Publications by authors named "Wing Yung"

21 Publications

  • Page 1 of 1

Multifunctional Nanoprobe for the Delivery of Therapeutic siRNA and Real-Time Molecular Imaging of Parkinson's Disease Biomarkers.

ACS Appl Mater Interfaces 2021 Mar 8;13(10):11609-11620. Epub 2021 Mar 8.

Department of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, New Territories, 999077 Hong Kong, P. R. China.

Parkinson's disease (PD) has been recently associated with the excessive expression of matrix metalloproteinase 3 (MMP3). One of the major challenges in treating PD is to effectively detect and inhibit the early MMP3 activities to relieve the neural stress and inflammation responses. Previously, numerous upconversion nanoparticle (UCNP)-based nanoprobes have been designed for the detection of biomarkers in neurodegenerative diseases. To further improve the performance of the conventional nanoprobes, we introduced novel reporting units and integrated the therapeutic reagents to fabricate a theragnostic platform for PD and other neurodegenerative diseases. Here, we designed a multifunctional UCNP/aggregation-induced emission luminogen (AIEgen)-based nanoprobe to effectively detect the time-lapse MMP3 activities in the inflammatory catecholaminergic SH-SY5Y cells and simultaneously deliver the MMP3-siRNA into the stressed catecholaminergic SH-SY5Y cells, inhibiting the MMP3-induced inflammatory neural responses. The unique features of our UCNP/AIEgen-based nanoprobe platform shed light on the development of a novel theragnostic probe for the early diagnosis and cure of neurodegenerative diseases.
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http://dx.doi.org/10.1021/acsami.0c22112DOI Listing
March 2021

MicroRNA-19a-PTEN Axis Is Involved in the Developmental Decline of Axon Regenerative Capacity in Retinal Ganglion Cells.

Mol Ther Nucleic Acids 2020 Sep 1;21:251-263. Epub 2020 Jun 1.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, PRC. Electronic address:

Irreversible blindness from glaucoma and optic neuropathies is attributed to retinal ganglion cells (RGCs) losing the ability to regenerate axons. While several transcription factors and proteins have demonstrated enhancement of axon regeneration after optic nerve injury, mechanisms contributing to the age-related decline in axon regenerative capacity remain elusive. In this study, we show that microRNAs are differentially expressed during RGC development and identify microRNA-19a (miR-19a) as a heterochronic marker; developmental decline of miR-19a relieves suppression of phosphatase and tensin homolog (PTEN), a key regulator of axon regeneration, and serves as a temporal indicator of decreasing axon regenerative capacity. Intravitreal injection of miR-19a promotes axon regeneration after optic nerve crush in adult mice, and it increases axon extension in RGCs isolated from aged human donors. This study uncovers a previously unrecognized involvement of the miR-19a-PTEN axis in RGC axon regeneration, and it demonstrates therapeutic potential of microRNA-mediated restoration of axon regenerative capacity in optic neuropathies.
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http://dx.doi.org/10.1016/j.omtn.2020.05.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327411PMC
September 2020

Infectious keratitis and orthokeratology lens use: a systematic review.

Infection 2017 Dec 22;45(6):727-735. Epub 2017 May 22.

Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, New Territories, Hong Kong.

Purpose: Myopia is a prevalent condition among Asians. Orthokeratology lens has gained popularity as a method of myopia control. This systematic review is to summarize the clinical profile of infectious keratitis in association with orthokeratology lens wear.

Methods: We searched in the PubMed and EMBASE for articles adopting the search strategy "(orthokeratology lens OR orthokeratology) AND (bacterial eye infection OR keratitis OR cornea ulcer OR microbial keratitis OR bacterial keratitis)", from the start date of the databases to August 23, 2016. Articles reporting infectious keratitis in orthokeratology lens users with data of individual cases were considered eligible for this systematic review. We recorded the outcome measures including method of diagnosis, etiological agents, duration and mode of treatment and treatment outcomes.

Results: Our literature search yielded 172 papers. After removing duplicated and irrelevant reports, we included 29 articles for data analysis, involving 173 eyes. Among all reported cases, the mean age at presentation was 15.4 ± 6.2 years, with a female preponderance (male-to-female ratio 1:1.7). Positive microbiological cultures were reported in 69.4% of cases, with Pseudomonas aeruginosa and Acanthamoeba being the most common etiological agents. The mean duration of hospitalization was 7.7 ± 6.7 days. Mean LogMAR visual acuity at presentation was 1.17 ± 0.78, increased to 0.33 ± 0.41 at final visit (p < 0.001).

