Publications by authors named "Ke Yao"

488 Publications

Effectiveness and safety of tafluprost in primary open-angle glaucoma and ocular hypertension: a post-marketing phase IV study in China.

BMC Ophthalmol 2022 Aug 5;22(1):332. Epub 2022 Aug 5.

Department of Cataract and Glaucoma, Wuhan Eyegood Ophthalmic Hospital, Wuhan, 430064, Hubei Province, China.

Background: Prostaglandin analogs (PGAs) are the first-line treatment for primary open-angle glaucoma (POAG) and ocular hypertension (OH). This study aimed to confirm the effectiveness and safety of Tapros® (0.0015% tafluprost eye drops) in Chinese patients with POAG and OH.

Methods: This phase IV, multicenter, non-comparative, prospective study enrolled patients with POAG and OH in China between 12/27/2017 and 04/15/2020. Patients who were treatment-naïve or untreated within one month (group A) or with unreached intraocular pressure (IOP) target after previous monotherapy of other PGAs (group B) or non-PGA IOP-lowering drugs (group C) were treated with 0.0015% tafluprost for three months. The IOP reduction, response rate, and safety were observed.

Results: There were 165, 89, and 31 patients in groups A, B, and C, with baseline IOPs of 22.4 ± 4.7, 21.0 ± 3.5, and 22.5 ± 3.2 mmHg, respectively. The least-square means and percentages of IOP reduction at 3 months for groups A, B, and C were 4.7 (19.8%), 1.6 (6.1%), and 4.6 mmHg (20.3%), respectively. A significant reduction in IOP was observed at each visit compared with baseline (all P < 0.05). At the final visit, 57.0% of the participants in group A achieved an IOP reduction of ≥ 20%, while 40.4% and 77.4% in groups B and C achieved an IOP reduction of ≥ 10%. Fifty-eight treatment-related adverse events occurred in 46 participants (15.7%), of which the most common one was conjunctival hyperemia (34/293, 11.6%).

Conclusions: Tafluprost showed a sustained and significant effect with tolerable adverse events in Chinese patients with POAG and OH who were treatment-naïve or untreated within one month or received prior treatments with unsatisfying outcomes.
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http://dx.doi.org/10.1186/s12886-022-02553-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9356508PMC
August 2022

Brain-Reactive Antibodies are Potential Biomarkers for Evaluating Therapeutic Efficacy in NPSLE Patients.

Neuropsychiatr Dis Treat 2022 4;18:1329-1340. Epub 2022 Jul 4.

Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People's Republic of China.

Purpose: Neuropsychiatric systemic lupus erythematosus (NPSLE) is the main cause of disability and death in systemic lupus erythematosus (SLE). It can cause cognitive impairment and organic brain syndrome. Brain-reactive antibodies, such as anti-DNA/anti-N-methyl-D-aspartate receptor (NMDAR) antibodies (DNRAbs), anti-microtubule-associated protein 2 (anti-MAP2) antibodies, and anti-glial fibrillary acidic protein (anti-GFAP) antibodies are thought to participate in the progression of NPSLE and thus considered potential diagnostic biomarkers, but whether they can be used for evaluating therapeutic efficacy in NPSLE is unknown.

Patients And Methods: Overall, 17 NPSLE patients and 10 non-SLE controls were included in this study. All the patients were treated with glucocorticoid (GC) pulse therapy. Serum and cerebrospinal fluid (CSF) concentrations of DNRAbs and anti-MAP2 and anti-GFAP antibodies were measured using enzyme-linked immunosorbent assay. The differences between the CSF concentrations of these antibodies in NPSLE patients before and after GC pulse therapy were analyzed.

Results: CSF concentrations of DNRAbs and anti-MAP2 and anti-GFAP antibodies were significantly higher in NPSLE patients compared to the non-SLE controls. Among the patients, CSF concentration of DNRAbs was significantly higher in the patients with acute confusional state (ACS) than in those with non-ACS diffuse NPSLE or focal NPSLE. Additionally, CSF concentration of DNRAbs was significantly correlated with QIgG (r=0.4884, =0.0467) and IgG index (r=0.5319, =0.0280) in NPSLE patients. Moreover, CSF concentrations of DNRAbs, anti-MAP2, and anti-GFAP antibodies and QIgG were significantly decreased after GC pulse therapy in NPSLE patients.

