2,101 research outputs found
Green tea polyphenols modulate carbon tetrachloride-induced liver injury in mice
No full textpublished_or_final_versionAnatomyDoctoralDoctor of Philosoph
Expression and function of hypoxia-inducible factor, cytokines and renin-angiotensin system in the carotid body during chronic andintermittent hypoxia
No full textpublished_or_final_versionPhysiologyDoctoralDoctor of Philosoph
An in vivo study on the distinctive role of inducible and endothelial nitric oxide synthase in carbon tetrachloride-induced liver injury
No full textpublished_or_final_versionabstractAnatomyDoctoralDoctor of Philosoph
Study on the use of potential prognostic parameters in breast cancer patients
No full textpublished_or_final_versionabstracttocSurgeryDoctoralDoctor of Philosoph
Protective mechanisms of chronic aerobic exercise and S-allylmercaptocysteine on non-alcoholic fatty liver disease
No full textNonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common cause of liver disease worldwide, which is closely associated with other metabolic syndrome such as obesity and type II diabetes and appears to be related to an increasing sedentary and poor dietary lifestyle. Currently, exercise is a first line therapeutic intervention for NAFLD/non-alcoholic steatohepatitis (NASH) management and at the same time hepato-protective traditional herbal derivatives are gaining much attention as supplementary treatment strategy for NAFLD. In this study, we investigated the beneficial effects and molecular mechanisms of aerobic exercise (lifestyle modification) and garlic derived S-allylmercaptocysteine (SAMC) (herbal derivative) in the pathogenesis of NAFLD/NASH. There are two major hypotheses in this study namely: a) chronic exercise training decreases inflammation and increases antioxidant responses in muscle, which might contribute to the enhancement of muscle insulin sensitivity partly through TRIM72/PI3K/Akt/mTOR pathway and the improvement of systemic insulin intolerance, and ultimately leading to amelioration of NASH; b) SAMC ameliorates NASH partly through induction of hepatic cytoprotective enzymes which may be dependent on AhR/Nrf2 pathway, leading to the suppression of NF-κB/IκBα pathway and NLRP3/6 inflammasomes activation, and ultimately contributing to the improvement of NASH. In this study, NASH was induced in two models including a) Sprague-Dawley rats fed with a high fat diet (HFD) containing 30% from fish oil for 12 weeks, and b) mice NASH model fed with a methionine-choline deficient (MCD) diet. In the first study, the protective mechanisms of aerobic exercise on NAFLD were investigated in the NASH rat model. Four-week exercise training 1) decreased body weight and fat mass; 2) attenuated hepatic histological injury; 2) reduced serum ALT level; 3) reduced serum free fatty acids (FFA), hepatic triglycerides (TG) contents and hepatic lipogenesis; 4) restored systemic glucose and insulin intolerance; 5) improved muscle insulin sensitivity partly through TRIM72/PI3K/Akt pathway, accompanied with an upregulation of glucose transporter 4 (GLUT4); 6) increased antioxidant responses partly under the regulation of Nrf2/Keap1 pathway in the muscle; and 7) decreased expressions of pro-inflammatory cytokines through NF-κB/IκBα pathway in the skeletal muscle. In the second study, the protective mechanisms of SAMC were investigated in the livers of both rat and mice NASH models, which showed 1) reduced body weight and fat mass; 2) attenuated hepatic histological injury; 3) improved NAFLD-related features including decreased serum ALT levels, reduced serum FFA and hepatic TG contents; 4) ameliorated hepatic oxidative stress; 5) induced xenobiotic response element (XRE)- and antioxidant response element (ARE)-driven drug metabolising enzymes (DMEs) including Akr7a3, Akr1b8, and NQO1 based on global transcriptomic profiles by RNA-sequencing in whole-liver tissues; 6) increased the nuclear translocation of AhR and Nrf2 which were master regulators of xenobiotic and antioxidant responses, respectively; 7) decreased protein expression of nuclear transcription factor NF-κB and hepatic production of proinflammatory cytokines; 8) diminished NLRP3 and NLRP6 inflammasomes. In conclusion, the present study proposes that both exercise training and garlic are effective in modulating the progression and outcome of NAFLD/NASH which could be used as supplementary therapeutic management strategy for NAFLD/NASH.published_or_final_versionBiomedical SciencesDoctoralDoctor of Philosoph
Prelimbic cortical stimulation ameliorates inflammation-induced social behavioural deficits and depressive-like behaviours