Conclusions: Despite early intervention and treatment, the majority of infections resulted in the formation of corneal scars and almost 10% of eyes needed surgical treatment. Timely awareness and treatment of keratitis should be emphasized to the users.
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http://dx.doi.org/10.1007/s15010-017-1023-2DOI Listing
December 2017

The multi-level impact of chronic intermittent hypoxia on central auditory processing.

Neuroimage 2017 08 19;156:232-239. Epub 2017 May 19.

Laboratory of Biomedical Imaging and Signal Processing, The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China; Department of Electrical and Electronic Engineering, The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China.

During hypoxia, the tissues do not obtain adequate oxygen. Chronic hypoxia can lead to many health problems. A relatively common cause of chronic hypoxia is sleep apnea. Sleep apnea is a sleep breathing disorder that affects 3-7% of the population. During sleep, the patient's breathing starts and stops. This can lead to hypertension, attention deficits, and hearing disorders. In this study, we apply an established chronic intermittent hypoxemia (CIH) model of sleep apnea to study its impact on auditory processing. Adult rats were reared for seven days during sleeping hours in a gas chamber with oxygen level cycled between 10% and 21% (normal atmosphere) every 90s. During awake hours, the subjects were housed in standard conditions with normal atmosphere. CIH treatment significantly reduces arterial oxygen partial pressure and oxygen saturation during sleeping hours (relative to controls). After treatment, subjects underwent functional magnetic resonance imaging (fMRI) with broadband sound stimulation. Responses are observed in major auditory centers in all subjects, including the auditory cortex (AC) and auditory midbrain. fMRI signals from the AC are statistically significantly increased after CIH by 0.13% in the contralateral hemisphere and 0.10% in the ipsilateral hemisphere. In contrast, signals from the lateral lemniscus of the midbrain are significantly reduced by 0.39%. Signals from the neighboring inferior colliculus of the midbrain are relatively unaffected. Chronic hypoxia affects multiple levels of the auditory system and these changes are likely related to hearing disorders associated with sleep apnea.
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http://dx.doi.org/10.1016/j.neuroimage.2017.05.036DOI Listing
August 2017

Lhx1/5 control dendritogenesis and spine morphogenesis of Purkinje cells via regulation of Espin.

Nat Commun 2017 05 18;8:15079. Epub 2017 May 18.

School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China.

In the cerebellar cortex, Purkinje cells (PCs) receive signals from different inputs through their extensively branched dendrites and serve as an integration centre. Defects in the dendritic development of PCs thus disrupt cerebellar circuitry and cause ataxia. Here we report that specific inactivation of both Lhx1 and Lhx5 in postnatal PCs results in ataxic mutant mice with abnormal dendritic development. The PCs in the mutants have reduced expression of Espin, an F-actin cytoskeleton regulator. We show that Espin expression is transcriptionally activated by Lhx1/5. Downregulation of Espin leads to F-actin mislocalization, thereby impairing dendritogenesis and dendritic spine maturation in the PCs. The mutant PCs therefore fail to form proper synapses and show aberrant electrophysiological properties. By overexpressing Espin, we can successfully rescue the defects in the mutant PCs. Our findings suggest that Lhx1/5, through regulating Espin expression, control dendritogenesis and spine morphogenesis in postnatal PCs.
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http://dx.doi.org/10.1038/ncomms15079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454373PMC
May 2017

Excessive Daytime Sleepiness Predicts Neurodegeneration in Idiopathic REM Sleep Behavior Disorder.

Sleep 2017 05;40(5)

Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR.

Study Objectives: To determine the association of excessive daytime sleepiness (EDS) with the conversion of neurodegenerative diseases in patients with idiopathic REM sleep behavior disorder (iRBD).

Methods: A total of 179 patients with iRBD (79.1% males, mean age = 66.3 ± 9.8 years) were consecutively recruited. Forty-five patients with Epworth Sleepiness Scale score ≥14 were defined as having EDS. Demographic, clinical, and polysomnographic data were compared between iRBD patients with and without EDS. The risk of developing neurodegenerative diseases was examined using Cox proportional hazards model.