Conclusion: These results indicate that CSF DNRAbs and anti-MAP2 and anti-GFAP antibodies are potential biomarkers for evaluating therapeutic efficacy in NPSLE.
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http://dx.doi.org/10.2147/NDT.S359698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9270050PMC
July 2022

BRAF inhibition promotes ER stress-mediated cell death in uveal melanoma.

Neoplasma 2022 Jun 30. Epub 2022 Jun 30.

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

Melanoma with a BRAF mutation is more common to develop into a fatal disease. BRAF mutation inhibitor-induced autophagy affects the drug efficacy in many cancer types. The role of autophagy during BRAF inhibition in uveal melanoma (UM) remains unclear. In this study, we examined the autophagic flux and compared the number of autophagic vacuoles during the BRAF inhibition in UM. The PKR-like endoplasmic reticulum (ER) kinase (PERK) arm was studied to test whether the ER stress was involved. The effects of downregulation of ER stress by targeting the PERK arm (pharmacologically and genetically) were also assessed. We found a dose-dependent increase of autophagic flux in OCM1A cells during the BRAF inhibition. This phenomenon was further verified by an enhanced number of GFP-LC3 puncta and was finally confirmed by raised autophagic index examined by transmission electron microscopy. Pathway analysis revealed that the vemurafenib (the BRAF inhibitor)-induced autophagy was independent of the MAPK signaling pathway. Instead, it was possibly regulated via the enhanced ER stress response. We further found that the inhibition of ER stress response rescued cell death. Therefore, our results suggest BRAF inhibition promotes ER stress response-induced autophagy in UM. Targeting ER stress response can partially revert autophagy and rescue cell death, which may impair the anti-tumor effect of BRAF inhibitor in UM.
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http://dx.doi.org/10.4149/neo_2022_220428N462DOI Listing
June 2022

Recent Advances of Intraocular Lens Materials and Surface Modification in Cataract Surgery.

Front Bioeng Biotechnol 2022 8;10:913383. Epub 2022 Jun 8.

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

Advances in cataract surgery have increased the demand for intraocular lens (IOL) materials. At present, the progress of IOL materials mainly contains further improving biocompatibility, providing better visual quality and adjustable ability, reducing surgical incision, as well as dealing with complications such as posterior capsular opacification (PCO) and ophthalmitis. The purpose of this review is to describe the research progress of relevant IOL materials classified according to different clinical purposes. The innovation of IOL materials is often based on the common IOL materials on the market, such as silicon and acrylate. Special properties and functions are obtained by adding extra polymers or surface modification. Most of these studies have not yet been commercialized, which requires a large number of clinical trials. But they provide valuable thoughts for the optimization of the IOL function.
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http://dx.doi.org/10.3389/fbioe.2022.913383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9213654PMC
June 2022

Evaluation of artificial intelligence models for the detection of asymmetric keratoconus eyes using Scheimpflug tomography.

Clin Exp Ophthalmol 2022 Jun 15. Epub 2022 Jun 15.

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

Background: To evaluate artificial intelligence (AI) models based on objective indices and raw corneal data from the Scheimpflug Pentacam HR system (OCULUS Optikgeräte GmbH, Wetzlar, Germany) for the detection of clinically unaffected eyes in patients with asymmetric keratoconus (AKC) eyes.

Methods: A total of 1108 eyes of 1108 patients were enrolled, including 430 eyes from normal control subjects, 231 clinically unaffected eyes from patients with AKC, and 447 eyes from keratoconus (KC) patients. Eyes were divided into a training set (664 eyes), a test set (222 eyes) and a validation set (222 eyes). AI models were built based on objective indices (XGBoost, LGBM, LR and RF) and entire corneal raw data (KerNet). The discriminating performances of the AI models were evaluated by accuracy and the area under the ROC curve (AUC).

Results: The KerNet model showed great overall discriminating power in the test (accuracy = 94.67%, AUC = 0.985) and validation (accuracy = 94.12%, AUC = 0.990) sets, which were higher than the index-derived AI models (accuracy = 84.02%-86.98%, AUC = 0.944-0.968). In the test set, the KerNet model demonstrated good diagnostic power for the AKC group (accuracy = 95.24%, AUC = 0.984). The validation set also proved that the KerNet model was useful for AKC group diagnosis (accuracy = 94.12%, AUC = 0.983).