No full textDeep brain stimulation (DBS) is a promising neuromodulation therapy for treatment-resistant depression. Previous studies have reported the comorbidity of neuroinflammation and depression, but the underlying mechanisms of the stimulation-induced antidepressive effects on neuroinflammatory elements remain largely unknown. This study aimed to investigate the anti-neuroinflammatory effects of DBS of the prelimbic cortex (PrL-DBS) in rat models of depression. Rats received either electric stimulation or sham stimulation of the prelimbic cortex and then underwent 3 weeks of a chronic unpredictable stress (CUS) paradigm. Rats were subjected to 1 hour of high-frequency stimulation (100 Hz) at 200 µA amplitude prior to testing for social interaction and depressive-like behaviours. Their brains were processed to further elucidate the anti-neuroinflammatory-related mechanisms of DBS-induced antidepressant activity. A further investigation in another animal depression model using a combined CUS and lipopolysaccharide (LPS) treatment paradigm was conducted to examine the anti-neuroinflammatory-dependent and/or -independent mechanisms of DBS-induced antidepressant activity. In both CUS- and CUS plus LPS-induced depression models, we observed increased social interaction and decreased forced swim immobility time in animals with DBS of the prelimbic cortex compared to sham stimulation. Interestingly, the gene expression study found significant neuroinflammatory-related changes after DBS. These results were further supported by the morphological analysis of microglial expression within the prefrontal cortical areas. The study findings demonstrated that PrL-DBS in rats enhanced social interaction and antidepressive-like behaviours. The results also showed that the DBS-induced changes in the neuroinflammatory environment were mediated by both neuroinflammatory-dependent and -independent mechanisms.published_or_final_versionBiomedical SciencesMasterMaster of Philosoph
A dual role for DLC1 in regulating avian cranial neural crest cell fate commitment and delamination
No full textIn response to neural crest inductive signals, cells in the open neural plate border
region are bestowed with competence to give rise to neural crest cells. Upon neural
tube closure, prospective neural crest cells undergo epithelial-mesenchymal
transition (EMT) to delaminate from the dorsal neuroepithelium, migrate and
differentiate into various cell types throughout the embryos. These sequential steps
of neural crest ontogeny are strictly governed by a gene regulatory network (GRN)
comprising of an array of transcription factors. However, the molecule mechanisms
leading to the emergence and segregation of definitive neural crest cells from other
lineages have remained elusive. Here, this study revealed that a RhoGTPase
activating (RhoGAP) protein, deleted in liver cancer 1 (DLC1) exhibits both
nuclear and cytoplasmic localization in the prospective avian cranial neural crest
cells. Intriguingly, forced expression and knockdown of DLC1 led to loss of neural
crest specifier genes, SOX9, SNAIL2 and FOXD3 expression and the expansion of
SOX2-positive neural progenitor domain into the neural crest forming territory while PAX7-positive neural plate border region remains unaltered, suggesting that
appropriate level of DLC1 expression in the nucleus is required for the segregation
of neural crest lineage through regulation of their specifier genes expression. This
is accomplished by an essential requirement of DLC1 to recruit PAX7 binding to
the cis-regulatory elements of NC specifier genes together with transcription
elongation factor B polypeptide 1 (TCEB1) for transcriptional regulation.
In addition, this study further showed that cytoplasmic DLC1 recruits a novel
partner, Serine-Threonine Kinase Receptor-Associated Protein (STRAP) which is
a WD-containing protein through its amino acid 69-322 region. The cooperation of
DLC1 and STRAP prevented SNAIL2 from degradation via inhibition of GSK3β
activity in an RHOA-independent manner, resulting in repression of its nuclear
target Cad6B for the proper onset of neural crest delamination. Together, these
findings unravel unprecedented subcellular roles of DLC1 in regulating both avian
cranial neural crest cell fate commitment and delamination, providing a new
paradigm for our understanding of the neural crest-GRN and also on future neural
crest reprograming studies.published_or_final_versionBiomedical SciencesDoctoralDoctor of Philosoph
Neuroplasticity and DNA methylation-related mechanism of L-methionine in cognition
No full textRecent studies have shed light on the importance of the dynamic property of DNA methylation in memory formation and maintenance. Methionine is an essential component in one-carbon metabolism, which plays a pivotal role in gene-environment interaction. The disruption of the one-carbon metabolism is implicated in the pathophysiology of various neurodegenerative disorders, for instance age-related dementia and Alzheimer’s disease (AD), in which memory loss is manifested as the core symptom.
