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Dive into the research topics where Andrew Chi-Yuen Chu is active.

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Featured researches published by Andrew Chi-Yuen Chu.


Free Radical Biology and Medicine | 2009

Mitochondrial UCP4 attenuates MPP+-and dopamine-induced oxidative stress, mitochondrial depolarization, and ATP deficiency in neurons and is interlinked with UCP2 expression

Andrew Chi-Yuen Chu; Philip Wing-Lok Ho; Ken Hon-Hung Kwok; Jessica Wing-Man Ho; Koon-Ho Chan; H Liu; Michelle Hiu-Wai Kung; Db Ramsden; Sl Ho

Mitochondrial uncoupling proteins (UCPs) uncouple oxidative phosphorylation from ATP synthesis. We explored the neuroprotective role of UCP4 with its stable overexpression in SH-SY5Y cells, after exposure to either MPP(+) or dopamine to induce ATP deficiency and oxidative stress. Cells overexpressing UCP4 proliferated faster in normal cultures and after exposure to MPP(+) and dopamine. Differentiated UCP4-overexpressing cells survived better when exposed to MPP(+) with decreased LDH release. Contrary to the mild uncoupling hypothesis, UCP4 overexpression resulted in increased absolute ATP levels (with ADP/ATP ratios similar to those of controls under normal conditions and ADP supplementation) associated with increased respiration rate. Under MPP(+) toxicity, UCP4 overexpression preserved ATP levels and mitochondrial membrane potential (MMP) and reduced oxidative stress; the preserved ATP level was not due to increased glycolysis. Under MPP(+) toxicity, the induction of UCP2 expression in vector controls was absent in UCP4-overexpressing cells, suggesting that UCP4 may compensate for UCP2 expression. UCP4 function does not seem to adhere to the mild uncoupling hypothesis in its neuroprotective mechanisms under oxidative stress and ATP deficiency. UCP4 overexpression increases cell survival by inducing oxidative phosphorylation, preserving ATP synthesis and MMP, and reducing oxidative stress.


Free Radical Biology and Medicine | 2010

Mitochondrial UCP5 is neuroprotective by preserving mitochondrial membrane potential, ATP levels, and reducing oxidative stress in MPP+ and dopamine toxicity.

Ken Hon-Hung Kwok; Philip Wing-Lok Ho; Andrew Chi-Yuen Chu; Jessica Wing-Man Ho; H Liu; David Chi-Wai Yiu; Koon-Ho Chan; Michelle Hiu-Wai Kung; Db Ramsden; Sl Ho

We explored the protective mechanisms of human neuronal mitochondrial uncoupling protein-5 (UCP5) in MPP(+)- and dopamine-induced toxicity after its stable overexpression in SH-SY5Y cells. We raised specific polyclonal antibodies. Overexpressed UCP5 localized in mitochondria but not in cytosol. UCP5 overexpression increased proton leak, decreased mitochondrial membrane potential (MMP), reduced ATP production, and increased overall oxygen consumption (demonstrating uncoupling activity). UCP5 overexpression did not affect other neuronal UCP expression (UCP2 and UCP4). Overexpressing UCP5 is protective against MPP(+)- and dopamine-induced toxicity. MPP(+) and dopamine exposure for 6h reduced MMP and increased superoxide levels. ATP levels in UCP5-overexpressing cells were preserved under MPP(+) and dopamine toxicity, comparable to levels in untreated vector controls. At 24h, UCP5 overexpression preserved MMP, ATP levels, and cell survival; attenuated superoxide generation; and maintained oxidative phosphorylation as indicated by lower lactate levels. MPP(+) and dopamine exposure induced UCP5 mRNA transcription but did not decrease transcript degradation, as inhibition of transcription by actinomycin-D abolished induction by either toxin. Compared with our previous studies on UCP4, we observed functional differences between UCP4 and UCP5 in enhancing mitochondrial efficiency. These neuronal UCP homologues may work synergistically to maintain oxidative balance (through uncoupling activities) and ATP production (by modifying MMP).