Conclusions: KerNet outperformed all the index-derived AI models. Based on the raw data of the entire cornea, KerNet was helpful for distinguishing clinically unaffected eyes in patients with AKC from normal eyes.
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http://dx.doi.org/10.1111/ceo.14126DOI Listing
June 2022

A novel gatifloxacin-loaded intraocular lens for prophylaxis of postoperative endophthalmitis.

Bioact Mater 2023 Feb 2;20:271-285. Epub 2022 Jun 2.

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

Postoperative endophthalmitis (POE) has been the most threatening complication after cataract surgery, which perhaps can be solved by the antibiotic-loaded intraocular lens (IOL). However, most drug-loaded IOLs demonstrate insufficient drug quantity, short release time, increased implantation-related difficulties or other noticeable drawbacks. To prevent POE and to address these deficiencies, a drug-loaded copolymer IOL, prepared from poly (urethane acrylate) prepolymer, isobornyl methacrylate (IBOMA), N-vinyl-2-pyrrolidone (NVP), Irgacure 819, RUVA-93, and gatifloxacin (GAT), was rapidly fabricated via photocuring and by using a 3D-printed mold. This composite displayed an outstanding and controllable GAT release behavior , a high light transmittance, and a moderate refractive index. Also, it demonstrated improved strain stress and elongation compared with the reference commercial acrylic IOL material. tests demonstrated satisfying released drug concentration at the early treatment stage. and studies further confirmed the remarkable bacterial inhibition and prevention of POE by the proposed IOL, which also displayed good biocompatibility. These findings suggested that the GAT-loaded IOL could be a promising implant to prevent and cure POE, also the proposed methods could inspire more designs for various medical applications.
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http://dx.doi.org/10.1016/j.bioactmat.2022.05.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9168518PMC
February 2023

Intraspecific Identification of Lingzhi Medicinal Mushroom, Ganoderma lingzhi (Agaricomycetes), Using ISSR Markers.

Int J Med Mushrooms 2022 ;24(4):43-52

Sichuan Key Laboratory of Quality and Innovation of Traditional Chinese Medicine, Institute of Fungus Medicinal Materials, Sichuan Academy of Chinese Medicine Science, Chengdu, 610041 Sichuan Province, People's Republic of China.

This study aimed to obtain a set of specific inter simple sequence repeat (ISSR) primers and establish a stable and accurate intraspecific identification method for Ganoderma lingzhi. A total of 117 G. lingzhi strains were identified using internal transcribed spacer sequences from 147 strains determined as G. lingzhi via simple morphological identification. Based on the sequences obtained, specific ISSR primers for G. lingzhi were screened and validated, and 15 specific ISSR primers showed polymorphic banding pattern with clear band resolution. Subsequently, ISSR PCRs of the 15 specific primers were performed for the 117 G. lingzhi strains. As expected, DNA analysis of the ISSR markers could distinguish G. lingzhi strains, with similarity coefficients ranging from 0.11 to 0.89. Thus, the 15 specific ISSR primers can be used for intraspecific identification and polymorphism analysis of G. lingzhi.
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http://dx.doi.org/10.1615/IntJMedMushrooms.2022043141DOI Listing
June 2022

Airborne fine particulate matter (PM) damages the inner blood-retinal barrier by inducing inflammation and ferroptosis in retinal vascular endothelial cells.

Sci Total Environ 2022 Sep 9;838(Pt 4):156563. Epub 2022 Jun 9.

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

This study was the first to explore the effect of airborne fine particulate matter (PM) exposure on the inner blood-retinal barrier (iBRB). In this study, retinal vascular permeability and diameter were enhanced in the PM-exposed animal model (1 mg/mL PM, 10 μL per eye, 4 times per day, 3 days), together with observable retinal edema and increased inflammation level in retina. PM-induced cell damage in human retinal microvascular endothelial cells (HRMECs) occurred in a time- and dose-dependent manner. Decreased cell viability, proliferation, migration, and angiogenesis, as well as increased apoptosis and inflammation, were observed. Iron overload and excessive lipid oxidation were also discovered after PM exposure (25, 50, and 100 μg/mL PM for 24 h), along with significantly altered expression of ferroptosis-related genes, such as prostaglandin-endoperoxide synthase 2, glutathione peroxidase 4, and ferritin heavy chain 1. Moreover, Ferrostatin-1, an inhibitor of ferroptosis, evidently alleviated the PM-induced cytotoxicity of HRMECs. The present study investigated the in vivo effects of PM on retinas, revealing that PM exposure induced retinal inflammation, vascular dilatation, and caused damage to the iBRB. The crucial role of ferroptosis was discovered during PM-induced HRMEC cytotoxicity and dysfunction, indicating a potential precautionary target in air pollution-associated retinal vascular diseases.
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http://dx.doi.org/10.1016/j.scitotenv.2022.156563DOI Listing
September 2022

Beneficial Actions of Essential Fatty Acids in Streptozotocin-Induced Type 1 Diabetes Mellitus.