In this thesis, I systematically reviewed the neuroepigenetic alterations involved in the pathophysiology of AD seen in literature as an attempt to delineate potential molecular deficits contributing to cognitive impairment. The influence of altered DNA methylation in AD on components involved in neurochemical pathways on memory formation was then examined. I then showed that protracted L-methionine (MET) treatment rescued memory deficits and attenuated amyloid burden through restoring MeCP2-CREB-BDNF and CaN-Akt-GSK3β cascades in 5xFAD transgenic mice. Following the findings that MET effectively normalized certain DNA methylation machinery in AD animal model, I investigated the effect of neuromodulation techniques on certain DNA methylation mechanisms that depend on neuronal activity, and made the case for the said mechanisms as possible memory modulation targets. I then extended the effects of MET on AD identified in the previous chapter to aged animals as a combined treatment paradigm with prelimbic cortical deep brain stimulation (PrL DBS). I showed that while MET alone had no behavioral effect on aged animals, it potentiated the memory-enhancing effect of PrL DBS. MET was able to rescue the global DNA hypomethylation observed in aged animals, and induce expression of plasticity-related genes and proteins in a synergistic manner with PrL DBS. I then showed that inhibition of DNMT in the hippocampus specifically abolished the memory-enhancing effect of PrL DBS, established the integral role of DNMT in mediating the effect of PrL DBS on cognition. Lastly, I proposed the epigenetic regulations of Bdnf gene as the key to memory extinction and BDNF modulation as a potential target for alleviating depression and fear-related anxiety disorders. Overall, my thesis presents evidence demonstrating the important role of DNA methylation in memory disorders and MET as a viable therapeutic in AD and dementia.published_or_final_versionBiomedical SciencesDoctoralDoctor of Philosoph
Nitric oxide production, oxidative stress, and inflammation in the rat adrenal medulla during chronic and intermittent hypoxia
No full textAdrenal gland, as an important effector tissue of the sympathetic nervous system, has critical roles in cardiovascular system under both chronic hypoxia (CH) and intermittent hypoxia (IH) conditions. Nitric oxide (NO), synthesized by nitric oxide synthases (NOS), is the most important intracellular signaling molecule, as well as free radical in response to hypoxia. Yet the regulation and effects of endogenous NO production mediated in the adrenal medulla induced by hypoxia remains largely unknown.
We first studied how endogenous NO production were regulated by different NOS in rat adrenal medulla in response to CH or IH. After CH, elevated levels of endogenous NO production, eNOS expression, and apoptotic chromaffin cells were observed in the adrenal medulla. However, a remarkable decreased endogenous NO production and nNOS expression were shown in the IH-treated adrenal medulla. These results suggested that, in the rat adrenal medulla, the elevation of NO production through increased protein level of eNOS may play a protective role in the adaptive response to CH; the reduction of NO production through decreased expression of nNOS is important for the pathophysiological response to IH.
The oxidative stress and cellular injury in the adrenal medulla under chronic intermittent hypoxia (CIH) condition is undefined. We tested the hypothesis that melatonin, a potent antioxidant, is protective against CIH-induced oxidative stress and local inflammation in the rat adrenal medulla. Results showed that levels of oxidative stress, lipid peroxidation, and inflammatory mediators were significantly increased after CIH treatment. Also, the protein levels of antioxidant enzymes were significantly lowered in the hypoxic group. Co-treatment of melatonin with hypoxia significantly reduced oxidative stress and inflammatory responses in the adrenal medulla. Moreover, the amount of apoptotic cells in the hypoxic groups was significantly less in the melatonin-treated group. Thus, melatonin may act as a protective agent against adrenal damages in patients with severe obstructive sleep apnea syndrome.
