Publications by authors named "Ke Yao"

419 Publications

Cataract-causing allele in CRYAA (Y118D) proceeds through endoplasmic reticulum stress in mouse model.

Zool Res 2021 May;42(3):300-309

Eye Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.

As small heat shock proteins, α-crystallins function as molecular chaperones and inhibit the misfolding and aggregation of β/γ-crystallins. Genetic mutations of are associated with protein aggregation and cataract occurrence. One possible process underlying cataract formation is that endoplasmic reticulum stress (ERS) induces the unfolded protein response (UPR), leading to apoptosis. However, the pathogenic mechanism related to this remains unexplored. Here, we successfully constructed a cataract-causing CRYAA (Y118D) mutant mouse model, in which the lenses of the CRYAA-Y118D mutant mice showed severe posterior rupture, abnormal morphological changes, and aberrant arrangement of crystallin fibers. Histological analysis was consistent with the clinical pathological characteristics. We also explored the pathogenic factors involved in cataract development through transcriptome analysis. In addition, based on key pathway analysis, up-regulated genes in CRYAA-Y118D mutant mice were implicated in the ERS-UPR pathway. This study showed that prolonged activation of the UPR pathway and severe stress response can cause proteotoxic and ERS-induced cell death in CRYAA-Y118D mutant mice.
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http://dx.doi.org/10.24272/j.issn.2095-8137.2020.354DOI Listing
May 2021

Targeting nutrient metabolism with FDA-approved drugs for cancer chemoprevention: Drugs and mechanisms.

Cancer Lett 2021 Apr 16;510:1-12. Epub 2021 Apr 16.

Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; Academy of Medical Sciences, Zhengzhou University, 40 North Daxue Road, Zhengzhou, Henan 450001, PR China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan 450008, PR China; Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou 450001, China; Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, Henan, China. Electronic address:

Proliferating cancer cells exhibit metabolic alterations and specific nutritional needs for adapting to their rapid growth. These changes include using aerobic glycolysis, lipid metabolic disorder, and irregular protein degradation. It may be useful to target metabolic abnormalities for cancer chemoprevention. Epidemiological and mechanism-related studies have indicated that many FDA-approved anti-metabolic drugs decrease tumor risk, inhibit tumor growth, or enhance the effect of chemotherapeutic drugs. Drugs targeting nutrient metabolism have fewer side effects with long-term use compared to chemotherapeutic drugs. The characteristics of these drugs make them promising candidates for cancer chemoprevention. Here, we summarize recent discoveries of the chemo-preventive effects of drugs targeting nutrient metabolic pathways and discuss future applications and challenges. Understanding the effects and mechanisms of anti-metabolic drugs in cancer has important implications for exploring strategies for cancer chemoprevention.
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http://dx.doi.org/10.1016/j.canlet.2021.03.029DOI Listing
April 2021

First Report of AG-2-2 IIIB Causing Foliar Blight on in China.

Plant Dis 2021 Apr 14. Epub 2021 Apr 14.

Guangxi University for Nationalities, 47874, Guangxi Key Laboratory for Polysaccharide Materials and Modifications, Nanning 530006, P.R. China, Nanning, China, 530006;

(Thunb.) Rchb. f. (Orchidaceae), a perennial plant, is a traditional Chinese herb (known as baiji) used to treat hemorrhage, scalding injuries, gastric ulcers, pulmonary diseases, and inflammation (Zu et al. 2019). In May 2019, foliar blight symptoms were observed on approximately 25% of (cv. Guiji No.1) plants in three plantations (∼4.5 hectares in total) in Ziyuan County, Guangxi Province, China. Initial symptoms were light brown, irregular, water-soaked spots on the plant leaves. Several spots often merged, forming large, irregular, lesions that extended onto the stem after a week and led to leaf abscission, and even plant death. To determine the causal agent, 5-mm squares cut from the margin of 6 infected leaves were surface disinfected in 1% sodium hypochlorite solution for 2 min, rinsed three times with sterile distilled water, plated on potato dextrose agar (PDA), and incubated at 28°C (12-h light-dark cycle) for 3 days. The emerging hyphal tip of a single mycelium was transferred to PDA to obtain pure cultures of the isolates. Twenty isolates were obtained, and 10 isolates (50%) were initially white before turning light brown (∼4 days). Septate hyphae were 4.29 to 10.75 μm (average 6.42 μm) in diameter and branched at right angles with a constriction at the origin of the branch point. Staining with 1% safranin O and 3% KOH solution (Bandoni 1979) revealed multinucleated cells (3 to 9 nuclei per cell, n = 142). This morphology was typical of Kühn (Meyer et al. 1990). For species confirmation by molecular identification, three isolates (BJ101.6, BJ101.11, and BJ102.2) were cultured on PDA for 4 days, then DNA was extracted from the mycelium using the CTAB method (Guo et al. 2000), and the ribosomal ITS1-5.8S-ITS2 region was amplified by PCR using the universal fungal primers ITS1 and ITS4 (White et al. 1990). Internal transcribed spacer (ITS) sequences of strains BJ101.6, BJ101.11, and BJ102 (deposited in GenBank under accession nos MT406271, MT892815, and MT892814, respectively) had over 99% similarity with those of AG-2-2 IIIB in GenBank (accession nos JX913810 and AB054858) (Carling et al. 2002; Hong et al. 2012). Phylogenetic analysis using ITS sequences showed that the isolates clustered monophyletically with strains of AG-2-2 IIIB. The AG of the isolates was confirmed by their ability to grow well on PDA at 35°C, which separates AG-2-2 IIIB from AG-2-2 IV (Inokuti et al. 2019). Based on morphological characteristics and nucleotide sequence analysis, the isolates were identified as AG-2-2 IIIB. Pathogenicity was tested using 1.5-year-old (cv. Guiji No.1) plants grown in a perlite and peat moss mixture (1:3) in 7-cm pots. Healthy leaves on plants were inoculated with an aqueous suspension (approximately 1 × 10 hyphal fragments/mL, 100 μL) prepared from cultures of strains BJ101.6, BJ101.11, and BJ102.2, each isolate was inoculated onto three plants; three other plants with sterile water served as controls. All plants were enclosed in transparent plastic bags and incubated in a greenhouse at 28°C for 14 days (12-h photoperiod). Three days post-inoculation, leaves exposed to the mycelial fragments had symptoms similar to those originally observed in the field. No symptoms were detected on control plants. Experiments were replicated three times with similar results. To fulfill Koch's postulates, AG-2-2 IIIB was re-isolated on PDA from symptomatic leaves and confirmed by sequencing, whereas no fungus was isolated from the control plants. To our knowledge, this is the first report of AG-2-2 IIIB causing foliar blight on in China, and these findings will be useful for further control strategies and research.
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http://dx.doi.org/10.1094/PDIS-02-21-0270-PDNDOI Listing
April 2021

Antimicrobial nanomedicine for ocular bacterial and fungal infection.

