Publications by authors named "Fen Fen Li"

26 Publications

  • Page 1 of 1

Association of polymorphisms in , and with myopia progression and polygenic risk prediction in children.

Br J Ophthalmol 2021 Apr 2. Epub 2021 Apr 2.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China

Aims: To assess the association of single-nucleotide polymorphisms (SNPs) with myopia progression for polygenic risk prediction in children.

Methods: Six SNPs ( rs4373767, rs13382811, rs7744813, rs2073560, rs7839488 and rs524952) were analysed in 1043 school children, who completed 3-year follow-up, using TaqMan genotyping assays. SNP associations with progression in spherical equivalent (SE) were analysed by logistic regression. Polygenic risk scores (PRS) were applied for computing the sum of the risk alleles of multiple SNPs corresponding to myopia progression, weighted by the effect sizes of corresponding SNPs.

Results: rs524952 showed significant association with fast progression (OR=1.32, 95% CI 1.10 to 1.59; p=0.003) and rs7744813 had nominal association (OR=1.32, 95% CI 1.04 to 1.67; p=0.02). In quantitative traits locus analysis, rs524952 and rs7744813 were associated with progression in SE (β=-0.038 D/year, p=0.008 and β=-0.042 D/year, p=0.02) and axial elongation (β=0.016 mm/year, p=0.01 and β=0.017 mm/year, p=0.027). rs13382811 also showed nominal association with faster progression in SE (β=-0.041 D/year, p=0.02). PRS analysis showed that children with the highest PRS defined by rs13382811, rs7744813 and rs524952 had a 2.26-fold of increased risk of fast myopia progression (p=4.61×10). PRS was also significantly associated with SE progression (R=1.6%, p=3.15×10) and axial elongation (R=1.2%, p=2.6×10).

Conclusions: In this study, multi-tiered evidence suggested SNPs in , and as risk factors for myopia progression in children. Additional attention and appropriate interventions should be given for myopic children with high-risk PRS as defined by rs524952, rs7744813 and rs13382811.
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http://dx.doi.org/10.1136/bjophthalmol-2020-318708DOI Listing
April 2021

Age Effect on Treatment Responses to 0.05%, 0.025%, and 0.01% Atropine: Low-Concentration Atropine for Myopia Progression Study.

Ophthalmology 2021 Jan 8. Epub 2021 Jan 8.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China; Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong SAR, China; Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong SAR, China; Hong Kong Eye Hospital, Hong Kong SAR, China; Department of Ophthalmology, Hong Kong Children's Hospital, Hong Kong SAR, China. Electronic address:

Purpose: To investigate the effect of age at treatment and other factors on treatment response to atropine in the Low-Concentration Atropine for Myopia Progression (LAMP) Study.

Design: Secondary analysis from a randomized trial.

Participants: Three hundred fifty children aged 4 to 12 years who originally were assigned to receive 0.05%, 0.025%, or 0.01% atropine or placebo once daily, and who completed 2 years of the LAMP Study, were included. In the second year, the placebo group was switched to the 0.05% atropine group.

Methods: Potential predictive factors for change in spherical equivalent (SE) and axial length (AL) over 2 years were evaluated by generalized estimating equations in each treatment group. Evaluated factors included age at treatment, gender, baseline refraction, parental myopia, time outdoors, diopter hours of near work, and treatment compliance. Estimated mean values and 95% confidence intervals (CIs) of change in SE and AL over 2 years also were generated.

Main Outcome Measures: Factors associated with SE change and AL change over 2 years were the primary outcome measures. Associated factors during the first year were secondary outcome measures.

Results: In 0.05%, 0.025%, and 0.01% atropine groups, younger age was the only factor associated with SE progression (coefficient of 0.14, 0.15, and 0.20, respectively) and AL elongation (coefficient of -0.10, -0.11, and -0.12, respectively) over 2 years; the younger the age, the poorer the response. At each year of age from 4 to 12 years across the treatment groups, higher-concentration atropine showed a better treatment response, following a concentration-dependent effect (P <0.05 for each age group). In addition, the mean SE progression in 6-year-old children receiving 0.05% atropine (-0.90 diopter [D]; 95% CI, -0.99 to -0.82) was similar to that of 8-year-old children receiving 0.025% atropine (-0.89 D; 95% CI, -0.94 to -0.83) and 10-year-old children receiving 0.01% atropine (-0.92 D; 95% CI, -0.99 to -0.85). All concentrations were well tolerated in all age groups.

Conclusions: Younger age is associated with poor treatment response to low-concentration atropine at 0.05%, 0.025%, and 0.01%. Among concentrations studied, younger children required the highest 0.05% concentration to achieve similar reduction in myopic progression as older children receiving lower concentrations.
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http://dx.doi.org/10.1016/j.ophtha.2020.12.036DOI Listing
January 2021

Exposure to Secondhand Smoke in Children is Associated with a Thinner Retinal Nerve Fiber Layer: The Hong Kong Children Eye Study.

Am J Ophthalmol 2021 03 29;223:91-99. Epub 2020 Oct 29.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China; Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong; Hong Kong Eye Hospital, Hong Kong SAR, China; Department of Ophthalmology, Hong Kong Children's Hospital SAR, China. Electronic address:

Purpose: We sought to assess the effects of exposure to secondhand smoke (SHS) on peripapillary retinal nerve fiber layer (p-RNFL) thickness in children.

Design: Cross-sectional study.

Methods: Children 6-8 years of age were consecutively recruited from the population-based Hong Kong Children Eye Study. All participants received comprehensive ophthalmic examinations and p-RNFL thickness was measured by spectral-domain optical coherence tomography. SHS data were derived from a validated questionnaire. Associations between p-RNFL thickness and SHS exposure status, number of smokers in the family, and quantity of smoking in the family were determined by multivariate linear regression after adjusting for potential confounders.

Results: Among the Hong Kong Children Eye Study cohort (n = 3,103), approximately one-third of children were exposed to SHS (35.4%, n = 1,097). Compared to those without exposure to SHS, children exposed to SHS had similar age (P = .83), gender (P = .17), body mass index (P = .44), birth weight (P = .23), and axial length (P = .34), but had lower family income (P < .001) and lower parental education level (P < .001). After adjusting for all the above factors, exposure to SHS was associated with a thinner global p-RNFL by 4.4 μm (P < .001). Reduced p-RNFL was also associated with increased numbers of smokers in the family (β = -3.40, P < .001) and increased quantity of SHS (β = -0.22, P < .001).