American Journal of Transplantation | 2004

Linking Inflammation to Acute Rejection in Small‐For‐Size Liver Allografts: The Potential Role of Early Macrophage Activation

Zhen-Fan Yang; David Ho; Andrew Chi-Yuen Chu; Yan-Qing Wang; Sheung Tat Fan

This study aims to investigate the immunological status of small‐for‐size liver allografts and possible mechanism that contributes to the accelerated immune response in these allografts. Eight experimental groups were: whole isografts; 40% isografts; whole allografts, no treatment; 40% allografts, no treatment; whole allografts with sodium salicylate intraperitoneal injection, D0‐3; 40% allografts with sodium salicylate, D0‐3; whole allografts with FK506 intramuscular injection D0‐3, and 40% allografts with FK506, D0‐3. The 40% allografts survived significantly shorter than whole allografts (p = 0.02). At 72 h after reperfusion, a higher number of macrophages infiltrated into the periportal area of small‐for‐size allografts than whole allografts. Remarkable up‐regulation of interleukin‐1β (IL‐1β), interleukin‐2 (IL‐2), interleukin‐10 (IL‐10) and interferon‐γ (IFN‐γ) messenger RNA (mRNA) levels were detected in small‐for‐size allografts within 24 h after reperfusion. Sodium salicylate administration reduced IL‐1β and IFN‐γ mRNA in both small‐for‐size and whole allografts, but it could decrease IL‐2 and IL‐10 mRNA levels only in small‐for‐size allografts. In vitro study revealed that CD80, CD86 and CD11b expression on macrophages was augmented after IL‐1β stimulation, whereas the up‐regulation could be blocked by sodium salicylate. In conclusion, early activation of macrophages as a result of graft injury might play an important role in the accelerated acute rejection process in small‐for‐size allografts.


Journal of Neuroscience Research | 2006

Knockdown of uncoupling protein-5 in neuronal SH-SY5Y cells: Effects on MPP+-induced mitochondrial membrane depolarization, ATP deficiency, and oxidative cytotoxicity.

Philip Wing-Lok Ho; Andrew Chi-Yuen Chu; Ken Hon-Hung Kwok; Michelle Hiu-Wai Kung; Db Ramsden; Sl Ho

Uncoupling proteins (UCPs) uncouple oxidative phosphorylation from ATP synthesis by dissipating proton gradient across mitochondrial inner membrane. The physiological role of neuronal specific UCP5 is unknown. We explored the effects of reduced UCP5 expression on mitochondrial membrane potential (MMP), oxidative stress, ATP levels, and cell viability, under normal and MPP+‐induced cytotoxic conditions, in human catecholaminergic SH‐SY5Y cells. UCP5 expression was reduced by 56% by siRNA, compared to scrambled‐siRNA controls. UCP5 knockdown induced apoptosis but did not affect basal levels of ATP, oxidative stress and MMP in the cells under normal conditions. However, UCP5 knockdown increased MPP+‐induced cytotoxicity by 15% and oxidative stress levels by 40%, and partially restored MPP+‐induced mitochondrial depolarization by 57%. UCP2 and UCP4 expression were unaffected by UCP5 knockdown. Exacerbation of cytotoxicity, oxidative stress and modification of MMP with reduced UCP5 expression in the face of MPP+ toxicity suggest that UCP5 might be physiologically important in the pathology of oxidative stress‐induced neurodegeneration.


Neurotoxicity Research | 2010

Mitochondrial uncoupling protein-2 (UCP2) mediates leptin protection against MPP+ toxicity in neuronal cells.

Philip Wing-Lok Ho; H Liu; Jessica Wing-Man Ho; Wei-Yi Zhang; Andrew Chi-Yuen Chu; Ken Hon-Hung Kwok; Xuan Ge; Koon-Ho Chan; Db Ramsden; Sl Ho

Mitochondrial dysfunction is involved in the pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD). Uncoupling proteins (UCPs) delink ATP production from biofuel oxidation in mitochondria to reduce oxidative stress. UCP2 is expressed in brain, and has neuroprotective effects under various toxic insults. We observed induction of UCP2 expression by leptin in neuronal cultures, and hypothesize that leptin may preserve neuronal survival via UCP2. We showed that leptin preserved cell survival in neuronal SH-SY5Y cells against MPP+ toxicity (widely used in experimental Parkinsonian models) by maintaining ATP levels and mitochondrial membrane potential (MMP); these effects were accompanied by increased UCP2 expression. Leptin had no effect in modulating reactive oxygen species levels. Stable knockdown of UCP2 expression reduced ATP levels, and abolished leptin protection against MPP+-induced mitochondrial depolarization, ATP deficiency, and cell death, indicating that UCP2 is critical in mediating these neuroprotective effects of leptin against MPP+ toxicity. Interestingly, UCP2 knockdown increased UCP4 expression, but not of UCP5. Our findings show that leptin preserves cell survival by maintaining MMP and ATP levels mediated through UCP2 in MPP+-induced toxicity.