Front Nutr 2022 19;9:890277. Epub 2022 May 19.

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

The essential fatty acids (EFA), n3 alpha-linolenic acid (ALA), and n6 linoleic acid (LA) are of benefit in diabetes mellitus, but their mechanisms of action are unknown. We, therefore, examined the effects of EFAs on the metabolism, gut microbiota, and inflammatory and retinal histopathology indices in streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) animals, and we assessed the levels of vitreal lipoxin A4 (LXA4)-derived from LA-in subjects with diabetic retinopathy (DR). STZ-induced T1DM rats received LA or ALA 100 μg/day intraperitoneally on alternate days for 21 days, and their blood glucose; lipid profile; plasma, hepatic, and retinal fatty acid profiles (by gas chromatography); retinal histology; activities of hepatic and retinal desaturases; and inflammatory markers (by qRT-PCR) were evaluated. Gut microbiota composition was assayed by 16S rDNA sequencing technology of the fecal samples, and their short-chain fatty acids and bile acids were assayed by gas chromatography, liquid chromatography coupled with tandem mass spectrometry, respectively. The human vitreal fatty acid profiles of subjects with proliferative DR and LXA4 levels were measured. LA and ALA significantly improved the plasma glucose and lipid levels; increased the abundance of (the ALA-treated group), (the LA-treated group) bacteria; enhanced acetate and butyrate levels; and augmented fecal and hepatic concentrations of cholic acid, chenodeoxycholic acid, and tauro ursodeoxycholic acid in ALA- and LA-treated animals. Significant STZ-induced decreases in plasma LA, gamma-linolenic acid, arachidonic acid, and ALA levels reverted to near normal, following LA and ALA treatments. Significant changes in the expression of desaturases; COX-2, 5-LOX, and 12-LOX enzymes; and cytokines in T1DM were reverted to near normal by EFAs. DR subjects also had low retinal LXA4 levels. The results of the present study show that ALA and LA are of significant benefit in reversing metabolism, gut microbiota, and inflammatory and retinal index changes seen in T1DM, suggesting that EFAs are of benefit in diabetes mellitus.
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http://dx.doi.org/10.3389/fnut.2022.890277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164285PMC
May 2022

Non-oxidative pentose phosphate pathway controls regulatory T cell function by integrating metabolism and epigenetics.

Nat Metab 2022 05 23;4(5):559-574. Epub 2022 May 23.

Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Regulatory T (T) cells are critical for maintaining immune homeostasis and preventing autoimmunity. Here, we show that the non-oxidative pentose phosphate pathway (PPP) regulates T function to prevent autoimmunity. Deletion of transketolase (TKT), an indispensable enzyme of non-oxidative PPP, in T cells causes a fatal autoimmune disease in mice, with impaired T suppressive capability despite regular T numbers and normal Foxp3 expression levels. Mechanistically, reduced glycolysis and enhanced oxidative stress induced by TKT deficiency triggers excessive fatty acid and amino acid catabolism, resulting in uncontrolled oxidative phosphorylation and impaired mitochondrial fitness. Reduced α-KG levels as a result of reductive TCA cycle activity leads to DNA hypermethylation, thereby limiting functional gene expression and suppressive activity of TKT-deficient T cells. We also find that TKT levels are frequently downregulated in T cells of people with autoimmune disorders. Our study identifies the non-oxidative PPP as an integrator of metabolic and epigenetic processes that control T function.
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http://dx.doi.org/10.1038/s42255-022-00575-zDOI Listing
May 2022

Ferrostatin-1-loaded liposome for treatment of corneal alkali burn via targeting ferroptosis.

Bioeng Transl Med 2022 May 8;7(2):e10276. Epub 2021 Dec 8.