Drug Deliv Transl Res 2021 Apr 11. Epub 2021 Apr 11.

Eye Center, the Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, 310009, People's Republic of China.

Ocular infection induced by bacteria and fungi is a major cause of visual impairment and blindness. Topical administration of antibiotics remains the first-line treatment, as effective eradication of pathogens is the core of the anti-infection strategy. Whereas, eye drops lack efficiency and have relatively low bioavailability. Intraocular injection may cause concurrent ocular damage and secondary infection. In addition, antibiotic-based management can be limited by the low sensitivity to multidrug-resistant bacteria. Nanomedicine is proposed as a prospective, effective, and noninvasive platform to mediate ocular delivery and combat pathogen or even resistant strains. Nanomedicine can not only carry antimicrobial agents to fight against pathogens but also directly active microbicidal capability, killing pathogens. More importantly, by modification, nanomedicine can achieve enhanced residence time and release time on the cornea, and easy penetration through corneal tissues into anterior and posterior segments of the eye, thus improving the therapeutic effect for ocular infection. In this review, several categories of antimicrobial nanomedicine are systematically discussed, where the efficiency and possibility of further embellishment and improvement to adapt to clinical use are also investigated. All in all, novel antimicrobial nanomedicine provides potent and prospective ways to manage severe and refractory ocular infections.
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http://dx.doi.org/10.1007/s13346-021-00966-xDOI Listing
April 2021

Microvascular comparison in younger and older patients with retinal vein occlusion analyzed by OCT angiography.

BMC Ophthalmol 2021 Apr 5;21(1):161. Epub 2021 Apr 5.

Eye Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, No.88, Jiefang Road, 310009, Hangzhou, China.

Background: To compare changes in retinal microvasculature of young and elderly patients with retinal vein occlusion (RVO) after anti-VEGF treatment.

Methods: RVO patients who underwent anti-VEGF treatment were retrospectively reviewed and categorized into two groups based on age. The OCT angiography images were obtained during each visit. Best corrected visual acuity (BCVA), vessel density (VD) and foveal avascular zone (FAZ) were measured and compared between the two groups. Vision improvements and retinal microvasculature changes were also correlated.

Results: Twenty patients with 20 eyes were enrolled in the younger group and 46 patients with 46 eyes were enrolled in the older group. Younger patients demonstrated better BCVA, higher VD and smaller FAZ than older patients at 12 months after the first anti-VEGF treatment. The improvement of VD was observed only in the younger group. A positive correlation between vision improvement and VD increase was noted.

Conclusions: Young patients with RVO can achieve rapid rehabilitation of deep retinal vasculature which lead to a better visual outcome.
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http://dx.doi.org/10.1186/s12886-021-01931-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022394PMC
April 2021

Non-Coding RNAs Steering the Senescence-Related Progress, Properties, and Application of Mesenchymal Stem Cells.

Front Cell Dev Biol 2021 19;9:650431. Epub 2021 Mar 19.

State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.

The thirst to postpone and even reverse aging progress has never been quenched after all these decades. Unequivocally, mesenchymal stem cells (MSCs), with extraordinary abilities such as self-renewal and multi-directional differentiation, deserve the limelight in this topic. Though having several affable clinical traits, MSCs going through senescence would, on one hand, contribute to age-related diseases and, on the other hand, lead to compromised or even counterproductive therapeutical outcomes. Notably, increasing evidence suggests that non-coding RNAs (ncRNAs) could invigorate various regulatory processes. With even a slight dip or an uptick of expression, ncRNAs would make a dent in or even overturn cellular fate. Thereby, a systematic illustration of ncRNAs identified so far to steer MSCs during senescence is axiomatically an urgent need. In this review, we introduce the general properties and mechanisms of senescence and its relationship with MSCs and illustrate the ncRNAs playing a role in the cellular senescence of MSCs. It is then followed by the elucidation of ncRNAs embodied in extracellular vesicles connecting senescent MSCs with other cells and diversified processes in and beyond the skeletal system. Last, we provide a glimpse into the clinical methodologies of ncRNA-based therapies in MSC-related fields. Hopefully, the intricate relationship between senescence and MSCs will be revealed one day and our work could be a crucial stepping-stone toward that future.
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http://dx.doi.org/10.3389/fcell.2021.650431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017203PMC
March 2021

Brain-Targeted Dual Site-Selective Functionalized Poly(β-Amino Esters) Delivery Platform for Nerve Regeneration.

Nano Lett 2021 Apr 2;21(7):3007-3015. Epub 2021 Apr 2.

Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, 226001 Nantong, Jiangsu, PR China.

Brain injuries are devastating central nervous system diseases, resulting in cognitive, motor, and sensory dysfunctions. However, clinical therapeutic options are still limited for brain injuries, indicating an urgent need to investigate new therapies. Furthermore, the efficient delivery of therapeutics across the blood-brain barrier (BBB) to the brain is a serious problem. In this study, a facile strategy of dual site-selective functionalized (DSSF) poly(β-amino esters) was developed using bio-orthogonal chemistry for promoting brain nerve regeneration. Fluorescence colocalization studies demonstrated that these proton-sponge DSSF poly(β-amino esters) targeted mitochondria through electrostatic interactions. More importantly, this delivery system could effectively accumulate in the injured brain sites and accelerate the recovery of the injured brain. Finally, this DSSF poly(β-amino esters) platform may provide a new methodology for the construction of dual regioselective carriers in protein/peptide delivery and tissue engineering.
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http://dx.doi.org/10.1021/acs.nanolett.1c00175DOI Listing
April 2021

Parameters of Capsulorrhexis and Intraocular Lens Decentration After Femtosecond and Manual Capsulotomies in High Myopic Patients With Cataracts.

