockout mouseLu, Song, 鲁嵩 January 2010 (has links)
published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy
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Molecular pathogenesis of abnormal chondrocyte differentiation in a transgenic mouse modelTsang, Kwok-yeung., 曾國揚. January 2006 (has links)
published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy
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Beneficial effects of lycium barbarum in rat depression modelZhang, Endong, 张恩东 January 2011 (has links)
published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy
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Pathogenesis of congenital cataract in a gamma-crystallin mutant mousemodelTam, Chung-nga., 談頌雅. January 2012 (has links)
Congenital cataract is a leading cause of visual disability among children worldwide.
It has a heterogeneous genetic basis; the cellular and molecular mechanisms for
cataractogenesis remain elusive. A spontaneously occurred autosomal dominant
mouse mutant named Secc, which displays small eye, cataract and closed eyelid, has
been obtained in our laboratory. By gene mapping and DNA sequencing, we identified
a single nucleotide deletion at position 273 of the Cryga gene, leading to a frame-shift
from the 3rd Greek Key motif of the A-crystallin (Cryga). The aim of this study is to
investigate the pathogenic mechanisms underlying the development of cataract in the
Secc mutant, as a disease model for understanding human congenital cataract. Initial
phenotype analysis showed that cataract was initiated in E14.5 CrygaSecc mutant
embryos, the nuclei of the primary lens fibres were scattered and failed to align in the
equatorial region. By E16.5, the secondary lens fibre cells were abnormally arranged
with poor lens suture formation. Apoptotic cells were found in the centre of the lens as
shown by TUNEL assay, cytoskeleton and cell adhesion in the lens centre were
disturbed as shown in immunohistochemistry analysis.
Previously by western blotting it was found that mutant -crystallins were enriched in
the insoluble fraction. I hypothesized that mutant A-crystallins might be misfolded
and protein aggregates were then formed. In this study, aggregation was observed in
semi-thin sections stained with toluidine blue. By co-staining using custom-made
anti-Secc antibody, CrygaSecc protein was found to be ubiquitinated and was wrapped
around by vimentin. Clearly, in the Secc mutant lens, aggresomes were formed for the
disposal of the misfolded proteins and to maintain cell survival. However, ultimately
cell death would occur in the mutant lens and contributed to cataract formation.
It is known that misfolded proteins would trigger unfolded protein response (UPR)
and heat shock protein (HSP) responses to facilitate folding and to prevent misfolded
proteins from intoxicating the cell. In order to determine which stress response
pathway was triggered, gene expression analysis by qRT-PCR was performed. The
expression of genes involved in the UPR pathways including BiP, CHOP and spliced
variant of XBP-1 were all up-regulated significantly in E14.5 and 16.5 mutant lenses.
In addition, among different ER stress related genes, cytosolic chaperones and
autophagy related genes, Hsp70 and BiP were upregulated, while Hsp40 and Hsp90aa
were downregulated in the homozygotes. The results suggested that both UPR and
HSP response pathways were triggered during cataractogenesis in the Secc mutant.
In conclusion, mutant A-crystallin appeared to trigger UPR, HSPs and cell death in
the fibre cells, while autophagy was not triggered. In the lens fibre cells, the
ubiquitin-proteasomal pathway was utilized for the removal of misfolded CrygaSecc
proteins. However, the stress perpetuated as the lens grew and produced more mutant
proteins. The mutant cells lost their normal cell adhesion, failed to maintain the
proper lens architecture, leading to cataract formation. Similar cellular mechanisms
could be implicated in human congenital cataract or age-related cataract development. / published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy
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Toll-like receptor-4 mediates obesity-induced nonalcoholic steatohepatitis through activation of X-box binding protein-1 in miceYe, Dewei., 叶得伟. January 2012 (has links)
Background and objectives:
Nonalcoholic steatohepatitis (NASH), which is characterized by concurrent
existence of hepatic steatosis and predominantly lobular necroinflammation, represents
the more advanced stage in the spectrum of nonalcoholic fatty liver disease (NAFLD).