Conclusions: Exposure to SHS in children was associated with a thinner p-RNFL. A thinner p-RNFL may increase the risk of irreversible visual impairment in the future. Our results provide evidence to recommend that children avoid exposure to SHS.
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http://dx.doi.org/10.1016/j.ajo.2020.10.016DOI Listing
March 2021

Genetic associations of myopia severities and endophenotypes in children.

Br J Ophthalmol 2020 Aug 14. Epub 2020 Aug 14.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China

Objective: To investigate the associations of multiple single-nucleotide polymorphisms (SNPs) with the severities and endophenotypes of myopia in children.

Methods: A total of 3300 children aged 5-10 years were recruited: 137 moderate and high myopia (SE≤-3.0D), 670 mild myopia (-3.0D-0.5D). 13 SNPs in 13 genes/loci were selected for genotyping in all subjects using TaqMan assays. Associations between each SNP with myopia severities and ocular traits (spherical equivalent (SE), axial length (AL) and corneal radius (CR)) were analysed.

Results: When compared with controls, SNPs rs4373767 (OR=1.15, p=0.038), rs7084402 (OR=1.18, p=0.005) and rs524952 (OR=1.14, p=0.025) showed nominal associations with overall myopia. rs4373767 and rs7084402 showed stronger associations with moderate and high myopia (rs4373767: OR=1.42, p=0.018; rs7084402: OR=1.33, p=0.025), while rs524952 had a stronger association with mild myopia (OR=1.14, p=0.025). rs524952 also showed a difference between emmetropia and hyperopia (p=0.018). In quantitative trait locus analysis, rs4373767, rs7744813 and rs524952 were correlated with both myopic SE (β=-0.09, p=0.03; β=-0.12, p=0.007; β=-0.13, p=0.0006, respectively) and AL (β=0.07, p=0.002; β=0.09, p=0.0008; β=0.07, p=0.0003, respectively). rs7839488 was correlated with both AL (β=0.07, p=0.005) and CR (β=0.02, p=0.006). Moreover, rs4373767-T (β=0.006; p=0.018), rs7744813-A (β=0.007; p=0.015) and rs524952-T (β=0.009; p=0.0006) were correlated with AL-CR ratio.

Conclusions And Relevance: and are genetic risk factors for moderate and high myopia, while and confer risk to excessive AL in children.
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http://dx.doi.org/10.1136/bjophthalmol-2020-316728DOI Listing
August 2020

Association of WNT7B and RSPO1 with Axial Length in School Children.

Invest Ophthalmol Vis Sci 2020 08;61(10):11

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.

Purpose: To evaluate the association between single-nucleotide polymorphisms (SNPs) in the ZC3H11B, RSPO1, C3orf26, GJD2, ZNRF3, and WNT7B genes and myopia endophenotypes in children.

Methods: Seven SNPs identified in previous genome-wide association studies of axial length (AL) were genotyped in 2883 Southern Han Chinese children. Multiple linear regression analyses were conducted to evaluate the genotype association with AL, spherical equivalent (SE), corneal curvature (CC), and central corneal thickness (CCT).

Results: Two SNPs-namely, rs12144790 in RSPO1 (allele T, P = 0.0066, β = 0.062) and rs10453441 in WNT7B (allele A, P = 8.03 × 10-6, β = 0.103)-were significantly associated with AL. The association of rs4373767 in ZC3H11B (allele C, P = 0.030, β = -0.053) could not withstand the correction for multiple testing. WNT7B rs10453441 showed a strong association with CC (P = 1.17 × 10-14, β = 0.053) and with CCT (P = 0.0026, β = 2.65). None of the tested SNPs was significantly associated with SE. The C allele of SNP rs12321 in ZNRF3 was associated with CC (P = 0.0060, β = -0.018).

Conclusions: This study revealed that the RSPO1 SNP rs12144790 was associated with AL, whereas WNT7B rs10453441 was associated with AL, CC, and CCT in children. A novel association between ZNRF3 rs12321 and CC was discovered. Our data suggest that the RSPO1 and WNT7B genes might exert their effects on multiple aspects of eye growth during childhood. Potential differences in the genetic profiles of AL between children and adults should be explored in larger cohorts.
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http://dx.doi.org/10.1167/iovs.61.10.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441295PMC
August 2020

Differential Effects on Ocular Biometrics by 0.05%, 0.025%, and 0.01% Atropine: Low-Concentration Atropine for Myopia Progression Study.

Ophthalmology 2020 12 7;127(12):1603-1611. Epub 2020 Jun 7.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China; Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong SAR, China; Hong Kong Eye Hospital, Hong Kong SAR, China. Electronic address:

Purpose: To evaluate changes in ocular biometrics in groups receiving 0.05%, 0.025%, and 0.01% atropine compared with placebo over 1 year based on the Low-Concentration Atropine for Myopia Progression (LAMP) study.

Design: Double-blinded, randomized, placebo-controlled trial.

Participants: Three hundred eighty-three children aged 4 to 12 years who were assigned randomly to receive 0.05%, 0.025%, 0.01% atropine, or placebo once daily in both eyes and completed the first year of the LAMP study.

Methods: Cycloplegic spherical equivalent (SE), axial length (AL), corneal curvature (K), and anterior chamber depth (ACD) were measured by IOLMaster. Corneal astigmatism and lens power were calculated. The ocular biometric parameter changes were compared among groups. Contributions to SE progression from ocular parameters were determined and compared among groups.

Main Outcome Measures: Changes in ocular biometrics and their associations with the changes in SE.

Results: Over 1 year, changes in AL were 0.20 ± 0.25 mm, 0.29 ± 0.20 mm, 0.36 ± 0.29 mm, and 0.41 ± 0.22 mm in the 0.05% atropine, 0.025% atropine, 0.01% atropine, and placebo groups, respectively (P < 0.001), with a concentration-dependent response. Corneal power remained stable, and its changes were similar across all atropine concentrations: -0.02 ± 0.14 diopter (D), -0.01 ± 0.14 D, -0.01 ± 0.12 D, and 0.01 ± 0.14 D in the 0.05% atropine, 0.025% atropine, 0.01% atropine, and placebo groups, respectively (P = 0.10). Lens power decreased over time in each concentration, but its changes also were similar across all concentrations: -0.31 ± 0.43 D, -0.38 ± 0.47 D, -0.40 ± 0.43 D, and -0.41 ± 0.43 D in the 0.05% atropine, 0.025% atropine, 0.01% atropine, and placebo groups, respectively (P = 0.24). Changes in ACD remained similar across all concentrations (P = 0.41). The contributions to SE progression from the ocular biometric changes after adjusting for age and gender in each concentration were similar across all groups (P > 0.05).