Front Med (Lausanne) 2021 11;8:640269. Epub 2021 Mar 11.

The Eye Center, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China.

To compare the parameters of capsulorrhexis and intraocular lens decentration after femtosecond laser capsulotomy and manual continuous curvilinear capsulorrhexis in high myopic patients with cataracts. This is a prospective consecutive non-randomized comparative cohort study. Selected patients with axial length > 26.0 mm were divided into femtosecond laser capsulotomy (FS) group and manual continuous curvilinear capsulorrhexis (CCC) group. Five experienced phacoemulsification surgeons conducted all surgeries. Intraoperative complications and post-operative anterior segment photography were recorded. Intraocular lens decentration, area of capsulorrhexis, circularity, and capsule overlap were measured at 1 week, 1 month, and 2 years after surgery. Between group differences of parameters were determined with independent-sample -test or the Mann-Whitney -test, analysis of variance test, Pearson chi-square test, and Spearman rank correlation test. The study included 142 eyes (108 patients), 68 eyes in the FS group, and 74 eyes in the CCC group. At 1 week, 1 month, and 2 years after surgery, the area of capsulorrhexis in the CCC group was significantly larger than in the FS group ( < 0.05), while no significant difference was noted in circularity values. The complete overlap ratio in the FS group was significantly higher than that in the CCC group ( < 0.05) at each measured timepoint. Significant correlations were noted between the anterior chamber depth and the area of capsulorrhexis in the CCC group ( = 0.25, = 0.04), but did not correlate in the FS group ( > 0.05). In patients with an anterior chamber depth >3 mm, the capsule-intraocular lens (IOL) overlap of the CCC group was less than that of the FS group at all measured timepoints after surgery ( < 0.05). Meanwhile, the IOL decentration in the CCC group was significantly greater than that of the FS group in those patients at 2 years after surgery ( < 0.05). In high myopic patients with cataracts, with anterior chamber depth more than 3 mm, femtosecond laser capsulotomy can achieve better capsulorrhexis sizing and centering. Due to more precise capsulotomy and a better capsule-IOL overlap in the FS group, femtosecond laser capsulotomy resulted in better long-term centration of the IOL.
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http://dx.doi.org/10.3389/fmed.2021.640269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990760PMC
March 2021

Crumbs proteins stabilize the cone mosaics of photoreceptors and improve vision in zebrafish.

J Genet Genomics 2021 Feb 13. Epub 2021 Feb 13.

Eye Center of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China; The Institute of Translational Medicine, Zhejiang University, Hangzhou, 310058, China; Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou, 310058, China. Electronic address:

Although the unique organization of vertebrate cone mosaics was first described long ago, both their underlying molecular basis and physiological significance are largely unknown. Here, we demonstrate that Crumbs proteins, the key regulators of epithelial apical polarity, establish the planar cellular polarity of photoreceptors in zebrafish. Via heterophilic Crb2a-Crb2b interactions, the apicobasal polarity protein Crb2b restricts the asymmetric planar distribution of Crb2a in photoreceptors. The planar polarized Crumbs proteins thus balance intercellular adhesions and tension between photoreceptors, thereby stabilizing the geometric organization of cone mosaics. Notably, loss of Crb2b in zebrafish induces a nearsightedness-like phenotype in zebrafish accompanied by an elongated eye axis and impairs zebrafish visual perception for predation. These data reveal a detailed mechanism for cone mosaic homeostasis via previously undiscovered apical-planar polarity coordination and propose a pathogenic mechanism for nearsightedness.
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http://dx.doi.org/10.1016/j.jgg.2020.12.002DOI Listing
February 2021

Comparison of trifocal or hybrid multifocal-extended depth of focus intraocular lenses: a systematic review and meta-analysis.

Sci Rep 2021 Mar 23;11(1):6699. Epub 2021 Mar 23.

Eye Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, China.

This meta-analysis aimed to evaluate the clinical outcomes following implantation of trifocal intraocular lenses (IOLs) or a hybrid multifocal-extended depth of focus (EDOF) IOL in cataract or refractive lens exchange surgeries. We examined 13 comparative studies with bilateral implantation of trifocal (898 eyes) or hybrid multifocal-EDOF (624 eyes) IOLs published through 1 March 2020. Better uncorrected and corrected near visual acuity (VA) were observed in the trifocal group (MD: - 0.143, 95% CI: - 0.192 to - 0.010, P < 0.001 and MD: - 0.149, 95% CI: - 0.217 to - 0.082, P < 0.001, respectively), while the hybrid multifocal-EDOF group presented better uncorrected intermediate VA (MD: 0.055, 95% CI: 0.016 to 0.093, P = 0.005). Trifocal IOLs were more likely to achieve spectacle independence at near distance (RR: 1.103, 95% CI: 1.036 to 1.152, P = 0.002). The halo photic effect was generated more frequently by the trifocal IOLs (RR: 1.318, 95% CI: 1.025 to 1.696, P = 0.031). Contrast sensitivity and subjective visual quality yielded comparable results between groups. Trifocal IOLs demonstrated better performance at near distance but apparently led to more photic disturbances. Our findings provided the most up-to-date and comprehensive evidence by comparing the benefits of advanced IOLs in clinical practice.
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http://dx.doi.org/10.1038/s41598-021-86222-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987991PMC
March 2021

The acts of opening and closing the eyes are of importance for congenital blindness: Evidence from resting-state fMRI.

Neuroimage 2021 06 17;233:117966. Epub 2021 Mar 17.