Magnetic Resonance in Medicine | 2008

Manganese-Enhanced MRI Detection of Neurodegeneration in Neonatal Hypoxic-Ischemic Cerebral Injury

Jian Yang; Pl Khong; Yanxin Wang; Andrew Chi-Yuen Chu; Sl Ho; Pik-To Cheung

In this study, we investigated the Mn‐enhanced MRI (MEMRI) for detecting neurodegenerative processes in neonatal hypoxic‐ischemic (H‐I) cerebral injury. Seven‐day‐old rats were induced with H‐I injury, and scanned for T1‐weighted image (T1WI) and T2‐weighted image (T2WI) with and without systemic MnCl2 administration. Serial histological analysis was performed for Mn‐superoxide dismutase (Mn‐SOD) and glutamine synthetase (GS), which are Mn‐binding enzymes against the oxidative stress and glutamate excitotoxicity in neurodegeneration. In the acute phase (first 2 days), the ipsilateral lesion exhibited no Mn enhancement in T1WIs, with histology showing no Mn‐SOD and GS production. In the mid‐phase (from day 3), Mn enhancement was found in the cortex, basal ganglia, and hippocampus, correlating with local Mn‐SOD and GS increase. In the late phase, the enhancement became more localized to the pericyst basal ganglia and cortex, and then gradually diminished. In T2WIs, a signal decrease was observed from day 3 in the corresponding regions. Hypointense voids gradually formed in the late phase, correlating with the local iron accumulation. H‐I rats without Mn2+ administration exhibited similar but weak changes in T1WIs and T2WIs from days 14 and 7, respectively. These results indicate that Mn2+ may be a useful in vivo probe for monitoring Mn‐SOD and GS enzymatic activities. Magn Reson Med, 2008.


PLOS ONE | 2013

Epigenetic Regulation of Pluripotent Genes Mediates Stem Cell Features in Human Hepatocellular Carcinoma and Cancer Cell Lines

Xiao Qi Wang; Ray Kit Ng; Xiaoyan Ming; Wu Zhang; Lin Chen; Andrew Chi-Yuen Chu; Roberta Pang; Chung Mau Lo; Sai Wah Tsao; Xuqing Liu; Ronnie Tung-Ping Poon; Sheung Tat Fan

Activation of the stem cell transcriptional circuitry is an important event in cancer development. Although cancer cells demonstrate a stem cell-like gene expression signature, the epigenetic regulation of pluripotency-associated genes in cancers remains poorly understood. In this study, we characterized the epigenetic regulation of the pluripotency-associated genes NANOG, OCT4, c-MYC, KLF4, and SOX2 in a variety of cancer cell lines and in primary tumor samples, and investigated the re-activation of pluripotency regulatory circuits in cancer progression. Differential patterns of DNA methylation, histone modifications, and gene expression of pluripotent genes were demonstrated in different types of cancers, which may reflect their tissue origins. NANOG promoter hypomethylation and gene upregulation were found in metastatic human liver cancer cells and human hepatocellular carcinoma (HCC) primary tumor tissues. The upregulation of NANOG, together with p53 depletion, was significantly associated with clinical late stage of HCC. A pro-metastatic role of NANOG in colon cancer cells was also demonstrated, using a NANOG-overexpressing orthotopic tumor implantation mouse model. Demethylation of NANOG promoter was observed in CD133+high cancer cells. In accordance, overexpression of NANOG resulted in an increase in the population of CD133+high cells. In addition, we demonstrated a cross-regulation between OCT4 and NANOG in cancer cells via reprogramming of promoter methylation. Taken together, epigenetic reprogramming of NANOG can lead to the acquisition of stem cell-like properties. These results underscore the restoration of pluripotency circuits in cancer cells as a potential mechanism for cancer progression.