Conclusions: Low-concentrations of atropine (0.05%, 0.025%, and 0.01%) have no clinical effect on corneal or lens power. Antimyopic effects of low-concentration atropine act mainly on reducing AL elongation, and therefore could reduce the risk of subsequent myopia complications.
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http://dx.doi.org/10.1016/j.ophtha.2020.06.004DOI Listing
December 2020

Two-Year Clinical Trial of the Low-Concentration Atropine for Myopia Progression (LAMP) Study: Phase 2 Report.

Ophthalmology 2020 07 21;127(7):910-919. Epub 2019 Dec 21.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.

Purpose: To evaluate the efficacy and safety of 0.05%, 0.025%, and 0.01% atropine eye drops over 2 years to determine which is the optimal concentration for longer-term myopia control.

Design: Randomized, double-masked trial extended from the Low-Concentration Atropine for Myopia Progression (LAMP) Study.

Participants: Three hundred eighty-three of 438 children (87%) aged 4 to 12 years with myopia of at least -1.0 diopter (D) originally randomized to receive atropine 0.05%, 0.025%, 0.01%, or placebo once daily in both eyes in the LAMP phase 1 study were continued in this extended trial (phase 2).

Methods: Children in the placebo group (phase 1) were switched to receive 0.05% atropine from the beginning of the second-year follow-up, whereas those in the 0.05%, 0.025%, and 0.01% atropine groups continued with the same regimen. Cycloplegic refraction, axial length (AL), accommodation amplitude, photopic and mesopic pupil diameter, and best-corrected visual acuity were measured at 4-month intervals.

Main Outcome Measures: Changes in spherical equivalent (SE) and AL and their differences between groups.

Results: Over the 2-year period, the mean SE progression was 0.55±0.86 D, 0.85±0.73 D, and 1.12±0.85 D in the 0.05%, 0.025%, and 0.01% atropine groups, respectively (P = 0.015, P < 0.001, and P = 0.02, respectively, for pairwise comparisons), with mean AL changes over 2 years of 0.39±0.35 mm, 0.50±0.33 mm, and 0.59±0.38 mm (P = 0.04, P < 0.001, and P = 0.10, respectively). Compared with the first year, the second-year efficacy of 0.05% and 0.025% atropine remained similar (P >0.1), but improved mildly in the 0.01% atropine group (P = 0.04). For the phase 1 placebo group, the myopia progression was reduced significantly after switching to 0.05% atropine (SE change, 0.18 D in second year vs. 0.82 D in first year [P < 0.001]; AL elongated 0.15 mm in second year vs. 0.43 mm in first year [P < 0.001]). Accommodation loss and change in pupil size in all concentrations remained similar to the first-year results and were well tolerated. Visual acuity and vision-related quality of life remained unaffected.

Conclusions: Over 2 years, the efficacy of 0.05% atropine observed was double that observed with 0.01% atropine, and it remained the optimal concentration among the studied atropine concentrations in slowing myopia progression.
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http://dx.doi.org/10.1016/j.ophtha.2019.12.011DOI Listing
July 2020

Association of Secondhand Smoking Exposure With Choroidal Thinning in Children Aged 6 to 8 Years: The Hong Kong Children Eye Study.

JAMA Ophthalmol 2019 Dec;137(12):1406-1414

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong.

Importance: Secondhand smoking is a risk to adult ocular health, but its effect on children's ocular development is not known.

Objective: To assess the association between choroidal thickness and secondhand smoking exposure in children.

Design, Setting, And Participants: Children aged 6 to 8 years were consecutively recruited from January 2016 to July 2017 from the population-based Hong Kong Children Eye Study at the Chinese University of Hong Kong Eye Centre. All participants underwent detailed ophthalmic investigations. Choroidal thickness was measured by swept-source optical coherence tomography, with built-in software that automatically segmented the choroid layer to analyze its terrain imagery. History of secondhand smoking was obtained from a questionnaire. Multiple linear regression analyses were performed to assess the correlation between choroidal thickness and secondhand exposure when controlling for confounding factors. Analysis began July 2018 and ended in April 2019.

Main Outcomes And Measurements: The association between children's choroidal thickness and their exposure to secondhand smoking.

Results: Of 1400 children, 941 (67.2%) had no exposure to secondhand smoking, and 459 (32.8%) had exposure to secondhand smoking. The mean (SD) age was 7.65 (1.09) years for children in the nonexposure group and 7.54 (1.11) years for children in the exposure group. After adjustment for age, sex, body mass index, axial length, and birth weight, exposure to secondhand smoking was associated with a thinner choroid by 8.3 μm in the central subfield, 7.2 μm in the inner inferior, 6.4 μm in the outer inferior, 6.4 μm in the inner temporal, and 7.3 μm in the outer temporal. Choroidal thinning with also associated with increased number of family smokers and increased quantity of secondhand smoking. An increase of 1 family smoker was associated with choroidal thinning by 7.86 μm in the central subfield, 4.51 μm in the outer superior, 6.23 μm in the inner inferior, 5.59 μm in the outer inferior, 6.06 μm in the inner nasal, and 6.55 μm in the outer nasal. An increase of exposure to 1 secondhand cigarette smoke per day was associated with choroidal thinning by 0.54 μm in the central subfield, 0.42 μm in the inner temporal, and 0.47 μm in the outer temporal.

Conclusions And Relevance: This investigation showed that exposure to secondhand smoking in children was associated with choroidal thinning along with a dose-dependent effect. These results support evidence regarding the potential hazards of secondhand smoking to children.
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http://dx.doi.org/10.1001/jamaophthalmol.2019.4178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802252PMC
December 2019

Low-Concentration Atropine Eye Drops for Myopia Progression.

Asia Pac J Ophthalmol (Phila) 2019 Sep-Oct;8(5):360-365

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Kowloon, Hong Kong.

Purpose: Atropine eye drops is an emerging therapy for myopia control. This article reviews the recent clinical trials to provide a better understanding of the use of atropine eye drops on myopia progression.

Methods: All randomized clinical trials of atropine eye drops for myopia progression in the literatures were reviewed.

