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ABSTRACT: Ultraviolet (UV)-induced damage plays a major role in ocular diseases, such as cataracts and retinal degeneration. UVB may also cause retinal phototoxicity and photic retinopathy. In this study, we explored the effects of UVB on the cell cycle and the role of silent mating type information regulation 2 homolog 1 (SIRT1) in the UVB-induced damage. UVB dose-dependently suppressed the growth of retinal pigment epithelial (RPE) cells by activating the phosphatidylinositol 3-kinase (PI3K) pathway and triggering cell cycle arrest at the S phase. SIRT1, an NAD-dependent histone deacetylase, is involved in multiple biological processes, such as the stress response and the regulation of the cell cycle. However, its role in the effects of UVB on RPE cells is unclear. We showed that UVB down-regulates SIRT1 expression in a dose-dependent manner. Resveratrol, an SIRT1 activator, prevented the UVB-induced damage by inhibiting AKT and ERK phosphorylation. A specific PI3K inhibitor attenuated the UVB-induced ERK1/2 and p53 phosphorylation. Finally, UVB activated the PI3K/AKT/ERK pathway by reducing the expression of SIRT1 in ARPE-19 cells. Our study, therefore, illustrated the molecular mechanisms of UVB-induced phototoxicity and damage of RPE cells. SIRT1 and resveratrol may be significant regulators, protecting against UVB-induced injury.
Toxicology in Vitro 05/2013; · 2.78 Impact Factor
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ABSTRACT: PURPOSE: Fibroblast growth factor-10 (FGF10) can modulate extracellular matrix associated genes and therefore it could be a myopia susceptibility gene. This study used an animal model, single nucleotide polymorphisms (SNPs) association and genetic functional assay to evaluate FGF10 gene for myopia. METHODS: The expression levels of FGF10 gene were compared among the form deprivation myopic (FDM) eyes, the fellow eyes of the FDM group and the normal eyes of experimental mice. In the present study 1,020 cases (≤-6.0 D) and 960 controls (≥-1.5 D) were enrolled from a Chinese population. Eight tagging SNPs were genotyped to test for an association between genotypes and myopia. The luciferase reporter assay was conducted for the particular SNP to assess the allelic effect on gene expression. RESULTS: The sclera of FDM eyes had a 2.57-fold higher level of FGF10 mRNA (p=0.018) than the fellow eyes. Although no SNP was associated with high myopia, SNP rs339501 was significantly associated with extreme myopia (≤-10D, p=0.008) and the OR was 1.58 for G allele carriers. The luciferase assay showed that the risk G allele significantly caused a higher expression level than the A allele (P = 0.011). CONCLUSIONS: The evidence suggested FGF10 to be a risk factor for myopia. The sclera of myopic eyes had higher FGF10 levels. The risk G allele of SNP rs339501 was associated with extreme myopia in human and caused a higher gene expression in the luciferase assay. It is concluded that the FGF10 could have been involved in the development of myopia.
Investigative ophthalmology & visual science 04/2013; · 3.43 Impact Factor
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ABSTRACT: We showed previously that single nucleotide polymorphism (SNP) rs662702 in PAX6 may be located in a microRNA-328 binding site that causes susceptibility to high myopia. Our study was done to elucidate the role of PAX6 and its relationship with microRNA-328 in myopia.
A luciferase assay was used to confirm microRNA-328 binding to the PAX6 locus. Clones containing each allele of rs662702 were created and tested for their binding affinity to microRNA-328. Because a low level of PAX6 is a risk factor for myopia, we tested whether knockdown of PAX6 affects retinal pigment epithelial (RPE) cells and scleral cells, as well as expression of myopia-related genes. We also tested for the effect of retinoic acid (RA) on microRNA-328 expression, since RA-responsive elements are predicted to lie in the microRNA-328 promoter.
MicroRNA-328 was shown to bind to the wild-type, but not mutant 3' untranslated region (UTR) of PAX6. The risk C allele of rs644242 had strong response to microRNA-328 but the protective T allele did not respond to microRNA-328. Down-regulation of PAX6 in RPE increased RPE proliferation, but reduced scleral cell proliferation. In addition, transforming growth factor (TGF)-β3 in the RPE and matrix malleoproteinase-2 (MMP2) in the sclera were increased, while collagen I and integrin β1 in the sclera were decreased. RA dose-dependently increased microRNA-328 expression and, in turn, suppressed PAX6 expression.