Results: After a mean follow-up of 5.8 years (SD = 4.3 years), 50 (27.9%) patients developed neurodegenerative diseases. There was a significantly higher proportion of conversion in patients with EDS compared to those without EDS (42.2 % vs. 23.1%, p = .01). EDS significantly predicted an increased risk of developing neurodegenerative diseases (adjusted hazard ratios [HR] = 2.56, 95% confidence interval [CI] 1.37 to 4.77) after adjusting for age, sex, body mass index, current depression, obstructive sleep apnea, and periodic limb movements during sleep. Further analyses demonstrated that EDS predicted the conversion of Parkinson's disease (PD) (adjusted HR = 3.55, 95% CI 1.59 to 7.89) but not dementia (adjusted HR = 1.48, 95% CI 0.44 to 4.97).

Conclusions: EDS is associated with an increased risk of developing neurodegenerative diseases, especially PD, in patients with iRBD. Our findings suggest that EDS is a potential clinical biomarker of α-synucleinopathies in iRBD.
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http://dx.doi.org/10.1093/sleep/zsx041DOI Listing
May 2017

Mortality and Its Risk Factors in Patients with Rapid Eye Movement Sleep Behavior Disorder.

Sleep 2016 Aug 1;39(8):1543-50. Epub 2016 Aug 1.

Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR.

Study Objectives: To determine the mortality and its risk factors in patients with rapid eye movement (REM) sleep behavior disorder (RBD).

Methods: A total of 205 consecutive patients with video-polysomnography confirmed RBD (mean age = 66.4 ± 10.0 y, 78.5% males) were recruited. Medical records and death status were systematically reviewed in the computerized records of the health care system. Standardized mortality ratio (SMR) was used to calculate the risk ratio of mortality in RBD with reference to the general population.

Results: Forty-three patients (21.0%) died over a mean follow-up period of 7.1 ± 4.5 y. The SMR was not increased in the overall sample, SMR (95% confidence interval [CI]) = 1.00 (0.73-1.33). However, SMR (95% CI) increased to 1.80 (1.21-2.58) and 1.75 (1.11-2.63) for RBD patients in whom neurodegenerative diseases and dementia, respectively, eventually developed. In the Cox regression model, mortality risk was significantly associated with age (hazard ratio [HR] = 1.05; 95% CI, 1.01-1.10), living alone (HR = 2.04; 95% CI, 1.39-2.99), chronic obstructive pulmonary disease (HR = 3.38; 95% CI, 1.21-9.46), cancer (HR = 10.09; 95% CI, 2.65-38.42), periodic limb movements during sleep (HR = 3.06; 95% CI, 1.50-6.24), and development of neurodegenerative diseases (HR = 2.84; 95% CI, 1.47-5.45) and dementia (HR = 2.66; 95% CI, 1.39-5.08).

Conclusions: Patients with RBD have a higher mortality rate than the general population only if neurodegenerative diseases develop. Several risk factors on clinical and sleep aspects are associated with mortality in RBD patients. Our findings underscore the necessity of timely neuroprotective interventions in the early phase of RBD before the development of neurodegenerative diseases.
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http://dx.doi.org/10.5665/sleep.6016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945313PMC
August 2016

Topical imiquimod before intradermal trivalent influenza vaccine for protection against heterologous non-vaccine and antigenically drifted viruses: a single-centre, double-blind, randomised, controlled phase 2b/3 trial.

Lancet Infect Dis 2016 Feb 9;16(2):209-18. Epub 2015 Nov 9.

Carol Yu Centre for Infection and Division of Infectious Diseases, University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Microbiology, University of Hong Kong, Hong Kong Special Administrative Region, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China. Electronic address:

Background: Pretreatment with topical imiquimod, a synthetic agonist of toll-like receptor 7, significantly improved the immunogenicity of influenza vaccination in elderly people. We aimed to clarify its effect in a younger age group.

Methods: In this double-blind, randomised controlled trial, we enrolled healthy volunteers aged 18-30 years in early 2014 to receive the 2013-14 northern-hemisphere winter trivalent influenza vaccine at the Queen Mary Hospital, (Hong Kong, China). Eligible participants were randomly assigned (1:1:1:1) to one of the four vaccination groups: the study group, topical imiquimod-cream followed by intradermal trivalent influenza vaccine (INF-Q-ID), or one of three control groups, topical aqueous-cream control followed by intradermal trivalent influenza vaccine (INF-C-ID), topical aqueous-cream control followed by intramuscular trivalent influenza vaccine (INF-C-IM), and topical imiquimod-cream followed by intradermal normal-saline injection (SAL-Q-ID). Randomisation was by computer-generated lists in blocks of four. The type of topical treatment was masked from volunteers and investigators, although not from the study nurse. Serum haemagglutination-inhibition and microneutralisation-antibody titres were assayed. The primary outcome was seroconversion at day 7 after treatment for three vaccine strains of influenza (A/California/07/2009 H1N1-like virus [A/California/H1N1], A/Victoria/361/2011 H3N2-like virus [A/Victoria/H3N2], and B/Massachusetts/2/2012-like virus [B/Yamagata lineage]) and four non-vaccine strains (A/HK/485197/14 [H3N2 Switzerland-like lineage], prototype A/WSN/1933 [H1N1], A/HK/408027/09 [prepandemic seasonal H1N1], and B/HK/418078/11 [Victoria lineage]). Analysis was done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT02103023.