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

Alkali burn is a potentially blinding corneal injury. During the progression of alkali burn-induced injury, overwhelmed oxidative stress in the cornea triggers cell damage, including oxidative changes in cellular macromolecules and lipid peroxidation in membranes, leading to impaired corneal transparency, decreased vision, or even blindness. In this study, we identified that ferroptosis, a type of lipid peroxidation-dependent cell death, mediated alkali burn-induced corneal injury. Ferroptosis-targeting therapy protected the cornea from cell damage and neovascularization. However, the specific ferroptosis inhibitor ferrostatin-1 (Fer-1) is hydrophobic and cannot be directly applied in the clinic. Therefore, we developed Fer-1-loaded liposomes (Fer-1-NPs) to improve the bioavailability of Fer-1. Our study demonstrated that Fer-1-NPs exerted remarkable curative effects regarding corneal opacity and neovascularization in vivo. The efficacy was comparable to that of dexamethasone, but without appreciable side effects. The significant suppression of ferroptosis (induced by lipid peroxidation and mitochondria disruption), inflammation, and neovascularization might be the mechanisms underlying the therapeutic effect of Fer-1-NPs. Moreover, the Fer-1-NPs treatment showed no signs of cytotoxicity, hematologic toxicity, or visceral organ damage, which further confirmed the biocompatibility. Overall, Fer-1-NPs provide a new prospect for safe and effective therapy for corneal alkali burn.
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http://dx.doi.org/10.1002/btm2.10276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9115688PMC
May 2022

Origin and Phylogeography of Chinese Cereal Cyst Nematode Revealed by Mitochondrial COI Sequences.

Phytopathology 2022 Aug 4:PHYTO12210532R. Epub 2022 Aug 4.

State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, P. R. China.

, a globally distributed plant-parasitic nematode, is one of the most significant pests on cereal crops. In China, it is widely distributed in cereal-growing areas of 16 provinces and causes serious yield losses. In the present study, a total of 98 populations of were collected from major wheat-growing regions in China and six other countries. The mitochondrial COI genes were amplified and analyzed. Forty-one mitochondrial COI haplotypes were identified, suggesting a high genetic diversity and endemism level of in China. Phylogenetic analysis showed that populations in China were divided into four clades. Significant evolutionary and genetic differences were found between Chinese (except Hubei) and foreign populations. Hap1, the most widely distributed haplotype, was considered to be a separate evolutionary origin in China. The gene flow of from the northwestern region to the north China region and Huang-Huai-Hai region was significant, so as the direction between north China and Huang-Huai-Hai region. We speculate that water flowing from the Yellow River and mechanical harvesters promoted gene exchange among these groups. A distance-based redundancy analysis showed that genetic distances observed among populations were explained foremost not only by geographic distance but also by temperature and precipitation. This study provides theoretical support for the origin and spread of populations in China and elsewhere in the world.
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http://dx.doi.org/10.1094/PHYTO-12-21-0532-RDOI Listing
August 2022

Anti-Oxidative and Anti-Inflammatory Micelles: Break the Dry Eye Vicious Cycle.

Adv Sci (Weinh) 2022 06 18;9(17):e2200435. Epub 2022 Apr 18.

Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, 310009, P. R. China.

Dry eye disease (DED) impacts ≈30% of the world's population and causes serious ocular discomfort and even visual impairment. Inflammation is one core cause of the DED vicious cycle, a multifactorial deterioration in DED process. However, there are also reactive oxygen species (ROS) regulating inflammation and other points in the cycle from the upstream, leading to treatment failure of current therapies merely targeting inflammation. Accordingly, the authors develop micelle-based eye drops (more specifically p38 mitogen-activated protein kinases (MAPK) inhibitor Losmapimod (Los)-loaded and ROS scavenger Tempo (Tem)-conjugated cationic polypeptide micelles, designated as MTem/Los) for safe and efficient DED management. Cationic MTem/Los improve ocular retention of conjugated water-soluble Tem and loaded water-insoluble Los via electrostatic interaction with negatively charged mucin on the cornea, enabling an increase in therapeutic efficiency and a decrease in dosing frequency. Mechanistically, MTem/Los effectively decrease ROS over-production, reduce the expression of proinflammatory cytokines and chemokines, restrain macrophage proinflammatory phenotypic transformation, and inhibit cell apoptosis. Therapeutically, the dual-functional MTem/Los suppress the inflammatory response, reverse corneal epithelial defect, save goblet cell dysfunction, and recover tear secretion, thus breaking the vicious cycle and alleviating the DED. Moreover, MTem/Los exhibit excellent biocompatibility and tolerability for potential application as a simple and rapid treatment of oxidative stress- and inflammation-induced disorders, including DED.
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http://dx.doi.org/10.1002/advs.202200435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9189644PMC
June 2022

Heterozygous variants c.781G>A and c.1066dup of cause familial nanophthalmos by impairing serine-type endopeptidase activity.