Results: Atropine eye drops 1% conferred the strongest efficacy on myopia control. However, its use was limited by the side effects of blurred near vision and photophobia. ATOM 2 study evaluated 0.5%, 0.1%, and 0.01% atropine on 400 myopic children, and suggested that 0.01% is the optimal concentration with good efficacy and minimal side effects. Since then, the use of atropine eye drops has been transitioned from high-concentration to low-concentration worldwide. Recent Low-concentration Atropine for Myopia Progression (LAMP) study evaluated 0.05%, 0.025%, 0.01% atropine eye drops and placebo group in 438 myopic children. The study firstly provided placebo-compared evidence of low-concentration atropine eye drops in myopia control. Furthermore, both efficacy and side effects followed a concentration-dependent response within 0.01% to 0.05% atropine. Among them, 0.05% atropine was the optimal concentration to achieve best efficacy and safety profile.

Conclusions: Low concentration atropine is effective in myopia control. The widespread use of low-concentration atropine, especially in East Asia, may help prevent the myopia progression for the high-risk children. Further investigations on the rebound phenomenon following drops cessation, and longer-term individualized treatment approach should be warranted.
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http://dx.doi.org/10.1097/APO.0000000000000256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784858PMC
January 2020

Association of the and genes with myopia of different severities.

Br J Ophthalmol 2020 10 12;104(10):1472-1476. Epub 2019 Jul 12.

Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong, New Territories, Hong Kong

Objective: To investigate the associations of single-nucleotide polymorphisms (SNPs) in the , and genes with severities of myopia in Chinese populations.

Methods: Based on previous myopia genome-wide association studies, five SNPs ( rs4373767, rs13382811, rs2730260, rs7839488 and rs9318086) were selected for genotyping in a Chinese cohort of 2079 subjects: 252 extreme myopia, 277 high myopia, 393 moderate myopia, 366 mild myopia and 791 non-myopic controls. Genotyping was performed by TaqMan assays. Allelic frequencies of the SNPs were compared with myopia severities and ophthalmic biometric measurements.

Results: The risk allele T of SNP rs4373767 was significantly associated with high myopia (OR=1.39, p=0.007) and extreme myopia (OR=1.34, p=0.013) when compared with controls, whereas rs13382811 (allele T, OR=1.33, p=0.018) and rs7839488 (allele G, OR=1.71, p=8.44E-05) were significantly associated with extreme myopia only. In contrast, there was no significant association of these SNPs with moderate or mild myopia. When compared with mild myopia, subjects carrying T allele of rs4373767 had a risk of progressing to high myopia (spherical equivalent ≤-6 dioptres) (OR=1.29, p=0.017). Similarly, the T allele of rs13382811 also imposed a significant risk to high myopia (OR=1.36, p=0.007). In quantitative traits analysis, SNPs rs4373767, rs13382811 and rs7839488 were correlated with axial length and refractive errors.

Conclusions: We confirmed as a susceptibility gene for high and extreme myopia, and and for extreme myopia in Chinese populations. Instead of myopia onset, these three genes were more likely to impose risks of progressing to high and extreme myopia.
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http://dx.doi.org/10.1136/bjophthalmol-2019-314203DOI Listing
October 2020

Effects of Sodium Montmorillonite on the Preparation and Properties of Cellulose Aerogels.

Polymers (Basel) 2019 Mar 4;11(3). Epub 2019 Mar 4.

Center for Degradable and Flame-Retardant Polymeric Materials, College of Chemistry, Sichuan University, Chengdu 610064, China.

In this study, first, a green and efficient NaOH/urea aqueous solution system was used to dissolve cellulose. Second, the resulting solution was mixed with sodium montmorillonite. Third, a cellulose/montmorillonite aerogel with a three-dimensional porous structure was prepared via a sol-gel process, solvent exchange and freeze-drying. The viscoelastic analysis results showed that the addition of montmorillonite accelerated the sol-gel process in the cellulose solution. During this process, montmorillonite adhered to the cellulose substrate surface via hydrogen bonding and then became embedded in the pore structure of the cellulose aerogel. As a result, the pore diameter of the aerogel decreased and the specific surface area of the aerogel increased. Furthermore, the addition of montmorillonite increased the compressive modulus and density of the cellulose aerogel and reduced volume shrinkage during the preparation process. In addition, the oil/water adsorption capacities of cellulose aerogels and cellulose/montmorillon aerogels were investigated.
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http://dx.doi.org/10.3390/polym11030415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473606PMC
March 2019

Genome-Wide Detection of Copy Number Variations in Unsolved Inherited Retinal Disease.

Invest Ophthalmol Vis Sci 2017 01;58(1):424-429

Division of Ophthalmic Genetics, Lab for Stem Cell & Retinal Regeneration, Institute of Stem Cell Research, The Eye Hospital, Wenzhou Medical University, Wenzhou, China.

Purpose: Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of Mendelian disorders that plays a crucial role in the etiology of blindness across the world. Molecular genetic diagnosis of IRD remains extremely complex and challenging because mutations are only detected in 40% to 60% of cases. In this study, we aimed to dissect the contributions of copy number variations (CNVs) in IRD patients.

Methods: A total of 50 patients were diagnosed with IRD, all of whom previously tested negative for pathogenic mutations in known disease genes. Single-nucleotide polymorphism array analysis was performed by using the HumanCoreExome BeadChip. Analyses of CNVs were carried out by using GenomeStudio, KaryoStudio, and cnvPartition. The putative pathogenic CNVs were further confirmed by real-time quantitative PCR.

Results: We identified four novel CNVs in three different genes (one duplication in USH2A gene, two duplications in CEP290 gene, and one duplication in RIMS2 gene) in total four families, at a detection rate of 8% (4/50). All of these CNVs are currently absent in all databases. Three variations are located in genes that are already known to cause inherited retinal disease: USH2A and CEP290, while the association between mutation in the RIMS2 gene and IRD is reported for the first time.

Conclusions: We performed whole-genome-wide CNV analyses in a large cohort as an alternative approach to molecular diagnosis of IRDs. This study dissected the contributions of CNVs of IRDs, not only increasing the yield in genetic testing but also suggesting the CNVs should be analyzed in the patients with IRDs.
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http://dx.doi.org/10.1167/iovs.16-20705DOI Listing
January 2017

Persistency of Enlarged Autolysosomes Underscores Nanoparticle-Induced Autophagy in Hepatocytes.