Findings: We enrolled 160 healthy volunteers between March 1 and May 31, 2014, and 40 participants were randomly assigned to each study group. For the A/California/H1N1 strain, seroconversion at day 7 occurred in 39 participants (98%) in the INF-Q-ID group, 25 (63%) in the INF-C-ID group, 18 (45%) in the INF-C-IM group, and none in the SAL-Q-ID group; for the A/Victoria/H3N2, this was 30 (75%) in the INF-Q-ID group, four (10%) in the INF-C-ID group, four (10%) in the INF-C-IM group, and none in the SAL-Q-ID group; and for the B/Massachusetts (Yamagata lineage) strain, this was 36 (90%) in the INF-Q-ID group, 27 (68%) in the INF-C-ID group, 17 (43%) in the INF-C-IM group, and one (3%) in the SAL-Q-ID group (p<0·0001 for all three vaccine strains). Adverse reactions were infrequent and self-limited and did not differ between the four groups. Furthermore, the seroconversion rate against the four non-vaccine strains was better in the INF-Q-ID group than in the control groups on days 7 and 21 (p<0·0001). The most common adverse events were grade 1 redness (five participants in the INF-Q-ID group, three in INF-C-ID, one in INF-C-IM, and one in SAL-Q-ID) and grade 1 swelling (seven participants in INF-Q-ID group, five in INF-C-ID, three in INF-C-IM, and two in SAL-Q-ID.

Interpretation: Topical application of imiquimod before intradermal trivalent influenza vaccine significantly improved immunogenicity against the vaccine influenza strains in young healthy individuals and increased immunogenicity against the non-vaccine strains, especially the antigenically drifted H3N2 strain of 2015, which was not included in the 2013-14 recommended vaccine. Further studies should be done to establish the efficacy and safety of this approach for other injectable vaccines to augment the onset and range of protection.

Funding: The Shaw Foundation Hong Kong, Health and Medical Research Fund (Hong Kong, China), The Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Disease for the HKSAR (Department of Health, Hong Kong, China), The Providence Foundation, Respiratory Viral Research Foundation.
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http://dx.doi.org/10.1016/S1473-3099(15)00354-0DOI Listing
February 2016

Fast 3-D temporal focusing microscopy using an electrically tunable lens.

Opt Express 2015 Sep;23(19):24362-8

In this paper, we present a 3-D temporal focusing microscope based on an electrically tunable lens (ETL) and a femtosecond regenerative laser amplifier. The focus-tunable lens provides a fast and compact way to perform non-mechanical z-scanning and resolves the blurry image issue compared with GVD-based z-scanning methods. The optical performance of the temporal focusing system, including z-scanning characteristics, the associated the magnification variation, and the lateral and axial resolution, has been studied and characterized using calibrated Rhodamine-6G thin film sample, fluorescent beads, and pollen samples. Lastly, we demonstrate the optical cross-sectioning and z-scanning capability with an in vivo experiment, where Ca(2+) imaging of neurons in GaCamp6 labeled zebrafish was performed.
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http://dx.doi.org/10.1364/OE.23.024362DOI Listing
September 2015

Injured adult retinal axons with Pten and Socs3 co-deletion reform active synapses with suprachiasmatic neurons.

Neurobiol Dis 2015 Jan 16;73:366-76. Epub 2014 Oct 16.