Eye Center of the 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China; Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou 310009, Zhejiang Province, China. Electronic address:

Volitional eye closure is observed only in conscious and awake humans, and is rare in animals. It is believed that eye closure can focus one's attention inward and facilitate activities such as meditation and mental imagery. Congenital blind individuals are also required to close their eyes for these activities. Resting-state functional magnetic resonance imaging (RS-fMRI) studies have found robust differences between the eyes-closed (EC) and eyes-open (EO) conditions in some brain regions in the sighted. This study analyzed data from 21 congenital blind individuals and 21 sighted controls by using amplitude of low-frequency fluctuation (ALFF) of RS-fMRI. The blind group and the sighted group shared similar pattern of differences between the EC and EO condition: ALFF was higher in the EC condition than the EO condition in the bilateral primary sensorimotor cortex, bilateral supplementary motor area, and inferior occipital cortex, while ALFF was lower in the EC condition than the EO condition in the medial prefrontal cortex, highlighting the "nature" effect on the difference between the EC and EO conditions. The results of other matrices such as fractional ALFF (fALFF) and regional homogeneity (ReHo) showed similar patterns to that of ALFF. Moreover, no significant difference was observed between the EC-EO pattern of the two subgroups of congenital blind (i.e., with and without light perception), suggesting that the EC-EO difference is irrespective of residual light perception which reinforced the "nature" effect. We also found between-group differences, i.e., more probably "nurture effect", in the posterior insula and fusiform. Our results suggest that the acts of closing and opening the eyes are of importance for the congenital blind, and that these actions and their differences might be inherent in the nature of humans.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117966DOI Listing
June 2021

Research progress on two-component signal transduction systems in .

Hua Xi Kou Qiang Yi Xue Za Zhi 2021 Feb;39(1):88-93

State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.

(), a Gram-negative oral anaerobe, is considered to be a major pathogenic agent involved in the onset and progression of chronic periodontitis. must be able to perceive and respond to the complicated changes in host to survive the environmental challenges, in which the two-component signal transduction systems (TCSs) play critical roles by connecting input signals to cellular physiological output. Canonical TCS consists of a sensor histidine kinase and a cognate response regulator that functions via a phosphorylation cascade. In this review, the roles of TCSs in were demonstrated by illustrating the target genes and modulation modes, which may help elucidate the underlying mechanisms in future studies.
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http://dx.doi.org/10.7518/hxkq.2021.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905415PMC
February 2021

Gluconeogenic enzyme PCK1 deficiency promotes CHK2 O-GlcNAcylation and hepatocellular carcinoma growth upon glucose deprivation.

J Clin Invest 2021 Apr;131(8)

Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, and.

Although cancer cells are frequently faced with a nutrient- and oxygen-poor microenvironment, elevated hexosamine-biosynthesis pathway (HBP) activity and protein O-GlcNAcylation (a nutrient sensor) contribute to rapid growth of tumor and are emerging hallmarks of cancer. Inhibiting O-GlcNAcylation could be a promising anticancer strategy. The gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) is downregulated in hepatocellular carcinoma (HCC). However, little is known about the potential role of PCK1 in enhanced HBP activity and HCC carcinogenesis under glucose-limited conditions. In this study, PCK1 knockout markedly enhanced the global O-GlcNAcylation levels under low-glucose conditions. Mechanistically, metabolic reprogramming in PCK1-loss hepatoma cells led to oxaloacetate accumulation and increased de novo uridine triphosphate synthesis contributing to uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis. Meanwhile, deletion of PCK1 also resulted in AMPK-GFAT1 axis inactivation, promoting UDP-GlcNAc synthesis for elevated O-GlcNAcylation. Notably, lower expression of PCK1 promoted CHK2 threonine 378 O-GlcNAcylation, counteracting its stability and dimer formation, increasing CHK2-dependent Rb phosphorylation and HCC cell proliferation. Moreover, aminooxyacetic acid hemihydrochloride and 6-diazo-5-oxo-L-norleucine blocked HBP-mediated O-GlcNAcylation and suppressed tumor progression in liver-specific Pck1-knockout mice. We reveal a link between PCK1 depletion and hyper-O-GlcNAcylation that underlies HCC oncogenesis and suggest therapeutic targets for HCC that act by inhibiting O-GlcNAcylation.
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http://dx.doi.org/10.1172/JCI144703DOI Listing
April 2021

Protection of retinal ganglion cells in glaucoma: Current status and future.

Exp Eye Res 2021 Apr 18;205:108506. Epub 2021 Feb 18.

Eye Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China; Key Laboratory of Ophthalmology of Zhejiang Province, Hangzhou, Zhejiang, 310009, China. Electronic address:

Glaucoma is a neuropathic disease that causes optic nerve damage, loss of retinal ganglion cells (RGCs), and visual field defects. Most glaucoma patients have no early signs or symptoms. Conventional pharmacological glaucoma medications and surgeries that focus on lowering intraocular pressure are not sufficient; RGCs continue to die, and the patient's vision continues to decline. Recent evidence has demonstrated that neuroprotective approaches could be a promising strategy for protecting against glaucoma. In the case of glaucoma, neuroprotection aims to prevent or slow down disease progression by mitigating RGCs death and optic nerve degeneration. Notably, new pharmacologic medications such as antiglaucomatous agents, antibiotics, dietary supplementation, novel neuroprotective molecules, neurotrophic factors, translational methods such as gene therapy and cell therapy, and electrical stimulation-based physiotherapy are emerging to attenuate the death of RGCs, or to make RGCs resilient to attacks. Understanding the roles of these interventions in RGC protection may offer benefits over traditional pharmacological medications and surgeries. In this review, we summarize the recent neuroprotective strategy for glaucoma, both in clinical trials and in laboratory research.
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http://dx.doi.org/10.1016/j.exer.2021.108506DOI Listing
April 2021

Identification and characterization of six β-crystallin gene mutations associated with congenital cataract in Chinese families.

Mol Genet Genomic Med 2021 Mar 17;9(3):e1617. Epub 2021 Feb 17.

Department of Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.

Background: This study aims to identify the underlying genetic defects of β-crystallin (CRYB) genes responsible for congenital cataracts in a group of Chinese families.

Methods: Detailed family history and clinical data of six Chinese families with autosomal dominant congenital cataracts were recorded. Targeted exome sequencing was applied to detect the underlying genetic defects for the families. Generated variants were confirmed by PCR and sanger sequencing. Afterward, bioinformatic analysis through several computational predictive programs was performed to assess impacts of mutations on protein structure and function.