Small 2017 02 7;13(7). Epub 2016 Dec 7.

The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, P. R. China.

The diverse biological effects of nanomaterials form the basis for their applications in biomedicine but also cause safety issues. Induction of autophagy is a cellular response after nanoparticles exposure. It may be beneficial in some circumstances, yet autophagy-mediated toxicity raises an alarming concern. Previously, it has been reported that upconversion nanoparticles (UCNs) elicit liver damage, with autophagy contributing most of this toxicity. However, the detailed mechanism is unclear. This study reveals persistent presence of enlarged autolysosomes in hepatocytes after exposure to UCNs and SiO nanoparticles both in vitro and in vivo. This phenomenon is due to anomaly in the autophagy termination process named autophagic lysosome reformation (ALR). Phosphatidylinositol 4-phosphate (PI(4)P) relocates onto autolysosome membrane, which is a key event of ALR. PI(4)P is then converted into phosphatidylinositol 4,5-bisphosphate (PI(4,5)P ) by phosphatidylinositol-4-phosphate 5-kinase. Clathrin is subsequently recruited by PI(4,5)P and leads to tubule budding of ALR. Yet it is observed that PI(4)P cannot be converted in nanoparticle-treated hepatocytes cells. Exogenous supplement of PI(4,5)P suppresses the enlarged autolysosomes in vitro. Abolishment of these enlarged autolysosomes by autophagy inhibitor relieves the hepatotoxicity of UCNs in vivo. The results provide evidence for disrupted ALR in nanoparticle-treated hepatocytes, suggesting that the termination of nanoparticle-induced autophagy is of equal importance as the initiation.
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http://dx.doi.org/10.1002/smll.201602876DOI Listing
February 2017

CFHR2-rs2986127 as a genetic protective marker for acute anterior uveitis in Chinese patients.

J Gene Med 2016 Aug;18(8):193-8

The State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, The Eye Hospital of Wenzhou Medical University, Wenzhou, China.

Background: Complement factor H (CFH) related proteins (CFHRs) play important roles in complement activation pathways, whereas previous studies have only shown that CFH can affect the development of uveitis. In the present study, we investigated the potential associations between one of single-nucleotide polymorphisms in the CFHR2 gene with acute anterior uveitis (AAU).

Methods: A total of 571 subjects, 283 patients diagnosed with AAU and 288 healthy adult controls, were recruited for this case-control study. CFHR2-rs2986127 was detected using Sequenom MassARRAY technology (Sequenom, San Diego, CA, USA).

Results: The stratified analyses for AAU patients with ankylosing spondylitis (AS) revealed a reduced frequency of the A allele in CFHR2-rs2986127 compared to controls (p = 0.033, odds ratio = 0.563, 95% confidence interval = 330-0.960). Further stratified analyses revealed a similar significantly reduced frequency in male AAU patients with AS compared to male controls (p = 0.036, odds ratio = 0.514, 95% confidence interval = 0.274-0.965) and in AAU patients without posterior segment involvement compared to controls (p = 0.048).

Conclusions: The present study reveals an association between CFHR2-rs2986127 and AAU diagnosis, especially with respect to gender, AS status and other clinical signs, such as posterior segment involvement. Our results may further enrich the growing understanding of uveitis genetics, and raise the clinical diagnostic accuracy of this disease. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/jgm.2890DOI Listing
August 2016

Identification of novel mutations by targeted exome sequencing and the genotype-phenotype assessment of patients with achromatopsia.

J Transl Med 2015 Oct 22;13:334. Epub 2015 Oct 22.

Department of Ophthalmology, Eye and ENT Hospital of Fudan University, 83 Fen Yang Road, Shanghai, 200031, People's Republic of China.

Background: Achromatopsia (ACHM) is a severe congenital autosomal recessive retinal disorder caused by loss of cone photoreceptors. Here, we aimed to determine the underlying genetic lesions and phenotypic correlations in two Chinese families with ACHM.

Methods: Medical history and clinical evaluation were obtained from both families. Targeted exome sequencing (TES) was performed on 201 disease-causing genes of inherited retinal dystrophies to screen for ACHM causative mutations in the two probands.

Results: The compound heterozygous mutations in CNGA3 (c.1074G > A, p.W358X; c.1706G > A, p.R569H) were identified in the first proband, and a novel homozygous mutation (c.968C > A, p.A323D) was detected in the other pedigree. The proposed topological model of the CNGA3 polypeptide suggested that the missense mutations primarily affected the transmembrane helix 5 and the cGMP-binding domain, respectively. Crystal structure modeling of the cyclic nucleotide-gated cation channel α-3 (CNGA3) protein encoded by the CNGA3 gene revealed an abnormal combined structure generated by R569H.

Conclusions: We firstly used the TES approach to identify genetic alterations in patients with ACHM. We uncovered three mutations in CNGA3, including one novel mutation. Our results not only expand the genotypic spectrum for CNGA3 mutations, but also demonstrate that the TES approach is a valuable tool for molecular diagnosis.
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http://dx.doi.org/10.1186/s12967-015-0694-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618873PMC
October 2015

Cigarette smoke-induced alveolar epithelial-mesenchymal transition is mediated by Rac1 activation.

Biochim Biophys Acta 2014 Jun 4;1840(6):1838-49. Epub 2014 Feb 4.

The Second Affiliated Hospital, Medical College of Zhejiang University, Hangzhou 310009, China. Electronic address:

Background: Epithelial-mesenchymal transition (EMT) is the major pathophysiological process in lung fibrosis observed in chronic obstructive pulmonary disease (COPD) and lung cancer. Smoking is a risk factor for developing EMT, yet the mechanism remains largely unknown. In this study, we investigated the role of Rac1 in cigarette smoke (CS) induced EMT.

Methods: EMT was induced in mice and pulmonary epithelial cells by exposure of CS and cigarette smoke extract (CSE) respectively.

Results: Treatment of pulmonary epithelial cells with CSE elevated Rac1 expression associated with increased TGF-β1 release. Blocking TGF-β pathway restrained CSE-induced changes in EMT-related markers. Pharmacological inhibition or knockdown of Rac1 decreased the CSE exposure induced TGF-β1 release and ameliorated CSE-induced EMT. In CS-exposed mice, pharmacological inhibition of Rac1 reduced TGF-β1 release and prevented aberrations in expression of EMT markers, suggesting that Rac1 is a critical signaling molecule for induction of CS-stimulated EMT. Furthermore, Rac1 inhibition or knockdown abrogated CSE-induced Smad2 and Akt (PKB, protein kinase B) activation in pulmonary epithelial cells. Inhibition of Smad2, PI3K (phosphatidylinositol 3-kinase) or Akt suppressed CSE-induced changes in epithelial and mesenchymal marker expression.