Division of Life Science, State Key Laboratory of Molecular Neuroscience, School of Science and Institute for Advance Study, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Center of Systems Biology and Human Health, School of Science and Institute for Advance Study, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. Electronic address:

Despite advances in promoting axonal regeneration after adult central nervous system injury, elicitation of a large number of lesion-passing axons reform active synaptic connections with natural target neurons remains limited. By deleting both Pten and Socs3 in retinal ganglion cells, we report that optic nerve axons after prechiasm lesion robustly reinnervate the hypothalamus, form new synapses with neurons in the suprachiasmatic nucleus (SCN), and re-integrate with the existing circuitry. Photic or electric stimulation of the retinal axons induces neuronal response in SCN. However both the innervation pattern and evoked responses are not completely restored by the regenerating axons, suggesting that combining with other strategies is necessary to overcome the defective rewiring. Our results support that boosting the intrinsic growth capacity in injured neurons promotes axonal reinnervation and rewiring.
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http://dx.doi.org/10.1016/j.nbd.2014.09.019DOI Listing
January 2015

The nucleosome assembly protein TSPYL2 regulates the expression of NMDA receptor subunits GluN2A and GluN2B.

Sci Rep 2014 Jan 13;4:3654. Epub 2014 Jan 13.

1] Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, China [2] Centre for Reproduction, Development and Growth, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, China.

TSPYL2 is an X-linked gene encoding a nucleosome assembly protein. TSPYL2 interacts with calmodulin-associated serine/threonine kinase, which is implicated in X-linked mental retardation. As nucleosome assembly and chromatin remodeling are important in transcriptional regulation and neuronal function, we addressed the importance of TSPYL2 through analyzing Tspyl2 loss-of-function mice. We detected down-regulation of N-methyl-D-aspartate receptor subunits 2A and 2B (GluN2A and GluN2B) in the mutant hippocampus. Evidence from luciferase reporter assays and chromatin immunoprecipitation supported that TSPYL2 regulated the expression of Grin2a and Grin2b, the genes encoding GluN2A and GluN2B. We also detected an interaction between TSPYL2 and CBP, indicating that TSPYL2 may activate gene expression through binding CBP. In terms of functional outcome, Tspyl2 loss-of-function impaired long-term potentiation at hippocampal Schaffer collateral-CA1 synapses. Moreover, mutant mice showed a deficit in fear learning and memory. We conclude that TSPYL2 contributes to cognitive variability through regulating the expression of Grin2a and Grin2b.
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http://dx.doi.org/10.1038/srep03654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888966PMC
January 2014

Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics.

Nat Commun 2013 ;4:1759

Vascular Biology Program, Departments of Pathology & Surgery, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

Increased vascular permeability contributes to many diseases, including acute respiratory distress syndrome, cancer and inflammation. Most past work on vascular barrier function has focused on soluble regulators, such as tumour-necrosis factor-α. Here we show that lung vascular permeability is controlled mechanically by changes in extracellular matrix structure. Our studies reveal that pulmonary vascular leakage can be increased by altering extracellular matrix compliance in vitro and by manipulating lysyl oxidase-mediated collagen crosslinking in vivo. Either decreasing or increasing extracellular matrix stiffness relative to normal levels disrupts junctional integrity and increases vascular leakage. Importantly, endotoxin-induced increases of vascular permeability are accompanied by concomitant increases in extracellular matrix rigidity and lysyl oxidase activity, which can be prevented by inhibiting lysyl oxidase activity. The identification of lysyl oxidase and the extracellular matrix as critical regulators of lung vascular leakage might lead to the development of new therapeutic approaches for the treatment of pulmonary oedema and other diseases caused by abnormal vascular permeability.
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http://dx.doi.org/10.1038/ncomms2774DOI Listing
November 2013

Flavonoid Myricetin Modulates GABA(A) Receptor Activity through Activation of Ca(2+) Channels and CaMK-II Pathway.

Evid Based Complement Alternat Med 2012 11;2012:758097. Epub 2012 Nov 11.

Epithelial Cell Biology Research Centre, The Chinese University of Hong Kong, Hong Kong.

The flavonoid myricetin is found in several sedative herbs, for example, the St. John's Wort, but its influence on sedation and its possible mechanism of action are unknown. Using patch-clamp technique on a brain slice preparation, the present study found that myricetin promoted GABAergic activity in the neurons of hypothalamic paraventricular nucleus (PVN) by increasing the decay time and frequency of the inhibitory currents mediated by GABA(A) receptor. This effect of myricetin was not blocked by the GABA(A) receptor benzodiazepine- (BZ-) binding site antagonist flumazenil, but by KN-62, a specific inhibitor of the Ca(2+)/calmodulin-stimulated protein kinase II (CaMK-II). Patch clamp and live Ca(2+) imaging studies found that myricetin could increase Ca(2+) current and intracellular Ca(2+) concentration, respectively, via T- and L-type Ca(2+) channels in rat PVN neurons and hypothalamic primary culture neurons. Immunofluorescence staining showed increased phosphorylation of CaMK-II after myricetin incubation in primary culture of rat hypothalamic neurons, and the myricetin-induced CaMK-II phosphorylation was further confirmed by Western blotting in PC-12 cells. The present results suggest that myricetin enhances GABA(A) receptor activity via calcium channel/CaMK-II dependent mechanism, which is distinctively different from that of most existing BZ-binding site agonists of GABA(A) receptor.
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http://dx.doi.org/10.1155/2012/758097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520426PMC
December 2012

Long-term in vivo imaging and measurement of dendritic shrinkage of retinal ganglion cells.