Results: A total of 53 participants (23 affected and 30 unaffected) from six unrelated Chinese families were recruited. Cataract phenotypes covered nuclear, total, posterior polar, pulverulent, snowflake-like, and zonular. Through targeted exome sequencing, six mutations in four β-crystallin genes were revealed which included five missense mutations CRYBB1 p.Q70P, CRYBB2 p.E23Q, CRYBB2 p.A49V, CRYBB2 R188C, CRYBA4 p.M14K and one splice mutation CRYBB3 c.75+1 G>A. In silico results predicted pathogenic for all four missense variants except variant CRYBB2-p.A49V yielded results as tolerant. The CRYBB3 c.75+1 G>A splice site mutation was predicted to be deleterious by leading to a broken splice site, a premature stop codon, and subsequently resulting in a short peptide of 113 amino acids, which may affect protein features.

Conclusion: The obtained results expanded mutational and phenotype spectrum of β-crystallin genes and offer clues for pathogenesis of congenital cataracts. The data also demonstrated that targeted exome sequencing is valuable for providing molecular diagnostic information for congenital cataract patients.
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http://dx.doi.org/10.1002/mgg3.1617DOI Listing
March 2021

The vital role of Gli1 mesenchymal stem cells in tissue development and homeostasis.

J Cell Physiol 2021 Feb 2. Epub 2021 Feb 2.

State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Periodontics, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.

The hedgehog (Hh) signaling pathway plays an essential role in both tissue development and homeostasis. Glioma-associated oncogene homolog 1 (Gli1) is one of the vital transcriptional factors as well as the direct target gene in the Hh signaling pathway. The cells expressing the Gli1 gene (Gli1 cells) have been identified as mesenchymal stem cells (MSCs) that are responsible for various tissue developments, homeostasis, and injury repair. This review outlines some recent discoveries on the crucial roles of Gli1 MSCs in the development and homeostasis of varieties of hard and soft tissues.
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http://dx.doi.org/10.1002/jcp.30310DOI Listing
February 2021

Dietary fatty acid intake, plasma fatty acid levels, and the risk of age-related macular degeneration (AMD): a dose-response meta-analysis of prospective cohort studies.

Eur J Nutr 2021 Jan 19. Epub 2021 Jan 19.

Eye Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China.

Purpose: Previous population studies on the associations between dietary fatty acids (FAs), plasma FAs levels, and the risk of age-related macular degeneration (AMD) have yielded inconclusive results. Herein, we conducted a dose-response meta-analysis to quantitatively evaluate the associations between specific type of dietary FAs, plasma FAs on early and advanced AMD risk.

Methods: PubMed, Web of Science, and EMBASE were systematically searched for observational cohort studies published through May 2020. For highest versus lowest comparison and dose-response analyses, the relative risk (RR) estimates with a 95% confidence interval (CI) were analyzed using random effects model.

Results: 11 studies with 167,581 participants were included in the meta-analysis. During the follow-up periods (ranging from 3 to 28 years), 6,318 cases of AMD were recorded. Dietary intake of docosahexaenoic acid (DHA) and eicosatetraenoic acid (EPA) combined (per 1 g/day increment) were found to be negatively associated with early AMD (RR: 0.67, 95% CI [0.51, 0.88]). Each 1 g/day increment of DHA (RR: 0.50, 95% CI [0.32, 0.78]) and EPA (RR: 0.40, 95% CI [0.18, 0.87]) was associated with a 50% and 60% reduction of early AMD risk, respectively. Plasma DHA (RR: 0.72, 95% CI [0.55, 0.95]) and EPA (RR: 0.57, 95% CI [0.40, 0.81]) indicated significant negative relationship with advanced AMD.

Conclusion: Increasing dietary intake of ω-3 polyunsaturated fatty acids (PUFAs), specifically DHA and EPA, were associated with a reduced risk of early subtype of AMD, while other types of FAs did not present significant results. Further research is warranted to explore the potential association between dietary FA, plasma FA levels, and advanced subtype of AMD.
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http://dx.doi.org/10.1007/s00394-020-02445-4DOI Listing
January 2021

Cataract-causing mutations L45P and Y46D impair the thermal stability of γC-crystallin.

Biochem Biophys Res Commun 2021 02 7;539:70-76. Epub 2021 Jan 7.

Eye Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, China. Electronic address:

Crystallin gene mutations are responsible for about half of the congenital cataract caused by genetic disorders. L45P and Y46D mutations of γC-crystallin have been reported in patients with nuclear congenital cataract. In this study, we explored the thermal stability of wild type (WT), L45P, and Y46D mutants of γC-crystallin at low and high concentrations, as well as the effect of αA-crystallin on the thermal stability of mutants. Spectroscopic experiments were used to monitor the structural changes on temperature-gradient and time-course heating process. Intermediate morphologies were determined through cryo-electron microscopy. The thermal stability of WT and mutants at concentrations ranging up to hundreds of milligrams were assessed via the UNcle multifunctional protein stability analysis system. The results showed that L45P and Y46D mutations impaired the thermal stability of γC-crystallin at low (0.2 mg/mL) and high concentrations (up to 200 mg/mL). Notably, with increase in protein concentration, the thermal stability of L45P and Y46D mutants of γC-crystallin simultaneously decreased. Thermal stability of L45P and Y46D mutants could be rescued by αA-crystallin in a concentration-dependent manner. The dramatic decrease in thermal stability of γC-crystallin caused by L45P and Y46D mutations contributed to congenital cataract in the mature human lens.
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http://dx.doi.org/10.1016/j.bbrc.2020.12.096DOI Listing
February 2021

Effect of surgery-first orthognathic approach on oral health-related quality of life.

Angle Orthod 2020 09;90(5):723-733

Objectives: To systematically evaluate the effect of the surgery-first approach (SFA) on oral health-related quality of life (OHRQoL) in patients with dentofacial deformities.

Materials And Methods: An electronic database search and hand search of selected journals and references were carried out. Studies investigating the OHRQoL of patients receiving SFA with or without a control group were included. The risk of bias was assessed by the Cochrane risk of bias tool in randomized clinical trials (RCTs) and the Newcastle-Ottawa Scale in non-RCTs.