Conclusions And General Significance: Altogether, these data suggest that CS initiates EMT through Rac1/Smad2 and Rac1/PI3K/Akt signaling pathway. Our data provide new insights into the fundamental basis of EMT and suggest a possible new course of therapy for COPD and lung cancer.
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http://dx.doi.org/10.1016/j.bbagen.2014.01.033DOI Listing
June 2014

Enhanced transdermal delivery of epidermal growth factor facilitated by dual peptide chaperone motifs.

Protein Pept Lett 2014 Jun;21(6):550-5

School of Life Sciences, University of Science and Technology of China, Hefei 230026, PR China.

TD1, a peptide chaperone consisting of the sequence ACSSSPHKHCG, has been shown to facilitate transdermal delivery for protein molecules via either co-administration or the fusion approach. We previously reported that a single TD1 motif, fused to the N-terminus of human epidermal growth factor (hEGF) can significantly enhance the transdermal efficiency of the recombinant EGF protein. In an effort to further increase the transdermal efficiency, we have created EGF fusion proteins harboring dual TD1 motifs: TD1-hEGF-TD1, containing one TD1 motif at both the N- and the Cterminus, and TD1-TD1-hEGF, containing two tandem TD1 motifs at the N-terminus. Both TD1-hEGF-TD1 and TD1- TD1-hEGF proteins, expressed in Escherichia coli and purified to apparent homogeneity, exhibited biological activity similar to unmodified hEGF, as revealed by their relative abilities to stimulate fibroblast growth, promote fibroblast migration, and activate the MAP kinase signaling cascade. On the other hand, both TD1-hEGF-TD1 and TD1-TD1-hEGF proteins exhibited a transdermal efficiency enhancement. The improvement was >5-fold compared to unmodified hEGF and 3-fold over the hEGF fusion protein with only one TD1 motif attached. These findings provided proof-of-concept for improving transdermal delivery of protein actives through rational protein design.
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http://dx.doi.org/10.2174/0929866521666131224110314DOI Listing
June 2014

AD-1, a novel ginsenoside derivative, shows anti-lung cancer activity via activation of p38 MAPK pathway and generation of reactive oxygen species.

Biochim Biophys Acta 2013 Aug 11;1830(8):4148-59. Epub 2013 Apr 11.

Medical College of Zhejiang University, Hangzhou, China.

Background: Ginseng is a traditional Chinese herb that has been used for thousands of years. In the present study, effects and mechanisms of AD-1 were evaluated for its development as a novel anti-lung cancer drug.

Methods: The cytotoxic activity was evaluated by MTT assay. Flow cytometry was employed to detect cell cycle, apoptosis and ROS. Western blot and immunohistochemistry were used to analyze signaling pathways. Lung cancer xenograft models were established by subcutaneous implantation of A549 or H292 cells into nude mice.

Results: AD-1 concentration-dependently reduces lung cancer cell viability without affecting normal human lung epithelial cell viability. In A549 and H292 lung cancer cells, AD-1 induces G0/G1 cell cycle arrest, apoptosis and ROS production. The apoptosis can be attenuated by a ROS scavenger - N-acetylcysteine (NAC). In addition, AD-1 up-regulates the expression of p38 and ERK phosphorylation. Addition of a p38 inhibitor SB203580, suppresses the AD-1-induced decrease in cell viability. Furthermore, genetic silencing of p38 attenuates the expression of p38 and decreases the AD-1-induced apoptosis. Treatment with NAC reduces AD-1-induced p38 phosphorylation, which indicates that ROS generation is involved in the AD-1-induced p38 activation. In mice, oral administration of AD-1 (10-40mg/kg) dose-dependently inhibited the growth of xenograft tumors without affecting body weight and decreases the expression of VEGF, MMP-9 and CD34 in tumor tissue. TUNEL staining confirms that the tumors from AD-1 treated mice exhibit a markedly higher apoptotic index.

Conclusions And General Significance: These data support development of AD-1 as a potential agent for lung cancer therapy.
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http://dx.doi.org/10.1016/j.bbagen.2013.04.008DOI Listing
August 2013

Deregulated expression of cry1 and cry2 in human gliomas.

Asian Pac J Cancer Prev 2012 ;13(11):5725-8

Department of Neurosurgery, The First People's Hospital of Jingmen, Jingmen, China.

Growing evidence shows that deregulation of the circadian clock plays an important role in the development of malignant tumors, including gliomas. However, the molecular mechanisms of gene chnages controlling circadian rhythm in glioma cells have not been explored. Using real time polymerase chain reaction and immunohistochemistry techniques, we examined the expression of two important clock genes, cry1 and cry2, in 69 gliomas. In this study, out of 69 gliomas, 38 were cry1-positive, and 51 were cry2-positive. The expression levels of cry1 and cry2 in glioma cells were significantly different from the surrounding non-glioma cells (P<0.01). The difference in the expression rate of cry1 and cry 2 in high-grade (grade III and IV) and low-grade (grade 1 and II) gliomas was non-significant (P>0.05) but there was a difference in the intensity of immunoactivity for cry 2 between high-grade gliomas and low-grade gliomas (r=-0.384, P=0.021). In this study, we found that the expression of cry1 and cry2 in glioma cells was much lower than in the surrounding non-glioma cells. Therefore, we suggest that disturbances in cry1 and cry2 expression may result in the disruption of the control of normal circadian rhythm, thus benefiting the survival of glioma cells. Differential expression of circadian clock genes in glioma and non-glioma cells may provide a molecular basis for the chemotherapy of gliomas.
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http://dx.doi.org/10.7314/apjcp.2012.13.11.5725DOI Listing
July 2013

Apple polyphenol protects against cigarette smoke-induced acute lung injury.

Nutrition 2013 Jan 8;29(1):235-43. Epub 2012 Sep 8.

Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, # 866 Yuhangtang Road, Hangzhou, 310058, China.