Invest Ophthalmol Vis Sci 2011 Mar 1;52(3):1539-47. Epub 2011 Mar 1.

Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong, Kowloon, Hong Kong, Peoples Republic of China.

Purpose: To monitor and measure dendritic shrinkage of retinal ganglion cells (RGCs) in a strain of transgenic mice (Thy-1 YFP) that expresses yellow fluorescent proteins in neurons under the control of a Thy-1 promoter.

Methods: A total of 125 RGCs from 16 eyes of Thy-1 YFP transgenic mice were serially imaged with a confocal scanning laser ophthalmoscope for 6 months after optic nerve crush. Quantitative analysis of cell body area, axon diameter, dendritic field, number of terminal branches, total dendritic branch length, branching complexity, symmetry, and distance from the optic disc was used to characterize the morphology of RGCs, describe the patterns of axonal and dendritic degeneration, identify the morphologic predictors for cell survival, and estimate the rate of dendritic shrinkage.

Results: RGC damage was observed prospectively to begin with progressive dendritic shrinkage, followed by loss of the axon and the cell body. In a small proportion of RGCs, progressive axonal changes including fragmentation, beading, retraction, and bulb formation were also observed. RGCs with a larger dendritic field and a longer total dendritic branch length in general have a better survival probability. The rate of dendritic shrinkage was variable with a slower rate observed in cells having a larger dendritic field, a longer total dendritic branch length, and a greater distance from the optic disc.

Conclusions: Estimating the probability of RGC survival and measuring the rate of dendritic shrinkage could become a new paradigm for investigating neuronal degeneration and evaluating the response of neuroprotective treatment.
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http://dx.doi.org/10.1167/iovs.10-6012DOI Listing
March 2011

A synergistic role of hyperthermic and pharmacological preconditioning to protect astrocytes against ischemia/reperfusion injury.

Neurochem Res 2011 Feb 3;36(2):312-8. Epub 2010 Dec 3.

Institute for Nautical Medicine and Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, People's Republic of China.

Recent studies provide solid evidence for the importance to delineate the co-relationship between preconditioning stimuli and therapeutic efficacy of drugs commonly used in clinic. However, very little is known about this important topic. In the present study, we investigated the effects of hyperthermia on the protective role of ginkgolides on astrocytes against ischemia/reperfusion (I/R) injury and also evaluated the effects of the timing of co-treatment of hyperthermia with ginkgolides on astrocytes against the I/R injury. We demonstrated that there is a synergistic action between hyperthermic and pharmacological preconditioning to protect astrocytes against the I/R injury. Our findings also showed that astrocytes have completely different responses to the treatment with hyperthermia or ginkgolides alone or co-treatment together at different stages of the I/R process. Hyperthermic preconditioning before the I/R can protect astrocytes against the I/R injury. However, if treated in the ischemia and reperfusion stage, hyperthermia exacerbates the cell injury and significantly attenuates the protective effectiveness of ginkgolides. These findings imply that the timing of treatment with hypothermia and/or ginkgolides is one of the key factors to determine their protective effects on the cells against the I/R injury.
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http://dx.doi.org/10.1007/s11064-010-0327-8DOI Listing
February 2011

The iron regulatory hormone hepcidin reduces ferroportin 1 content and iron release in H9C2 cardiomyocytes.

J Nutr Biochem 2009 Nov 22;20(11):860-5. Epub 2008 Nov 22.

National Key Laboratory of Chinese Medicine and Molecular Pharmacology (Shenzhen) and Laboratory of Brain Iron Metabolism, Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Hong Kong.