Results: A total of seven articles met the eligible criteria and were included, of which six were cohort studies and one was an RCT, and six assessed the OHRQoL of the SFA with conventional orthodontic-surgical treatment (COST) as a control and one without. A total of 214 patients were examined, with sample sizes in studies ranging from 9 to 50. A total of 3 articles successfully measured the OHRQoL both before and after treatment in both the SFA and conventional orthodontic-surgical treatment groups. A total of six cohort studies were classified as low to moderate risk of bias, and the RCT was classified as high.

Conclusions: The SFA could improve the OHRQoL of patients with dentofacial deformities similar to conventional orthodontic-surgical treatment at the end of complete treatment. In addition, it increases OHRQoL immediately at the beginning of treatment without a deterioration.
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http://dx.doi.org/10.2319/112619-749.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032263PMC
September 2020

TGFβ Signaling in Photoaging and UV-Induced Skin Cancer.

J Invest Dermatol 2021 Apr 7;141(4S):1104-1110. Epub 2021 Jan 7.

Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; Veterans Affairs Medical Center, VA Eastern Colorado Health Care System, Aurora, Colorado, USA. Electronic address:

UVR is a major etiology for premature skin aging that leads to photoaging and UV-induced skin cancers. In the skin, TGFβ signaling is a growth inhibitor for keratinocytes and a profibrotic factor in the dermis. It exerts context-dependent effects on tumor progression. Chronic UV exposure likely causes TGFβ1/SMAD3 signaling activation and contributes to metalloproteinase-induced collagen degradation and photoinflammation in photoaging. UV irradiation also causes gene mutations in key elements of the TGFβ pathway, including TGFβRI, TGFβRII, SMAD2, and SMAD4. These mutations enable tumor cells to escape from TGFβ-induced growth inhibition and induce genomic instability and cancer stem cells, leading to the initiation, progression, invasion, and metastasis of cutaneous squamous cell carcinoma (cSCC). Furthermore, UV-induced mutations cause TGFβ overexpression in the tumor microenvironment (TME) of cSCC, basal cell carcinoma (BCC), and cutaneous melanoma, resulting in inflammation, angiogenesis, cancer-associated fibroblasts, and immune inhibition, supporting cancer survival, immune evasion, and metastasis. The pleiotropic effects of TGFβ provide possible treatment options for photoaging and skin cancer. Given the high UV-induced mutational burden and immune-repressive TME seen in cSCC, BCC, and cutaneous melanoma, treatment with the combination of a TGFβ signaling inhibitor and immune checkpoint blockade could reverse immune evasion to reduce tumor growth.
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http://dx.doi.org/10.1016/j.jid.2020.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987776PMC
April 2021

Involvement of the NLRC4 inflammasome in promoting retinal ganglion cell death in an acute glaucoma mouse model.

Exp Eye Res 2021 02 15;203:108388. Epub 2020 Dec 15.

Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. Electronic address:

Purpose: To explore the role of nucleotide-binding oligomerization domain-like receptors (NLRs) family caspase-activation and the recruitment domain containing 4 (NLRC4) inflammasome in retinal ganglion cell (RGC) injury induced by an acute glaucoma mouse model.

Method: A mouse model of acute ocular hypertension, which can lead to retinal ischemia-reperfusion (I/R) injury, was established. The expression level of NLRC4 was detected by polymerase chain reaction and western blotting. Localized expression of NLRC4 was detected by examining immunofluorescence in eyeball sections. Intravitreal adeno-associated virus 2(AAV2) administration was used to knockdown retinal Nlrc4. Fluoro-Gold labeled RGCs and TdT-mediated dUTP nick end labeling were used to evaluate the survival and apoptosis of RGCs. Tlr4 mice were utilized to explore whether NLRC4 inflammasome is influenced by Toll-like receptor4 (TLR4).

Results: NLRC4, expressed in RGCs and microglial cells, was actively involved in mouse retinal I/R injury. Knockdown of Nlrc4 using an AAV2 vector caused an obvious reduction in the generation of IL-1β led by the rapidly elevated intraocular pressure, and thereby improved the RGC survival. In addition, activation of the NLRC4 inflammasome could influence the phosphorylation of p38 and Jun N-terminal kinase, which was largely dependent on TLR4 signaling.

Conclusion: Our study demonstrated the role of NLRC4 inflammasome in promoting RGC damage in mouse retinal I/R injury. Inhibition of NLRC4 might be leveraged as a potential therapeutic target in glaucomatous retinopathy.
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http://dx.doi.org/10.1016/j.exer.2020.108388DOI Listing
February 2021

Advances in pharmacotherapy of cataracts.

Ann Transl Med 2020 Nov;8(22):1552

Eye Center of the Second Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, China.

Cataracts, the leading cause of vision impairment worldwide, arise from abnormal aggregation of lens proteins. According to the World Health Organization, cataracts cause more than 40% of blindness cases. As the population ages, the prevalence of cataracts will increase rapidly. Although cataract surgery is regarded as effective, it still suffers from complications and high cost, and could not meet the increasingly surgery demand. Therefore, pharmacological treatment for cataracts is a cheaper and more readily available option for patients, which is also a hot topic for years. Anti-cataract drug screening was previously mainly based on the specific pathogenic factors: oxidative stress, excess of quinoid substances, and aldose reductase (AR) activation. And several anti-cataract drugs have been applied in the clinic, while the effect is still unsatisfied. Makley and Zhao recently identified two kinds of novel pharmacological substances (25-hydroxycholesterol, lanosterol) that can reverse lens opacity by dissolving the aggregation of crystallin proteins, indicating that protein aggregation is not an endpoint and could be reversed with specific small-molecule drugs, significantly boosting the development of the cataract pharmacopeia and being regarded as a new dawn for cataract treatment. Our team built a novel optimized platform and had screened several potential therapeutic agents from a collection of lanosterol derivatives. In this review, we would mainly focus on the advancement of cataract pharmacotherapy based on the targets for anti-cataract drugs.
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http://dx.doi.org/10.21037/atm-20-1960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729355PMC
November 2020

Amnion-Derived Mesenchymal Stem Cell Exosomes-Mediated Autophagy Promotes the Survival of Trophoblasts Under Hypoxia Through mTOR Pathway by the Downregulation of EZH2.