Cancer Letters | 2014

Regulatory B cells accelerate hepatocellular carcinoma progression via CD40/CD154 signaling pathway

Yan Shao; Chung Mau Lo; Chang Chun Ling; X Liu; Kevin Tak-Pan Ng; Andrew Chi-Yuen Chu; Yuen Yuen Ma; Chang Xian Li; Sheung Tat Fan; Kwan Man

Human hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide with a poor prognosis of limited survival. The role of regulatory B cell (Breg), a new important B cell subset, in HCC progression remains unclear. We firstly found that the percentage of B cells at tumor margin was significantly higher than that in tumor and non-tumor regions. Especially, increased intrahepatic B cells at tumor margin were positively associated with tumor invasive features and more tumor recurrence. Besides, HCC patients had a significantly higher percentage of circulating Bregs than healthy people. Increased circulating Bregs were correlated with advanced tumor staging, tumor multiplicity and venous infiltration. Next, we firstly revealed that human Bregs promoted HCC tumor growth independent of Tregs in SCID mice. The migration of Bregs from blood into tumor was also confirmed in mice. Finally, we further explored the molecular mechanism of Bregs promoting proliferation and migration of HCC cells in vitro. Bregs promoted HCC growth and invasiveness by directly interacting with liver cancer cells through the CD40/CD154 signaling pathway.


Journal of Neuroscience Research | 2005

Methyl-4-phenylpyridinium ion modulates expression of mitochondrial uncoupling proteins 2, 4, and 5 in catecholaminergic (SK-N-SH) cells

Philip Wing-Lok Ho; David Yiu-Leung Chan; Ken Hon-Hung Kwok; Andrew Chi-Yuen Chu; Jessica Wing-Man Ho; Michelle Hiu-Wai Kung; Db Ramsden; Sl Ho

Methyl‐4‐phenylpyridinium ion (MPP+), a specific dopaminergic neurotoxin, inhibits mitochondrial complex I activity, generates reactive oxygen species (ROS), reduces ATP production, and induces cell death. We explored changes in expression of uncoupling proteins (UCPs 2, 4, and 5) following MPP+‐induced toxicity in SK‐N‐SH cells over 72 hr at the transcriptional (quantification of mRNA by real‐time RT‐PCR) and translational (Western analysis) levels. UCP5 mRNA and protein were markedly up‐regulated (1 mM MPP+ at 72 hr caused a twofold increase, P < 0.01), as was UCP4 mRNA, albeit to a much lesser extent. Surprisingly, UCP2 mRNA levels decreased at 24 hr (P < 0.05) but thereafter significantly increased to greater than control levels at 72 hr (P < 0.05), although UCP2 protein levels were decreased throughout (1 mM MPP+ at 72 hr caused a reduction of 50%, P < 0.01). The increase in ROS production may be attenuated by UCP4 and UCP5 up‐regulation. The consequence of decreased UCP2 levels is unclear, although this may represent an adaptive response to declines in ATP levels, the subsequent increase in mRNA being a response to further increases in oxidative stress.


Amyotrophic Lateral Sclerosis | 2006

Clinical phenotypes of a large Chinese multigenerational kindred with autosomal dominant familial ALS due to Ile149Thr SOD1 gene mutation

Gardian C. Y. Fong; Ken H. H. Kwok; You-Qiang Song; Ts Cheng; Philip Wing-Lok Ho; Andrew Chi-Yuen Chu; Michelle Hiu-Wai Kung; Kh Chan; W Mak; Raymond T.F. Cheung; Db Ramsden; Sl Ho

About 10% of amyotrophic lateral sclerosis (ALS) cases are familial. We identified a five‐generation Chinese family with autosomal dominant familial ALS (FALS). We performed a detailed family study, clinical and electromyographic validation, and SOD1, VEGF and CNTF mutation analyses. Forty‐five living members (16 affected) were studied and DNA samples collected. Genealogical data were collected for deceased members. Based on the duration between symptom onset to ventilator dependence, they were divided into rapidly progressive (range 1–18 months, mean (SD) duration = 12.08 (±6.10) months, mean (SD) age of symptom onset = 39.75 (±9.84) years) and slowly progressive groups (>18 months; mean (SD) age of onset = 37.25 (±5.32) years old). We identified a heterozygous mutation of ATT to ACT of SOD1 gene at codon 149 in exon 5 resulting in substitution of isoleucine to threonine. It co‐segregated with all affected members and 11 non‐symptomatic members. We report a large multigenerational Chinese FALS kindred with I149T mutation in SOD1. No polymorphisms or mutations were found to date in two known modifier genes, namely, VEGF and CNTF, which were associated with heterogeneity in the phenotype within this kindred. Follow‐up of the family will be helpful to explore any potential disease markers.

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Sl Ho

University of Hong Kong

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Db Ramsden

University of Birmingham

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H Liu

University of Hong Kong

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Koon-Ho Chan

University of Hong Kong

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Kwan Man

University of Hong Kong

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