Iron plays a key pathophysiological role in a number of cardiac diseases. Studies on the mechanisms of heart iron homeostasis are therefore crucial for understanding the causes of excessive heart iron. In addition to iron uptake, cellular iron balance in the heart also depends on iron export. We provided evidence for the existence of iron exporter ferroportin 1 (Fpn1) in the heart in a recent study. The presence of hepcidin, a recently discovered iron regulatory hormone, was also confirmed in the heart recently. Based on these findings and the inhibiting role of hepcidin on Fpn1 in other tissues, we speculated that hepcidin might be able to bind with, internalize and degrade Fpn1 and then decrease iron export in heart cells, leading to an abnormal increase in heart iron and iron mediated cell injury. We therefore investigated the effects of hepcidin on the contents of Fpn1 and iron release in H9C2 cardiomyocyte cell line. We demonstrated that hepcidin has the ability to reduce Fpn1 content as well as iron release in this cell. The similar regulation patterns of hepcidin on the Fpn1 and iron release suggested that the decreased iron release resulted from the decreased content of Fpn1 induced by hepcidin. We also found that hepcidin has no significant effects on ceruloplasmin (CP) and hephaestin (Heph)--two proteins required for iron release from mammalian cells. The data imply that Fpn1, rather than Heph and CP, is the limited factor in the regulation of iron release from heart cells under physiological conditions.
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http://dx.doi.org/10.1016/j.jnutbio.2008.07.014DOI Listing
November 2009

Lipopolysaccharide induces a significant increase in expression of iron regulatory hormone hepcidin in the cortex and substantia nigra in rat brain.

Endocrinology 2008 Aug 1;149(8):3920-5. Epub 2008 May 1.

Laboratory of Brain Iron Metabolism, Department of Applied Biology & Chemical Technology, Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.

Hepcidin plays an essential role in maintaining normal iron homeostasis outside the brain. This recently discovered iron regulation hormone is predominantly expressed in the liver, and regulated by iron and hypoxia. As an antimicrobial peptide, this hormone is also elevated during infections and inflammation. In this study we investigated the expression of hepcidin mRNA and protein in different brain regions, including the cortex, hippocampus, striatum, and substantia nigra, and the effects of lipopolysaccharide (LPS) on the expression of hepcidin using quantitative real-time RT-PCR and immunofluorescence analysis. Our data provided further evidence for the existence of hepcidin in all the regions we examined. We also demonstrated for the first time that LPS administration by iv injection can regulate the expression of hepcidin mRNA and protein not only in peripheral organs such as the liver, but also in the brain. LPS induced a significant increase in the expression of hepcidin mRNA and protein in the cortex and substantia nigra, but not in the hippocampus and striatum, indicating a regionally specific regulation of LPS on hepcidin in the brain. The relevant mechanisms and the functions of hepcidin in the brain remain to be elucidated.
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http://dx.doi.org/10.1210/en.2007-1626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2488231PMC
August 2008

Ginkgolides mimic the effects of hypoxic preconditioning to protect C6 cells against ischemic injury by up-regulation of hypoxia-inducible factor-1 alpha and erythropoietin.

Int J Biochem Cell Biol 2008 22;40(4):651-62. Epub 2007 Oct 22.

Institute for Nautical Medicine, Jiangsu Key Laboratory of Neuroregeneration and School of Nursing, Nantong University, Nantong 226001, People's Republic of China.

Hypoxic preconditioning can play a significant neuroprotective role. However, it has not been employed clinically because of safety concerns. To find a safer preconditioning stimulus that is both practical and effective, we investigated whether ginkgolides are capable of preconditioning as hypoxia to protect C6 cells against ischemic injury. We demonstrated that both ginkgolides (37.5microg/mL) and hypoxia (1% O(2) for 16h) can significantly increase cell viabilities and expression of phosphorylated glycogen synthase kinase (p-GSK), phosphorylated extracellular signal-regulated kinase (p-ERK), hypoxia-inducible factor-1 alpha (HIF-1alpha) and erythropoietin (EPO) in ischemic cells. The inhibitors of mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3'-kinase (PI3K) significantly but not completely reduced the enhanced expression of these proteins and cell viabilities induced by ginkgolides and hypoxic preconditioning. These indicated that ginkgolides could mimic hypoxic preconditioning by increasing expression of HIF-1alpha as well as its target protein EPO and that the ginkgolides and hypoxic preconditioning role might be partly mediated by the activation of the p42/p44-mitogen-activated protein kinase and phosphatidylinositol 3'-kinase/AKT/glycogen synthase kinase 3beta pathways. The similar tendency in the changes of protein expression, cell viabilities and responses to MAPK or PI3K inhibitors of the cells treated with ginkgolides and hypoxia suggests that ginkgolides and hypoxic preconditioning might operate by similar mechanisms. The findings also imply that ginkgolides might have the potential for clinical use to prevent injury in high-risk conditions.
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http://dx.doi.org/10.1016/j.biocel.2007.10.013DOI Listing
July 2008

Distribution and electrophysiological effects of motilin in Purkinje cells.