Objective: Chronic obstructive pulmonary disease (COPD) is a complex chronic inflammatory disease involving oxidative stress as well as a wide variety of cells activated from smoking cigarettes. There have been disappointingly few therapeutic advances in drug therapy for COPD. Plant polyphenols have been the topic of much research regarding their antioxidant activities and antiinflammatory and immunomodulatory effects. In the present study, we ask whether apple polyphenol provides protection against cigarette smoke (CS)-induced acute lung injury.

Methods: ICR mice were exposed to CS for 4 d with increasing exposure time for up to 6 h per day to elicit epithelial cells injury. One hour before smoke exposure, mice were treated with apple polyphenol (APP) by gavage; all examinations were performed 18 h after the last CS exposure.

Results: APP at 30, 100, or 300 mg not only significantly dose-dependently reduced the CS-induced accumulation of inflammatory cells and gene/protein expression of proinflammatory factors both in the lung and in bronchoalveolar lavage fluid, but also significantly reversed oxidative stress in the lungs. Additionally, treatment with APP also significantly regulated the CS-induced imbalance of matrix metalloproteinases-9/tissue inhibitor of metalloproteinase-1 expression in the lungs. To investigate further the possible signaling pathway of APP effects, we examined protein expression of p-P38 MAPK by immunohistochemistry that found treatment with APP significantly decreased the CS-induced increases of p-P38 expression in the lungs.

Conclusion: Taken together, APP may be a potential dietary nutrient supplement agent to improve quality of life of COPD patients by inhibiting CS-exposed acute lung injury via P38 MAPK signaling pathway.
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http://dx.doi.org/10.1016/j.nut.2012.04.008DOI Listing
January 2013

Shp2 plays an important role in acute cigarette smoke-mediated lung inflammation.

J Immunol 2012 Sep 13;189(6):3159-67. Epub 2012 Aug 13.

Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, China 310058.

Cigarette smoke (CS), the major cause of chronic obstructive pulmonary disease, contains a variety of oxidative components that were implicated in the regulation of Src homology domain 2-containing protein tyrosine phosphatase 2 (Shp2) activity. However, the contribution of Shp2 enzyme to chronic obstructive pulmonary disease pathogenesis remains unclear. We investigated the role of Shp2 enzyme in blockading CS-induced pulmonary inflammation. Shp2 levels were assessed in vivo and in vitro. Mice (C57BL/6) or pulmonary epithelial cells (NCI-H292) were exposed to CS or cigarette smoke extract (CSE) to induce acute injury and inflammation. Lungs of smoking mice showed increased levels of Shp2, compared with those of controls. Treatment of lung epithelial cells with CSE showed elevated levels of Shp2 associated with the increased release of IL-8. Selective inhibition or knockdown of Shp2 resulted in decreased IL-8 release in response to CSE treatment in pulmonary epithelial cells. In comparison with CS-exposed wild-type mice, selective inhibition or conditional knockout of Shp2 in lung epithelia reduced IL-8 release and pulmonary inflammation in CS-exposed mice. In vitro biochemical data correlate CSE-mediated IL-8 release with Shp2-regulated epidermal growth factor receptor/Grb-2-associated binders/MAPK signaling. Our data suggest an important role for Shp2 in the pathological alteration associated with CS-mediated inflammation. Shp2 may be a potential target for therapeutic intervention for inflammation in CS-induced pulmonary diseases.
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http://dx.doi.org/10.4049/jimmunol.1200197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496208PMC
September 2012

Simvastatin delivery via inhalation attenuates airway inflammation in a murine model of asthma.

Int Immunopharmacol 2012 Apr 8;12(4):556-64. Epub 2012 Feb 8.

The First People's Hospital of Wujiang City 215200, China.

The dose-response of the pleiotropic effects of statins on airway inflammation has not yet been established and may differ from that of their cholesterol-lowering effects. High oral doses of statins may have adverse effects, and it may be possible to overcome the side effects and low clinical efficacy by administering statins via inhalation. In this study, we hypothesize that simvastatin is a potential anti-inflammatory drug with biological and pharmacokinetic properties suitable for delivery by the inhaled route. Mice were immunized with ovalbumin (OVA) and then challenged with aerosol OVA. Simvastatin was locally delivered by inhalation (i.h.) and intratracheal injection (i.t.) or systematically delivered by intraperitoneal injection (i.p.) and gavage (i.g.) during the OVA challenge. In a mouse model of asthma, i.h. simvastatin significantly and dose-dependently attenuated airway inflammation, remodeling and hyperresponsiveness in a RhoA-dependent pathway. Upon comparing the pharmacodynamics, i.h. simvastatin had a more potent effect than that of i.g. and i.p. simvastatin, and the i.h. or i.t. delivery routes led to a higher drug concentration in local lung tissue and a lower drug concentration in the plasma than that obtained by the i.g. These results suggest that simvastatin is a potential anti-inflammatory drug for airway inflammatory diseases with properties suitable for delivery by inhalation, which will probably reduce the side effects and increase clinical efficacy.
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http://dx.doi.org/10.1016/j.intimp.2012.01.012DOI Listing
April 2012

Oral administration of allergen extracts from mugwort pollen desensitizes specific allergen-induced allergy in mice.

Vaccine 2012 Feb 10;30(8):1437-44. Epub 2012 Jan 10.

Affiliated First Hospital of Medical College, Zhejiang University, Hangzhou 310009, China.

Clinically, sublingual immunotherapy (SLIT) using allergen extracts effectively alleviates the symptoms of allergic rhinitis and asthma. We hypothesized that oral administration of a high-dose of allergen extracts imitates SLIT, which may prevent IgE-related responses in allergic diseases. In the present study, we investigated the effects of oral administration of allergen extracts from mugwort pollen (MP) on allergen-induced inflammation and airway hyperresponsiveness (AHR) in an allergic mouse model. After administration of MPdrop containing Art v 1 and Art v 4 extracts derived from MP specifically in MP-sensitized mice, the effects of MPdrop on AHR, inflammatory cell accumulation, cytokine production in the bronchoalveolar lavage fluid and lung tissue, and serum IgE and IgG levels were investigated. The results indicated that MPdrop not only prevented the AHR in response to methacholine in a dose-dependent manner but also significantly reduced the total serum and allergen-specific IgE levels. All of the maximal effects were achieved at a dose of 100μg/(kgd) and were comparable to the effects of dexamethasone at a dose of 0.5mg/(kgd). Furthermore, oral administration of MPdrop dose-dependently elevated allergen-specific serum IgG2a levels, reduced total and allergen-specific IgE levels and normalized the imbalance between the Th1 cytokine IL-12 and Th2 cytokines IL-4 and IL-5. Finally, oral administration of MPdrop significantly reduced goblet cell hyperplasia and eosinophilia in the MP-sensitized allergic mouse model. These data suggest that MPdrop effectively improves specific allergen-induced inflammation and AHR in MP-sensitized and -challenged mice and provides the rationale for clinical use of MPdrop in the specific allergen-induced asthma.
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http://dx.doi.org/10.1016/j.vaccine.2012.01.005DOI Listing
February 2012

Protective effects of liquiritin apioside on cigarette smoke-induced lung epithelial cell injury.