We elaborated the relationship among myopia development, SNP rs662702, microRNA-328 and RA. The data imply that reduction of miR-328 and/or RA can be potential strategies for myopia prevention or treatment.
Investigative ophthalmology & visual science 03/2012; 53(6):2732-9. · 3.43 Impact Factor
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ABSTRACT: Fibroblast growth factor-2 (FGF2) has been implied in the development of myopia according to previous studies investigating FGF2 in the sclera and retinal pigment epithelium. This study measured retinal FGF2 gene expression in an animal model and also tested for the association between single nucleotide polymorphisms (SNPs) in FGF2 and high myopia.
The guinea pigs were assigned to 2 groups: form deprivation myopia (FDM) for two weeks and normal control (free of form deprivation). Biometric measurement was performed and FGF2 expression levels were compared among the FDM eyes, the fellow eyes of the FDM group and the normal eyes in retina. We also enrolled 1,064 cases (≤-6.0 D) and 1,001 controls (≥-1.5 D) from a Chinese population residing in Taiwan. Six tagging SNPs were genotyped to test for an association between genotypes and high myopia.
The FDM eyes had the most prominent changes of refraction and axial length. Compared with the mRNA levels of FGF2 in the normal eyes, the FDM eyes had the highest levels of mRNA (p=0.0004) followed by the fellow eyes (p=0.002). The FDM and normal eyes became more myopic compared with the fellow eyes, but the fellow eyes became more hyperopic (p=0.004) in the end of the experiment which may be due to its relatively short axial length when compared with normal eyes (p=0.05). The SNP genotypes were all in Hardy-Weinberg equilibrium. However, none of the SNPs were significantly associated with high myopia (all p values >0.1).
We identified a significant change of FGF2 expression in the FDM eyes but FGF2 genetic variants are unlikely to influence susceptibility to myopia. There may be a systemic effect to influence gene expression and refraction on the fellow eyes, which may perturb emmetropization in the fellow eyes. Our data also suggest using normal eyes rather than the fellow eyes as the control eyes when study the form deprivation myopia.
Molecular vision 01/2012; 18:471-8. · 2.20 Impact Factor
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ABSTRACT: Ultraviolet B (UVB) radiation may cause the inflammation of retinal pigment epithelium (RPE) cells and play a role in development of age-related macular degeneration (AMD). The activation of the complement factor B (CFB) gene has been shown to be involved in formation of AMD. Here our results revealed that UVB induces IL-6/STAT3 signaling activation and the UVB-induced STAT3 is able to regulate the CFB expression in ARPE-19 cells. Tannic acid (TA) is a kind of water-soluble polyphenol and may have anti-inflammation effects. We also found that TA attenuates the UVB-induced IL-6 protein production, the STAT3 phosphorylation and the CFB expression. Taken together, these findings suggest UVB-induced inflammation of RPE can be mediated through the IL-6/STAT3/CFB pathway, and TA has a protected effect via the inhibition to the inflammatory response.
Cellular Immunology 11/2011; 273(1):79-84. · 1.97 Impact Factor
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ABSTRACT: The paired box 6 (PAX6) is involved in eye development and associated with several ocular diseases. Conflicting results have been reported regarding the association between PAX6 polymorphism and myopia. This case-control study and functional assay were conducted to identified a functional risk polymorphism for myopia.
The study cohort included 1083 cases (≤ -6.0 D) and 1096 controls (≥ -1.5 D) from a Chinese population residing in Taiwan. Four common tag single-nucleotide polymorphisms (SNPs) and an SNP at the 3' untranslated region (UTR) were selected. Secondary analyses were conducted in which cases and controls were redefined based on different spherical refractions. Permutation was used to adjust for multiple testing. The luciferase reporter assay was conducted for the 3'UTR SNP to assess the allelic effect on gene expression.