Neuroreport 2007 Aug;18(13):1345-9

Department of Pathology, Qingdao Municipal Hospital, Qingdao, China.

Evidence exists that motilin immunoreactivity is highly expressed in Purkinje cells. In this study, immunohistochemistry and whole-cell patch-clamp recording were performed to investigate the spatial distribution and electrophysiological effects of motilin receptors in the cerebellum. We show here that motilin receptors are strongly expressed in Purkinje cells of the human and rat cerebellum. Motilin at 10 nM depolarized Purkinje cells of the rat cerebellum, and this was mimicked by the motilin receptor agonist erythromycin. The depolarization evoked by motilin persisted in the presence of tetrodotoxin, glutamate and gamma-amino-n-butyric acid receptor antagonists, indicating that motilin excited the Purkinje cells by activating the receptor expressed on the neurons recorded. We suggest that motilin may serve specific neural functions in the cerebellum.
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http://dx.doi.org/10.1097/WNR.0b013e328273bc98DOI Listing
August 2007

Boca: an open-source RDF store for building Semantic Web applications.

Brief Bioinform 2007 May 8;8(3):195-200. Epub 2007 May 8.

IBM Internet Technology, Cambridge, MA, USA.

This article presents the design goals and features of the open-source Boca RDF server in the context of a community of cancer-tumor modeling investigators. Boca supplements the desirable data features of the Semantic Web with important enterprise and application features to power a new generation of Semantic-Web-based applications. The data features enable the integration and retrieval of tremendous quantities of diverse data. The enterprise features promote data integrity, fidelity, provenance and robustness. The application features provide for collaborative applications and dynamic user interfaces.
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http://dx.doi.org/10.1093/bib/bbm017DOI Listing
May 2007

Excitatory effect of histamine on neuronal activity of rat globus pallidus by activation of H2 receptors in vitro.

Neurosci Res 2005 Nov 6;53(3):288-97. Epub 2005 Sep 6.

Department of Biological Science and Technology and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Mailbox 426, Nanjing University, Nanjing 210093, China.

Previous studies have revealed distribution of histaminergic fibers and presence of histamine receptors in globus pallidus (GP). In this study, the brain slice preparation of adult rats was used to examine the effect of histamine on the spontaneous unitary discharge of GP neurons and the underlying receptor mechanism. Ninety-five GP neurons were extracellularly recorded from 42 slices containing the GP, of which 87 (91.6%) were excited by the stimulation of histamine. The histamine-induced excitation was concentration-dependent and persisted in low Ca2+/high Mg2+ medium (n = 9), demonstrating that the action of histamine on the GP neurons was postsynaptic. The excitatory effect of histamine on the GP neurons was not blocked by selective histamine H1 receptor antagonist triprolidine (n = 16) or chlorpheniramine (n = 6), but was effectively suppressed by ranitidine, a highly selective histamine H2 receptor antagonist (n = 21). On the other hand, highly selective histamine H2 receptor agonist dimaprit mimicked the excitatory effect of histamine on the GP neurons (n = 23), while histamine H1 receptor agonists, including 2-pyridylethylamine (n = 22), 2-thiazolyethylamine (n = 9) and betahistine (n = 9), did not cause GP neurons any response. The dimaprit-induced GP neuronal excitation was effectively antagonized by selective histamine H2 receptor antagonist ranitidine (n = 14) but not influenced by selective histamine H1 receptor antagonist triprolidine (n = 12). Moreover, adenylate cyclase (AC) activator forskolin (n = 7) was observed to evoke GP neurons an excitatory response, whereas the histamine-induced excitation was effectively reduced by H-89 (n = 9), a selective and potent inhibitor of protein kinase A (PK(A)). Finally, it was noted that neurons of both subdivisions of the GP, the internal (GPi, n = 35) and external (GPe, n = 60) segment, showed no differences in their responses to stimulations of the tested histaminergic reagents. These results demonstrated that histamine excited GP (including GPi and GPe) neurons via histamine H2 receptors and H2 receptors linked intracellular G-protein-AC-PK(A) signaling pathway, suggesting that the hypothalamic histaminergic afferent fibers innervating GP may play an important modulatory role in motor control through its excitatory effect on GP neurons.
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http://dx.doi.org/10.1016/j.neures.2005.07.008DOI Listing
November 2005