Br J Ophthalmol 2022 Apr 5. Epub 2022 Apr 5.

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

Background/aims: Nanophthalmos is a rare developmental, bilateral, sporadic or hereditary form of microphthalmos. In this study, the heterozygous variants c.781G>A and c.1066dup of the gene were identified in two patients with nanophthalmos. This study reports the clinical manifestation and the underlying pathogenic mechanism.

Methods: Whole-exome sequencing was performed to identify the pathogenic genes in a Chinese family with nanophthalmos. The molecular simulation was used to predict the structures of wild-type or mutant PRSS56. The PRSS56 wild-type or mutation overexpression cellular models have been constructed accordingly. The subcellular localisation was then observed using immunofluorescence and Western-blot techniques. The Folin-Ciocalteu assay was carried out to evaluate serine-type endopeptidase activity, and a wound-healing assay was used to examine the cellular migratory ability.

Results: The whole-exome sequencing revealed that heterozygous variants c.781G>A and c.1066dup of the gene might contribute to nanophthalmos. Both variants were not identified in the dbSNP, 1000 Genome project or ESP6500 databases. Furthermore, the variants were highly conserved and were involved in biological functions. The mutations result in destructive protein structure and impede serine-type endopeptidase activity, thereby impairing subcellular localisation and cellular migration.

Conclusion: The c.781G>A and c.1066dup variants of the might negatively affect protein structures, subcellular localisation, serine-type endopeptidase activity and cellular migratory ability. Together, these changes could lead to the development of nanophthalmos. This study identifies the PRSS56 gene as a potential target for nanophthalmos diagnosis and treatment.
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http://dx.doi.org/10.1136/bjophthalmol-2021-320909DOI Listing
April 2022

Differential responses to immune checkpoint inhibitor dictated by pre-existing differential immune profiles in squamous cell carcinomas caused by same initial oncogenic drivers.

J Exp Clin Cancer Res 2022 Apr 2;41(1):123. Epub 2022 Apr 2.

UPMC Hillman Cancer Center, Division of Hematology and Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA.

Background: While immune checkpoint inhibitors (ICI) were approved for head and neck squamous cell carcinomas (HNSCCs), the response rate remains relatively low. Mechanisms underlying ICI unresponsiveness versus sensitivity are not fully understood.

Method: To better delineate differential responses to ICI treatment, we employed mouse SCC models, termed KPPA tumors that were caused by deleting p53 and hyperactivating PIK3CA, two most frequently mutated genes in human HNSCCs. We transplanted two KPPA tumor lines (TAb2 versus TCh3) into C57BL/6 recipients and examined the immune tumor microenvironment using flow cytometry. Furthermore, we employed single-cell RNA sequencing to identify the difference in tumor infiltrating lymphocytes (TILs).

Results: We found that different KPPA tumors exhibited heterogeneous immune profiles pre-existing treatment that dictated their sensitivity or unresponsiveness to anti-PD-L1. Unresponsive TAb2 tumors were highly enriched with functional tumor-associated macrophages (TAMs), especially M2-TAMs. In contrast, sensitive TCh3 tumors contained more CD8 TILs with better effector functions. TAb2 tumor cells drastically expanded F4/80 TAMs from bone marrow precursors, requiring CSF1 and VEGF. Consistently, a higher combined expression of VEGF-C and CSF1 predicts worse survival in PIK3CA/TP53 HNSCC patients. Unresponsive TAb2 tumors upregulated distinct signaling pathways that correlate with aggressive tumor phenotypes. While anti-PD-L1 did not affect the TME of TAb2 tumors, it significantly increased the number of CD8 TILs in TCh3 tumors.

Conclusions: We uncovered tumor-intrinsic differences that may underlie the differential responses to ICI by establishing and employing two SCC tumor lines, TAb2 vs. TCh3, both of which harbor TP53 deletion and PIK3CA hyperactivation. Our study indicates the limitation of stratifying cancers according to their genetic alterations and suggests that evaluating HNSCC tumor-intrinsic cues along with immune profiles in the TME may help better predict ICI responses. Our experimental models may provide a platform for pinpointing tumor-intrinsic differences underlying an immunosuppressive TME in HNSCCs and for testing combined immunotherapies targeting either tumor-specific or TAM-specific players to improve ICI efficacy.
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http://dx.doi.org/10.1186/s13046-022-02337-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8976353PMC
April 2022

Cataract-Causing S93R Mutant Destabilized Structural Conformation of βB1 Crystallin Linking With Aggregates Formation and Cellular Viability.