SNPs rs644242 and rs662702 had marginal significance (P = 0.063), and further analyses showed that these SNPs were associated with extreme myopia (≤ -11 D). The OR for extreme myopia was 2.1 (empiric P = 0.007) for the CC genotype at SNP rs662702 at the 3'UTR. The functional assay for SNP rs662702 demonstrated that the C allele had a significantly lower expression level than did the T allele (P = 0.0001). SNP rs662702 was predicted to be located in the microRNA-328 binding site, which may explain the differential allelic effect on gene expression. CONCLUSIONS; In this study, a functional SNP was identified at the 3'UTR that influences the risk for extreme myopia. The functional assay suggested that the risk allele can reduce PAX6 protein levels which significantly increases the risk for myopia.
Investigative ophthalmology & visual science 03/2011; 52(6):3500-5. · 3.43 Impact Factor
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ABSTRACT: Autism is a neurodevelopmental disorder with a strong genetic component. Previous studies have mapped the disease to chromosome 7q, where the homeobox transcription factor ENGRAILED 2 (EN2) gene is located. EN2 is specifically involved in patterning the region that gives rise to the cerebellum. In the present work, we carried out a case-control study to determine whether 2 intronic single-nucleotide polymorphisms (SNPs) of EN2 are a susceptibility to autism in a Han Chinese population.
We enrolled 184 cases of DSM-IV-TR diagnosed autistic disorder, 225 controls of unrelated healthy volunteers and 409 randomly selected controls from the community who lives in the adjacent geographical regions for this study. Two SNPs (rs1861972, rs1861973) at the EN2 gene that have been reported to be associated with autism underwent analysis among our studied cohorts. Both the UNPHASE and PHASE statistical programs were utilized for evaluating the association of EN2 SNPs with autism based on allelic and genotypic frequencies and haplotype compositions accompanied with the goodness-of-fit method of the chi(2) test. The gender difference was also investigated by using 2-side Fisher's exact test treated as a covariate in logistic regression analysis.
Both the allelic and genotypic distributions of the 2 polymorphisms were concordant with Hardy-Weinberg equilibrium. Significant differences were found for cases versus community and overall controls. By using the UNPHASE and PHASE programs, the 2-marker haplotype A-C of EN2 was identified to have a protective effect for autism, indicating that the ethnic difference might confound the EN2 association with autism. Therefore, more EN2 gene association studies of Han Chinese populations are warranted to confirm this finding.
Neuropsychobiology 02/2008; 57(1-2):3-8. · 2.67 Impact Factor
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ABSTRACT: Reduced scleral collagen accumulation has been found in the development of myopia. Single nucleotide polymorphisms (SNPs) at the type I collagen alpha-1 gene (COL1A1) may cause different susceptibilities to myopia. We conducted a case-control study to systematically examine COL1A1 as a candidate gene for high myopia. A case was defined as spherical refraction <or=-6 D and control >or=-1.5 D. The study comprised 471 cases and 623 controls, and ten tagging SNPs were genotyped. None of the SNPs reached the significant level of 0.05. Subset analysis on cases with a strong family history did not demonstrate significant results. We could not find an interaction between gene and near work. Exploratory analyses by changing the cutoff values to re-define cases and controls did not improve the results. Haplotype analysis did not yield significant association with myopia. This study failed to demonstrate COL1A1 as a significant risk factor for high myopia.
Journal of Human Genetics 01/2007; 52(4):374-7. · 2.57 Impact Factor
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ABSTRACT: We studied the relationship between high myopia and the MMP3 and TIMP1 genes.
Case-control study.
We enrolled 150 high myopic individuals (< or = -6 diopters) and 262 controls (> or = -1.5 diopters) initially, and another 216 cases and 474 controls were enrolled for genotyping promising polymorphisms for replication. Thirteen polymorphisms were genotyped in the initial data. Logistic regression was used to test for genetic effects. Subset analyses were performed according to the education level and family history.
There was no significant association between any polymorphism and high myopia in the initial data. Among the highly educated subjects, the 5A/6A polymorphism at the MMP3 gene suggested a potential relationship with high myopia, and it was genotyped in the follow-up samples. However, this polymorphism failed to show any significant results in the overall subjects.
The two genes may not play a crucial role for high myopia in young Taiwanese men.