NASH exhibits dramatically increased risk of progression to end-stage liver diseases
than simple steatosis. Therefore, the progression of hepatic steatosis to steatohepatitis is
the crucial step in the development of obesity-related NASH. Toll like receptor 4
(TLR4), a master regulator of innate immunity, is the principal receptor for endotoxin,
which is a central mediator of liver inflammation associated with both alcoholic and
nonalcoholic liver disease. However, due to a lack of suitable animal models which
fully recapitulate the natural history of obesity-induced NASH, the precise
pathophysiological function of TLR4 signaling in the development of this disease
remains poorly understood.
The objective of this study is to investigate the role of TLR4 in mediating
inflammatory responses in obesity-induced NASH using both in vivo and ex vivo
approaches, and to unveil cellular and molecular mechanisms responsible for TLR4
actions.
Key findings:
1. To address the role of TLR4 in the pathogenesis of NASH, we crossed ApoEdeficient
mice (ApoE-/-) with TLR4 mutant mice (TLR4-/-) to generate ApoE-/-
/TLR4 wild type mice (ApoE-/-/TLR4-WT) and ApoE-/-/TLR4-/- mice. Noticeably,
when fed with high fat high cholesterol (HFHC) diet, ApoE-/-/TLR4-WT mice
developed the typical pathology of NASH (hepatic steatosis, lobular inflammation,
and hepatocyte ballooning) in the context of obesity and metabolic syndrome,
suggesting HFHC-fed ApoE-/- mice as a suitable animal model for NASH.
2. TLR4 inactivation protected ApoE-/- mice against HFHC diet-induced liver injury,
as indicated by a significant improvement in liver histology, a a marked reduction
in serum ALT activity, a dramatic repression of inflammatory infiltrates, as well as
an obvious decrease in hepatic production of pro-inflammatory cytokines.
3. In ApoE-/-/TLR4-WT mice, TLR4 expression was selectively elevated in Kupffer
cells in response to HFHC diet feeding.
4. The activation of XBP1, a transcription factor involved in endoplasmic reticulum
stress, was markedly elevated in liver of ApoE-/-/TLR4-WT mice fed with HFHC
diet, whereas this change was abrogated in HFHC diet-fed ApoE-/-/TLR4-/- mice.
5. In rat primary Kupffer cells, treatment with anti-oxidants blocked endotoxininduced
activation of XBP1 and NF-κB, leading to decreased cytokine production.
In addition, siRNA-mediated knockdown of XBP1 inhibited NF-κB activation and
cytokine production resulted from the treatment with the TLR4 agonist LPS.
6. In ApoE-/-/TLR4-WT mice, adenovirus-mediated expression of dominant negative
XBP1 had no obvious effect on HFHC diet-induced hepatic steatosis and ROS
production, but markedly decreased lobular inflammation, NF-κB activation,
cytokine production in the liver and significantly reduced serum levels of ALT.
Conclusions:
These findings support the role of TLR4 in Kupffer cells as a key player in
mediating the progression of simple steatosis to NASH, by inducing ROS-dependent
activation of XBP1. In light of the obligatory role of XBP1 in TLR4-induced liver
inflammation and injury, therapeutic interventions that inhibit TLR4/XBP1 activation
may represent a promising strategy for treatment of NASH. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy
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Mechanisms and Implications of Fracture in Cardiovascular StentsEverett, Kay Dee Furman January 2014 (has links)
Cardiovascular stents are one of the most widely implanted medical devices, with over 1 million implanted each year in the United States alone. While stent failure modes of restenosis and thrombosis have been widely examined, there is an increasing appreciation of the propensity for stents to fracture and break after implantation. It remains unclear however what causes these fractures, which patients and devices are most susceptible, and whether fracture results in failure of device function. / Engineering and Applied Sciences
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