Front Mol Biosci 2022 14;9:844719. Epub 2022 Mar 14.

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

Cataract, opacity of the eye lens, is the leading cause of visual impairment worldwide. The crucial pathogenic factors that cause cataract are misfolding and aggregation of crystallin protein. βB1-crystallin, which is the most abundant water-soluble protein in mammalian lens, is essential for lens transparency. A previous study identified the missense mutation βB1-S93R being responsible for congenital cataract. However, the exact pathogenic mechanism causing cataract remains unclear. The S93 residue, which is located at the first Greek-key motif of βB1-crystallin, is highly conserved, and its substitution to Arginine severely impaired hydrogen bonds and structural conformation, which were evaluated Molecular Dynamic Simulation. The βB1-S93R was also found to be prone to aggregation in both human cell lines and . Then, we isolated the βB1-S93R variant from inclusion bodies by protein renaturation. The βB1-S93R mutation exposed more hydrophobic residues, and the looser structural mutation was prone to aggregation. Furthermore, the S93R mutation reduced the structural stability of βB1-crystallin when incubated at physiological temperature and made it more sensitive to environmental stress, such as UV irradiation or oxidative stress. We also constructed a βB1-S93R cellular model and discovered that βB1-S93R was more sensitive to environmental stress, causing not only aggregate formation but also cellular apoptosis and impaired cellular viability. All of the results indicated that lower solubility and structural stability, sensitivity to environmental stress, vulnerability to aggregation, and impaired cellular viability of βB1-S93R might be involved in cataract development.
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http://dx.doi.org/10.3389/fmolb.2022.844719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964140PMC
March 2022

A Quartet Network Analysis Identifying Mechanically Responsive Long Noncoding RNAs in Bone Remodeling.

Front Bioeng Biotechnol 2022 9;10:780211. Epub 2022 Mar 9.

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

Mechanical force, being so ubiquitous that it is often taken for granted and overlooked, is now gaining the spotlight for reams of evidence corroborating their crucial roles in the living body. The bone, particularly, experiences manifold extraneous force like strain and compression, as well as intrinsic cues like fluid shear stress and physical properties of the microenvironment. Though sparkled in diversified background, long noncoding RNAs (lncRNAs) concerning the mechanotransduction process that bone undergoes are not yet detailed in a systematic way. Our principal goal in this research is to highlight the potential lncRNA-focused mechanical signaling systems which may be adapted by bone-related cells for biophysical environment response. Based on credible lists of force-sensitive mRNAs and miRNAs, we constructed a force-responsive competing endogenous RNA network for lncRNA identification. To elucidate the underlying mechanism, we then illustrated the possible crosstalk between lncRNAs and mRNAs as well as transcriptional factors and mapped lncRNAs to known signaling pathways involved in bone remodeling and mechanotransduction. Last, we developed combinative analysis between predicted and established lncRNAs, constructing a pathway-lncRNA network which suggests interactive relationships and new roles of known factors such as H19. In conclusion, our work provided a systematic quartet network analysis, uncovered candidate force-related lncRNAs, and highlighted both the upstream and downstream processes that are possibly involved. A new mode of bioinformatic analysis integrating sequencing data, literature retrieval, and computational algorithm was also introduced. Hopefully, our work would provide a moment of clarity against the multiplicity and complexity of the lncRNA world confronting mechanical input.
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http://dx.doi.org/10.3389/fbioe.2022.780211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8959777PMC
March 2022

Restoring nuclear entry of Sirtuin 2 in oligodendrocyte progenitor cells promotes remyelination during ageing.

Nat Commun 2022 03 9;13(1):1225. Epub 2022 Mar 9.

Department of Pathology of Sir Run Run Shaw Hospital and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, Center for Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China.