Front Cell Dev Biol 2020 11;8:545852. Epub 2020 Nov 11.

Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China.

Human amnion-derived mesenchymal stem cells (AD-MSCs) have been reported as a promising effective treatment to repair tissue. Trophoblast dysfunction during pregnancy is significantly involved in the pathogenesis of preeclampsia (PE). To understand how AD-MSCs regulated trophoblast function, we treated trophoblasts with AD-MSC-derived exosomes under hypoxic conditions. The treatment markedly enhanced the trophoblast proliferation and autophagy. Furthermore, significant decrease of EZH2 levels and inactivation of mTOR signaling were observed in AD-MSC exosomes-treated trophoblasts. Consistent with these findings, overexpression of EZH2 activated the mTOR signaling in trophoblasts, and reduced the autophagy and survival of trophoblasts, even in the presence of AD-MSC-derived exosomes. In addition, EZH2 inhibition exhibited the same trophoblast autophagy-promoting effect as induced by AD-MSC-derived exosomes, also accompanied by the inactivation of mTOR signaling. Importantly, when EZH2 was overexpressed in trophoblasts treated with PQR620, a specific mTOR signaling inhibitor, the autophagy and proliferation in trophoblasts were decreased. Studies on human placental explants also confirmed our findings by showing that the expression levels of EZH2 and mTOR were decreased while the autophagy-associated protein level was increased by AD-MSC-derived exosome treatment. In summary, our results suggest that EZH2-dependent mTOR signaling inactivation mediated by AD-MSC-derived exosomes is a prerequisite for autophagy augmentation in hypoxic trophoblasts.
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http://dx.doi.org/10.3389/fcell.2020.545852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693549PMC
November 2020

Cataract-causing mutations L45P and Y46D promote γC-crystallin aggregation by disturbing hydrogen bonds network in the second Greek key motif.

Int J Biol Macromol 2021 Jan 2;167:470-478. Epub 2020 Dec 2.

Eye Center of the Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang Province, China; Institute of Translational Medicine, School of Medicine, Zhejiang University, 268 Kaixuan Road, Hangzhou, Zhejiang Province, China. Electronic address:

Congenital cataracts caused by genetic disorders are the primary cause of child blindness across the globe. In this work, we investigated the underlying molecular mechanism of two mutations, L45P and Y46D of γC-crystallin in two Chinese families causing nuclear congenital cataracts. Spectroscopic experiments were performed to determine structural differences between the wild-type (WT) and the L45P or Y46D mutant of γC-crystallin, and the structural stabilities of the WT and mutant proteins were measured under environmental stress (ultraviolet irradiation, pH disorders, oxidative stress, or chemical denaturation). The L45P and Y46D mutants had lower protein solubility and more hydrophobic residues exposed, making them prone to aggregation under environmental stress. The dynamic molecular simulation revealed that the L45P and Y46D mutations destabilized γC-crystallin by altering the hydrogen bonds network around the Trp residues in the second Greek key motif. In summary, L45P and Y46D mutants of γC-crystallin caused more hydrophobic residues to be solvent-exposed, lowered the solubility of γC-crystallin, and increased aggregation propensity under environmental stress. These might be the pathogenesis of γC-crystallin L45P and Y46D mutants related to congenital cataract.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.11.158DOI Listing
January 2021

A new heterozygous mutation in the stop codon of (p.X176Y) is liable for congenital posterior pole cataract in a Chinese family.

Ophthalmic Genet 2021 04 4;42(2):139-143. Epub 2020 Dec 4.

Department of Eye Center, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.

: The present study aims to identify the underlying genetic defects in a Chinese family with autosomal dominant congenital cataracts (ADCC).: Detailed family histories and clinical data were recorded. Targeted exome sequencing of 54 known cataract-associated genes combined with high-throughput next-generation sequencing was conducted followed by Sanger sequencing and bioinformatic analysis to identify the causative gene lesion for the family.: A four-generation Chinese family with posterior pole type cataract were enrolled. Enrichment of targeted genes revealed a new heterozygous p.X176Y mutation in the stop codon of αB-crystallin () gene, which resulted in the loss of the stop codon and prolongation of the mutant protein by 19 amino acid residues (p.X176Yfs19*). Sanger sequencing showed complete co-segregation with the disease. The elongated mutant protein was predicted to be pathogenic by forming new α-helix and random-coil in the secondary structure as well as producing an extended strand in the tertiary structure, potentially leading to increased hydrophobicity and reduced protein stability.: Our report added a new mutation in the spectrum of congenital cataracts. The data suggested that X176 residue in the COOH-terminal is of crucial importance for the αB-crystallin protein function which was valuable for further study of the pathogenesis of congenital cataracts.: αB-crystallin; DNA: deoxyribonucleic acid; PCR: polymerase chain reaction; TES: targeted exome sequencing; ACD: αB-crystallin domain.
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http://dx.doi.org/10.1080/13816810.2020.1855665DOI Listing
April 2021

βB2 W151R mutant is prone to degradation, aggregation and exposes the hydrophobic side chains in the fourth Greek Key motif.

Biochim Biophys Acta Mol Basis Dis 2021 02 25;1867(2):166018. Epub 2020 Nov 25.

Eye Center of the Second Affiliated Hospital, Medical College of Zhejiang University, 88 Jiefang Road, Hangzhou 310009, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310020, China. Electronic address:

Studies have established that congenital cataract is the major cause of blindness in children across the globe. The β-crystallin protein family is the richest and most soluble structural protein in the lens. Their solubility and stability are essential in maintaining lens transparency. In this study, we identified a novel βB2 mutation W151R in a rare progressive cortical congenital cataract family and explored its pathogenesis using purified protein and mutant related cataract-cell models. Due to its low solubility and poor structural stability, the βB2 W151R mutation was prone to aggregation. Moreover, the W151R mutation enhanced the exposure of the hydrophobic side chains in the fourth Greek Key motif, which were readily degraded by trypsin. However, upon the administration of lanosterol, the negative effect of the W151R mutation was reversed. Therefore, lanosterol is a potential therapeutic option for cataracts.
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http://dx.doi.org/10.1016/j.bbadis.2020.166018DOI Listing
February 2021

Activation of the ATP-P2X pathway by TRPV4 in acute ocular hypertension.