American Journal of Ophthalmology 10/2006; 142(3):518-20. · 4.22 Impact Factor
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ABSTRACT: To evaluate the agreement of higher-order aberrations (HOAs) between aberrometers based on the Hartmann-Shack wavefront technology.
Department of Ophthalmology, Tri-Service General Hospital, Taipei, Taiwan.
Three clinical aberrometers WaveScan (Visx Inc.), LADARWave (Alcon Inc.), and Zywave (Bausch & Lomb Inc.) were used to measure HOAs in 34 cycloplegic eyes in 17 subjects. All the measurements in each subject were performed in 1 visit to reduce the impact of biologic fluctuation of HOAs. Each device was operated by an independent experienced operator, and the operators were blind to the data obtained from the other aberrometers. Root mean square (RMS) of coma, spherical aberration, and total 3rd- and 4th-order HOAs were compared between any 2 devices by a paired t test.
WaveScan had the lowest mean RMS, whereas Zywave reported the highest mean RMS for any HOAs. The coefficients of variation were similar between any 2 devices. Paired t tests of RMS yielded a P value <.01 in 9 of 12 comparisons. In general, the largest discrepancies of HOA measures were between WaveScan and Zywave, and similar data were found between LADARWave and WaveScan. More than 80% of the absolute difference of HOA RMS between LADARWave and WaveScan, 50% to 78% between LADARWave and Zywave, and 38% to 59% between WaveScan and Zywave were within +/-0.1 microm.
Significant discrepancies in HOA measurements were found among the 3 popular aberrometers. The HOA RMS data were closer between LADARWave and WaveScan, and HOA RMS by Zywave was generally higher than the other 2 devices. The 3 devices had comparable measurement variation.
Journal of Cataract [?] Refractive Surgery 12/2005; 31(11):2153-6. · 2.26 Impact Factor
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ABSTRACT: Aberrant calpain activation is a key mediator of neuron death. We examined the cell-permeable calpain inhibitor MDL28170 in the pathophysiological processes after spinal cord injury (SCI) including p35-p25- cyclin-dependent kinase-5 (Cdk5) activation, tau hyperphosphorylation, neuron cell death, calpain I activation, astrogliosis, and microglia activation. Our study showed that intrathecal administration of MDL28170 improved neurologic dysfunction, prevented neuron loss, decreased the number of apoptotic cells, and abated astrogliosis and microglia activation 7 days after spinal cord hemisection in rats. Reverse transcription polymerase chain reaction demonstrated calpain inhibition significantly attenuated the ratio of proapoptotic Bax/anti-apoptotic Bcl-2 mRNA in the lesion and penumbra after SCI. Calpain, the calcium-activated proteolytic enzyme, was found to digest p35 to its truncated product, p25. Moreover, abnormal Cdk5 activation by p25 and subsequent tau hyperphosphorylation triggers pathologic events leading to neurodegeneration and neurofibrillary tangles. We found p35-p25-Cdk5 activation and tau hyperphosphorylation in SCI, and then we showed that intrathecal MDL28170 treatment could diminish p35 truncation, and abrogate aberrant tau phosphorylation. Double labeling of calpain I and phosphorylated tau (AT8) in the same cells of spinal cord lesion further implicated pathogenesis of SCI. In conclusion, MDL28170 abated calpain I activation, inhibited apoptosis and neuron loss, quenched microglia and astrocyte activation, and significantly improved neurologic deficit one week after spinal cord hemisection. The neuroprotective mechanisms of calpain inhibitor in SCI could be attenuating upregulation of Bax/Bcl-2 ratio, preventing p35 truncation in the lesion and penumbra, and abrogating tau hyperphosphorylation.