Previous studies have shown that CIH associated with recurrent apnea induced oxidative stress and pathophysiological changes in the cardiovascular system. Yet the mechanism of the CIH-induced oxidative stress and local inflammation in the adrenal medulla was undefined. We therefore determined whether the up-regulation of the expression of NADPH oxidase (NOX) mediated by renin-angiotensin system (RAS) may take part in the injuries caused by CIH in the rat adrenal medulla. We found that CIH treatment dramatically induced marker levels of adrenal oxidative stress, inflammation, macrophage infiltration, and apoptosis in rats. Co-treatment with NOX inhibitor, apocynin, counteracted such reactions. Furthermore, the mRNA levels of NOX subunits (p22PHOX, NOX2, and NOX4) and RAS components (ATG, AT1, and AT2) were increased significantly in the CIH group, but reduced in apocynin-treated CIH group, supporting the involvement of NOX and RAS in CIH-induced adrenal injury. In conclusion, we defined the roles of NO production, NOX, and RAS in the rat adrenal injury during hypoxic conditions. We also found that melatonin can protect adrenal medulla from hypoxia-induced damages in rat.published_or_final_versionPhysiologyDoctoralDoctor of Philosoph
Pathophysiological role of monoamine oxidase-A in the activation of indoleamine-2, 3-dioxygenase and neurodegeneration in the hippocampus induced by chronic intermittent hypoxia in rodents
No full textObstructive sleep apnea (OSA) has been shown to be associated with major depressive disorder (MDD) in patients. However, there is a lack of pathophysiological mechanisms to depict the causal relationship. The hippocampus is an important brain region that manifests neuropathies in psychiatric disorders. Overactivation of monoamine oxidase-A (MAO-A) and cytokine-sensitive indoleamine-2,3-dioxygenase (IDO-1) have been reported in the brains of clinically depressed patients and animals, and leads to deregulated serotonin metabolism and neurodegeneration. Yet, the involvement of MAO-A and IDO-1 mediating hippocampal serotonin depletion and neurodegeneration resulting in depressive-like behavior in experimental animals under chronic intermittent hypoxia (CIH), a hallmark clinical manifestation of OSA patients, is largely unknown. In my study, I found that rats given CIH treatment (Apnea-Hyponea Index =60) displayed significant depressive-like behaviors. There were significant increases in the MAO-A activity, serotonin metabolic turnover, oxidative stress, nuclear factor kappa B (NFKB) cascade activation, neuroinflammation, IDO-1 activation and apoptotic markers in the hippocampus of CIH-treated rats. In addition, there were marked alterations in the neuroarchitecture of the CA1 and CA3 pyramidal neurons revealed by Golgi staining.
Patients suffered from Cushing syndrome (CS) were shown to be co-morbid with sleep apnea reported in medical literature. Patients with CS are at a high risk of developing depression. However, the exacerbative effect of OSA on the progression of depressive-like behaviors in patients with CS is not clearly understood. Therefore, in the next study, rats were given repeated corticosterone (CORT) injections for 14 days and CIH treatment at day 8 lasting for a week. I found that CIH aggravated CORT-induced depressive-like behaviors in the rats through exacerbating the MAO-A activity resulting in oxidative stress, inflammation, and IDO-1 activation, leading to serotonin deficiency and neurodegeneration.
The brain permeable multifunctional drug M30 possesses brain selective MAO-inhibition and iron-chelating antioxidative properties. Protective effects of M30 have been shown in animal and cell models of neurodegenerative diseases with its anti-oxidative, anti-inflammatory and anti-apoptotic effects. However, the beneficial effects of M30 against depression induced by CIH or by concurrent treatment of CIH and CORT remain elusive. In my studies, I found that M30 pre-treatment remarkably prevented the onset of depression, ameliorated serotonin turnover, oxidative stress, inflammation, IDO-1 activation, restored serotonin depletion and abrogated the impairment of dendritic abnormalities in the hippocampus induced by CIH and co-treatment of CIH and CORT.
Obesity is a risk factor of OSA and the exacerbative effect of CIH on the hippocampal neurodegeneration and altered serotonin metabolism in obese mice is examined in the last study. C57Bl/6 mice were given high fat diet treatment (45% energy from fat) for 12 weeks and CIH treatment at 9th week lasting for a month. I found that elevated levels of MAO-A activity, oxidative stress, inflammation, IDO-1 activation, serotonin metabolic turnover and hippocampal neurodegeneration were the most prominent in high fat diet and CIH co-treated mice.
Collectively, these findings suggest that the axis of MAO-A/Oxidative Stress/Inflammation/IDO-1/Neurodegeneration plays an important role in the induction of depressive-like behaviors under CIH conditions and co-morbid complications.published_or_final_versionBiomedical SciencesDoctoralDoctor of Philosoph
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