Int J Ophthalmol 2020 18;13(11):1697-1704. Epub 2020 Nov 18.

Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China.

Aim: To measure the expression of transient receptor potential cation channel subfamily V member 4 (TRPV4) in the rat cornea and determine whether it is related to adenosine triphosphate (ATP) generation in a rat model of acute ocular hypertension (AOH).

Methods: Immunofluorescence staining of TRPV4, P2X2 receptor, P2X3 receptor, and β3-tubulin in rat corneal longitudinal sections and paved was performed to clearly display histological structures. Rat models of AOH and agonist/antagonist-treated groups were established and corneal ATP was measured using an ATP assay. The independent -test and simple linear correlation model were adopted for statistical analyses.

Results: Immunofluorescence staining of rat cornea sections revealed that epithelial and endothelial membranes showed strong immunoreactivity for TRPV4 and P2X2 receptor and coexpression with β3-tubulin in the rat corneal epithelial layer. Corneal ATP was significantly higher in the AOH rat model than in the control (<0.05) and apparently lower after pretreatment by applying eyedrops of TRPV4 antagonist RN1734 with 30-40 mm Hg intraocular pressure (IOP; <0.05). A simple linear regression model showed a positive correlation between rat corneal ATP and IOP values (=0.996, =0.0134) from the normal IOP (113 mm Hg) to 40 mm Hg. At 10-40min after anterior chamber injection of GSK1016790A (0.01 mL, 50 nmol/L in 0.9% NaCl), corneal ATP was significantly higher than in the control group (<0.05), which peaked at 10min. The ATP concentration of the normal epithelium was higher than that of the endothelium in the AOH rat model and after anterior chamber injection of GSK1016790A (<0.05).

Conclusion: The ATP concentration in the AOH rat cornea is increased by TRPV4 activation.
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http://dx.doi.org/10.18240/ijo.2020.11.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590884PMC
November 2020

GSK3β-Mediated Expression of CUG-Translated WT1 Is Critical for Tumor Progression.

Cancer Res 2021 02 12;81(4):945-955. Epub 2020 Nov 12.

College of Medicine, Zhengzhou University, Henan, China.

The () gene is well known as a chameleon gene. It plays a role as a tumor suppressor in Wilms' tumor but also acts as an oncogene in other cancers. Previously, our group reported that a canonical AUG starting site for the WT1 protein (augWT1) acts as a tumor suppressor, whereas a CUG starting site for the WT1 protein (cugWT1) functions as an oncogene. In this study, we report an oncogenic role of cugWT1 in the AOM/DSS-induced colon cancer mouse model and in a urethane-induced lung cancer model in mice lacking cugWT1. Development of chemically-induced tumors was significantly depressed in cugWT1-deficient mice. Moreover, glycogen synthase kinase 3β promoted phosphorylation of cugWT1 at S64, resulting in ubiquitination and degradation of the cugWT1 associated with the F-box WD repeat-containing protein 8. Overall, our findings suggest that inhibition of cugWT1 expression provides a potential candidate target for therapy. SIGNIFICANCE: These findings demonstrate that CUG-translated WT1 plays an oncogenic role , and GSK3β-mediated phosphorylation of cugWT1 induces its ubiquitination and degradation in concert with FBXW8.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1880DOI Listing
February 2021

Interplay of MPP5a with Rab11 synergistically builds epithelial apical polarity and zonula adherens.

Development 2020 11 19;147(22). Epub 2020 Nov 19.

Eye Center of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China

Adherens junction remodeling regulated by apical polarity proteins constitutes a major driving force for tissue morphogenesis, although the precise mechanism remains inconclusive. Here, we report that, in zebrafish, the Crumbs complex component MPP5a interacts with small GTPase Rab11 in Golgi to transport cadherin and Crumbs components synergistically to the apical domain, thus establishing apical epithelial polarity and adherens junctions. In contrast, Par complex recruited by MPP5a is incapable of interacting with Rab11 but might assemble cytoskeleton to facilitate cadherin exocytosis. In accordance, dysfunction of MPP5a induces an invasive migration of epithelial cells. This adherens junction remodeling pattern is frequently observed in zebrafish lens epithelial cells and neuroepithelial cells. The data identify an unrecognized MPP5a-Rab11 complex and describe its essential role in guiding apical polarization and zonula adherens formation in epithelial cells.
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http://dx.doi.org/10.1242/dev.184457DOI Listing
November 2020

EZH2-dependent epigenetic modulation of histone H3 lysine-27 contributes to psoriasis by promoting keratinocyte proliferation.

Cell Death Dis 2020 10 3;11(10):826. Epub 2020 Oct 3.

Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

Psoriasis is characterized by keratinocyte hyperproliferation. While significant progress has been made in understanding the molecular mechanism regulating the proliferation of keratinocytes, little is known about the epigenetic factors that control this process. EZH2 and EZH2 mediated trimethylation of histone H3 lysine 27 (H3K27me3) was previously shown ectopically expressed in carcinoma and mediated proliferation, thereby we sought to clarify the role of EZH2-H3K27me3 in the proliferation of psoriatic keratinocyte. Interestingly, we found that EZH2 and H3K27me3 were both overexpressed in the epidermis of psoriatic lesional skin compared to normal skin. In vitro, the expression of EZH2 and H3K27me3 was stimulated in human keratinocytes treated with mixture of psoriasis-related cytokines pool (TNF-α, IFN-γ, IL-17A, and IL-22). Knockdown of EZH2 significantly reduced keratinocyte proliferative activity. Results from mRNA microarray analysis suggested that Kallikrein-8 (KLK8) might be the target gene of EZH2 in psoriatic keratinocytes. Overexpression or knockdown KLK8 could partially reverse the abnormal proliferation of keratinocytes caused by knockdown or overexpression of EZH2. In vivo, the inhibitor of EZH2, GSK126 could ameliorate the imiquimod-induced psoriasiform lesion. These results suggest that EZH2 might be a therapeutic target for the treatment of psoriasis.
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http://dx.doi.org/10.1038/s41419-020-03028-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532974PMC
October 2020