Journal of Neuropathology and Experimental Neurology 02/2005; 64(1):15-26. · 4.26 Impact Factor
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ABSTRACT: Frontal intracerebral haemorrhage (ICH) is a common result of cranial trauma. Outcome differences between bilateral and unilateral frontal ICH are not well studied but would be valuable to predict prognosis in clinical practice. Two aims are proposed in this study: first to compare the risk of developing delayed ICH after bilateral or unilateral frontal ICH, and second to determine the variables helpful to predict outcome according to the Glasgow Outcome Scale (GOS). Between January 1993 and December 1997, 694 consecutive patients with traumatic ICH were admitted to the Chang Gung Medical Center within 24 h of the trauma. Patients with ICH in sites other than the frontal lobes were excluded. A total of 161 cases (mean age 46.3+/-20.3 years), including 57 bilateral (mean age 52.5+/-18.7 years) and 104 unilateral (mean age 42.9+/-20.5 years) traumatic frontal ICH were studied. Twenty-eight of 57 patients (49%) with bifrontal ICH versus 17 of 104 patients (16%) with unilateral frontal ICH had a further, delayed ICH. In 42 of 45 patients (93%) with delayed ICH, this occurred within 5 days of the initial trauma. Multivariate logistic regression was used to select significant predictors of outcome. We found that delayed ICH (p<0.001), age (p=0.004) and mechanism of injury (p=0.001) explained the worse outcome in patients with bifrontal ICH. The best-fitting logistic regression model included three variables: delayed ICH (p=0.011), initial GCS (p=0.023), and a sum score of clinical and radiological variables (p=0.003). Bifrontal ICH tended to occur in older patients after a fall and was associated with a higher risk of developing delayed ICH or brain stem compression compared to unilateral ICH damage. Using these three variables - delayed ICH, initial GCS, and the sum score - in a logistical regression model is useful to predict outcome in patients with traumatic frontal ICH and may aid patient management.
Journal of Clinical Neuroscience 11/2004; 11(8):849-53. · 1.25 Impact Factor
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ABSTRACT: To investigate the impact of a positive family history of high myopia on the level and onset of myopia and its ocular components.
A cross-sectional study was conducted. The participants (aged 17 to 45 years) were categorized into four groups: normal, mild, moderate, and high myopia. The age of first glasses for myopia was used as the onset of myopia. The impact of the family history on the level and the onset of myopia was quantified. Parental effect on corneal curvature (CC), anterior chamber depth (ACD), and axial length (AXL) was analyzed.
The study included 185 normal subjects, 170 mild, 140 moderate, and 392 high myopes. Family history was strongly associated with the probands' status (P < 6 x 10(-12)). When there was >or=1 highly myopic parent, the odds ratios (ORs) of developing mild or moderate myopia were between 2.5 and 3.7 (95% CI: 1.1-6.5) and the ORs of having high myopia were > 5.5 (95% CI: 3.2-12.6). A strong association (P = 2 x 10(-6)) between parental myopic state and the AXL in the subjects was also found, but there was no statistical relationship for ACD or CC. There was an association between high myopia in parents and the onset of myopia in children. Siblings had a weaker association with the level of myopia and had no effect on the onset of myopia.
This study found strong familial effects on the level and onset of myopia even after adjusting for environmental factors. The parental effect on ocular components in their offspring was primarily on AXL.
Investigative Ophthalmology & Visual Science 10/2004; 45(10):3446-52. · 3.60 Impact Factor
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ABSTRACT: To compare the keratometry measurements in children by the handheld Nikon Retinomax K-Plus2 (Rmax) and the on-table Topcon KR8100 autokeratometers and evaluate the degree of agreement in the 2 instruments between children with and without cycloplegia.
Department of Ophthalmology, Kaohsiung Municipal United Hospital, and Chang-Gung Memorial Hospital, Kaohsiung, Taiwan.
The first cohort comprised 61 children who were consecutively collected in the pediatric ophthalmology clinic. The keratometry was measured under cycloplegia. The second cohort included 156 school children who received routine vision screening without cycloplegia. The horizontal and vertical keratometry data were measured by both instruments. The mean bias and agreement between the 2 types of measurements were evaluated.
Both horizontal and vertical keratometry data from the Rmax were systemically and mildly lower than the data from the Topcon. The mean keratometric difference in the 2 types of instruments was minimal and clinically acceptable: 72% to 85% was within +/-0.5 diopter. The agreement of measured data in the children without cycloplegia was higher than that in the children with cycloplegia.
The handheld Retinomax provided comparable data to that of the conventional on-table Topcon. It is useful in the clinic to measure keratometry in children and therefore may offer a convenient tool for assessing corneal curvature for fitting contact lenses or for implanting intraocular lenses in young children.