Fundam Clin Pharmacol 2012 Aug 1;26(4):473-83. Epub 2011 Jun 1.

Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, Yuhangtang Rd-866, Hangzhou, China.

Cigarette smoking is associated with an increased incidence of chronic obstructive pulmonary disease (COPD). In this study, we hypothesized that liquiritin apioside (LA), a main flavonoid component from Glycyrrhiza uralensis, had antioxidant properties by inducing glutathione (GSH) biosynthesis via the inhibition of cytokines and protected lung epithelial cells against cigarette smoke-mediated oxidative stress. A549 cells were treated with cigarette smoke extract (CSE) and/or LA. ICR mice were exposed to cigarette smoke (CS) for four days with increasing exposure time for up to 6 h per day to elicit epithelial cells injury. One hour before smoke exposure, mice were treated with LA by gavage; 18 h after the last CS exposure all examinations were performed. Treatment with LA concentration-dependently prevented CSE-induced cytotoxicity, increase of TGF-β and TNF-α mRNA expression, depletion of GSH and apoptosis in A549 cells. LA at doses 3, 10 and 30 mg/kg dose-dependently inhibited pulmonary neutrophil and macrophage inflammation. Lung sections of the CS-exposed LA treated mice showed an apparently reduced pulmonary inflammation and a significant inhibitory effect on mucus containing goblet cells in the large airways. Furthermore, the CS-induced pulmonary release of TGF-β, TNF-α and myeloperoxidase activity was reduced, and superoxide dismutase activity was enhanced.These results indicate that protective roles of LA on CS-induced the lung epithelial cell injury are mediated by inhibiting TGF-β and TNF-α expression and increasing anti-oxidative levels of GSH, suggesting that LA might be effective as protective agent against epithelial injury in COPD.
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http://dx.doi.org/10.1111/j.1472-8206.2011.00956.xDOI Listing
August 2012

M(3) muscarinic receptor antagonist bencycloquidium bromide attenuates allergic airway inflammation, hyperresponsiveness and remodeling in mice.

Eur J Pharmacol 2011 Mar 28;655(1-3):83-90. Epub 2011 Jan 28.

Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, Hangzhou, China.

M(3) muscarinic receptors are localized on inflammatory cells, airway smooth muscle, and submucosal glands, known to mediate bronchoconstriction, mucus secretion, and airway remodeling. It is hypothesized bencycloquidium bromide (BCQB), a novel M(3) receptor antagonist, might have potential effects on airway hyperresponsiveness, inflammation and airway remodeling in a murine model of asthma. Mice sensitized and challenged with ovalbumin developed airway inflammation. Bronchoalveolar lavage fluid was examined to determine the total and differential cell counts, and cytokine levels. Lung tissues were evaluated for cell infiltration, mucus hypersecretion, airway remodeling, and the expression of inflammatory biomarkers. Airway hyperresponsiveness was monitored by direct airway resistance analysis. Inhalation administration of BCQB significantly not only reduced ovalbumin-induced airway hyperresponsiveness comparing to methacholine, and prevented the ovalbumin-induced increase in total cell counts and eosinophil counts. Reverse transcriptase polymerase chain reaction analysis of whole lung lysates revealed that BCQB markedly suppressed ovalbumin-induced mRNA expression of eotaxin, IL-5, IL-4 and MMP-9, and increased mRNA expression of IFN-γ and TIMP-1 in a dose-dependent manner. Substantial IFN-γ/IL-4 (Th1/Th2) levels were recovered in bronchoalveolar lavage fluid after BCQB treatment. In addition, histological studies showed that BCQB dramatically inhibited ovalbumin-induced lung tissue eosinophil infiltration, airway mucus production and collagen deposition in lung tissues. Results reported in current paper suggest that M(3) receptors antagonist may provide a novel therapeutic approach to treat airway inflammation, hyperresponsiveness and remodeling.
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http://dx.doi.org/10.1016/j.ejphar.2011.01.024DOI Listing
March 2011

Characterization of bencycloquidium bromide, a novel muscarinic M(3) receptor antagonist in guinea pig airways.

Eur J Pharmacol 2011 Mar 24;655(1-3):74-82. Epub 2011 Jan 24.

Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, Hangzhou 310058, China.

In this study we have investigated the antagonist affinity, efficacy and duration of action of bencycloquidium bromide (BCQB), a selective muscarinic M(3) receptor antagonist, as a possible clinical bronchodilator for the treatment of chronic obstructive pulmonary disease (COPD) and asthma. In competition studies, BCQB showed high affinity toward the M(3) receptor in Chinese hamster ovary (CHO) cells (M(3) pKi=8.21, M(2) pKi=7.21, and M(1) pKi=7.86); pA(2)=8.85, 8.71 and 8.57 in methacholine-induced contraction of trachea, ileum and urinary bladder, 8.19 in methacholine-induced bradycardia of right atrium in vitro, respectively. In function studies, duration of inhibition of carbachol-induced tonic contraction, BCQB and ipratropium had a very similar onset and offset of action, but onset faster and offset slower than that of tiotropium. After treatment with intratracheally instilled or the inhalation route, BCQB protects against methacholine or antigen-induced bronchoconstriction in a dose-dependent manner in the normal and sensitized guinea pigs in vivo. BCQB and ipratropium-induced inhibitory activity was short lasting, as it declined quickly when compared to tiotropium. These results suggest that BCQB bind muscarinic M(3) receptors with high affinity. On this basis we speculate that a putative BCQB-based therapy for COPD might require more than once-a-day administration to be as effective as the currently employed once-daily therapy with tiotropium. Nevertheless, Inhalable M(3)-selective compounds may spare M(2)-cardiac receptors and reduce the risks of cardiovascular events associated with the long-term treatment of these agents.
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http://dx.doi.org/10.1016/j.ejphar.2011.01.017DOI Listing
March 2011