Journal of Cataract [?] Refractive Surgery 04/2004; 30(3):669-74. · 2.26 Impact Factor
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ABSTRACT: Hypoxic-ischemic (H-I) encephalopathy is a major contributor to morbidity and mortality in infants and children. To delineate the nature and mechanism(s) of neuroprotection via erythropoietin (EPO) gene therapy, we evaluated the effects of single intravenous injection of naked plasmid DNA encoding EPO in H-I infant rats. Single administration of naked plasmid containing EPO cDNA driven under cytomegalovirus promoter (pCMV-EPO) by rapid injection via the tail vein produced a remarkable level of human EPO protein in the circulation, peaking at one day and lasting for 14 days after injection. There were significant improvements of water maze task in H-I rats after EPO gene therapy. Our data showed that the mechanisms of EPO gene therapy were rescue of CA1 neurons from lethal H-I injury, prevention of neuronal apoptosis in CA1 region, and decrease of glial activation in corpus callosum. This could be the first report of successful treatment of H-I injury by a single intravenous infusion of EPO gene.
Biochemical and Biophysical Research Communications 03/2004; 314(4):1064-71. · 2.48 Impact Factor
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ABSTRACT: To compare the measurement of refractive errors (sphere, cylinder, and axis) between the hand-held Retinomax and on-table Topcon autorefractors in cyclopleged and noncyclopleged young children. The average bias and measurement agreement were assessed.
Observational cross-sectional study.
The study included 114 cyclopleged and 156 noncyclopleged young children. The mean difference between the two methods and the 95% limits of agreement were calculated to evaluate the average bias. Two types of analyses were conducted to assess the degree of agreement. First, the proportion of the absolute mean differences was presented in different ranges (<or=0.25, 0.25-0.5, 0.5-0.75, 0.75-1.0, and >1.0 diopters for sphere and cylinder; 0-10, 11-20 and >20 degrees for axis). Second, the paired t test was conducted to evaluate the consistency of two types of measurements.
The data by the Retinomax had mild bias (0.59 diopters) toward a lower sphere data under noncycloplegia but no bias under cycloplegia. For cylinder and axis, there was either no bias or clinically acceptable bias (0.02-0.13 diopters for cylinder and 2-7 degrees for axis) regardless of cycloplegia. Besides the sphere data under noncycloplegia, in general 90% of the mean differences of sphere and cylinder were within 0.5 diopters. More than 97% of the difference in axis under cycloplegia and 68% under noncycloplegia were within 20 degrees. After adjusting for mild bias, the paired t test showed very consistent results.
The data by the Retinomax were consistent with those by the Topcon. The Retinomax is a useful instrument to screen refractive errors in young children.
American Journal of Ophthalmology 01/2004; 136(6):1120-8. · 4.22 Impact Factor
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The Journal of trauma 12/2002; 53(5):1006-9. · 2.48 Impact Factor
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The Journal of Trauma and Acute Care Surgery. 10/2002; 53(5):1006-1009.
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ABSTRACT: Lung cancer is the most prevalent malignant tumor in the world. Metastasis of the disease causes death in lung cancer patients. Recent study has shown that multiple cascades of gene defects occur in lung cancer. In this report, we established a novel H1299/EGFP tumor model to determine whether H1299 transfected with the enhanced green fluorescent protein (EGFP) gene in vitro and xenotransplanted into SCID mouse lung would permit the detection of lung cancer micrometastasis in vivo. We demonstrated that EGFP-transduced H1299 cells maintained stable high-level EGFP expressions during their growth in vivo. EGFP fluorescence clearly demarcated the primary seeding place and readily allowed for the visualization of distant micrometastasis and local invasion at the single-cell level. Small metastatic and locally invasive foci, including those immediately adjacent to the tumor's leading invasive edge, were almost undetectable by routine hematoxylin and eosin staining and immunohistochemistry. The GFP tagged lung cancer model is superior for the detection and study of physiologically relevant patterns of lung cancer invasion and metastasis in vivo.
Clinical and Experimental Metastasis 02/2002; 19(4):359-68. · 3.52 Impact Factor