The age-dependent decline in remyelination potential of the central nervous system during ageing is associated with a declined differentiation capacity of oligodendrocyte progenitor cells (OPCs). The molecular players that can enhance OPC differentiation or rejuvenate OPCs are unclear. Here we show that, in mouse OPCs, nuclear entry of SIRT2 is impaired and NAD levels are reduced during ageing. When we supplement β-nicotinamide mononucleotide (β-NMN), an NAD precursor, nuclear entry of SIRT2 in OPCs, OPC differentiation, and remyelination were rescued in aged animals. We show that the effects on myelination are mediated via the NAD-SIRT2-H3K18Ac-ID4 axis, and SIRT2 is required for rejuvenating OPCs. Our results show that SIRT2 and NAD levels rescue the aged OPC differentiation potential to levels comparable to young age, providing potential targets to enhance remyelination during ageing.
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http://dx.doi.org/10.1038/s41467-022-28844-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8907257PMC
March 2022

Emerging pro-drug and nano-drug strategies for gemcitabine-based cancer therapy.

Asian J Pharm Sci 2022 Jan 1;17(1):35-52. Epub 2021 Jul 1.

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

Gemcitabine has been extensively applied in treating various solid tumors. Nonetheless, the clinical performance of gemcitabine is severely restricted by its unsatisfactory pharmacokinetic parameters and easy deactivation mainly because of its rapid deamination, deficiencies in deoxycytidine kinase (DCK), and alterations in nucleoside transporter. On this account, repeated injections with a high concentration of gemcitabine are adopted, leading to severe systemic toxicity to healthy cells. Accordingly, it is highly crucial to fabricate efficient gemcitabine delivery systems to obtain improved therapeutic efficacy of gemcitabine. A large number of gemcitabine pro-drugs were synthesized by chemical modification of gemcitabine to improve its biostability and bioavailability. Besides, gemcitabine-loaded nano-drugs were prepared to improve the delivery efficiency. In this review article, we introduced different strategies for improving the therapeutic performance of gemcitabine by the fabrication of pro-drugs and nano-drugs. We hope this review will provide new insight into the rational design of gemcitabine-based delivery strategies for enhanced cancer therapy.
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http://dx.doi.org/10.1016/j.ajps.2021.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8888143PMC
January 2022

Construction and Biocompatibility Evaluation of Fibroin/Sericin-Based Scaffolds.

ACS Biomater Sci Eng 2022 04 1;8(4):1494-1505. Epub 2022 Mar 1.

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

Because tissue responses to implants determine the success or failure of tissue engineering products, fibroin/sericin-based scaffolds including bionic silk scaffolds, native silk fibers, fibroin fibers, and regenerated fibroin have been fabricated, and their biocompatibility was investigated. Fibroin/sericin-based scaffolds were characterized by scanning electron microscopy (SEM) and X-ray diffraction (XRD). Bionic silk scaffolds were beneficial to silk fiber formation through self-assembly. Histological and immunofluorescent staining analysis demonstrated that bionic silk scaffolds did not show significant inflammatory responses. Immunization analysis showed that soluble fibroin and sericin did not show obvious immunogenicity. This work supplied an effective approach to design fibroin/sericin-based scaffolds for tissue engineering and drug delivery.
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http://dx.doi.org/10.1021/acsbiomaterials.1c01426DOI Listing
April 2022

Letter to the Editor.

Angle Orthod 2022 03;92(2):299

Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

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http://dx.doi.org/10.2319/1945-7103-92.2.299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8887406PMC
March 2022

Lens capsule-related complications in femtosecond laser-assisted cataract surgery: a study based on video analysis.

Br J Ophthalmol 2022 Feb 1. Epub 2022 Feb 1.

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

Purpose: To analyse the occurrence and potential causes of lens capsule-related complications during femtosecond laser-assisted cataract surgery (FLACS).

Methods: This prospective consecutive cohort study included the first 1600 eyes (from 1140 consecutive patients) who received FLACS performed by the same surgeon from May 2015 to December 2018. The potential causes and characteristic signs of capsulotomy-related complications, including incomplete capsulotomies and radial anterior capsule (AC) tears, were summarised based on the agreement of two ophthalmologists after they analysed the surgical videos. Subgroup analysis was conducted to characterise the capsulotomy learning curve.

Results: Of the 1600 eyes, 52 (3.25%) had incomplete capsulotomies and 22 (1.38%) had radial AC tears. The most common causes of incomplete capsulotomies were eye tilt (16 eyes, 30.77%), air bubbles or ocular secretions at the interface (14 eyes, 26.92%) and white cataracts (7 eyes, 13.46%). Additionally, 54.55% (12/22) of AC tears were due to incomplete capsulotomy and secondary capsulorhexis. A significant difference was noted between the first 200 eyes and subsequent groups in terms of the incidence of incomplete capsulotomies. No difference was observed in the incidence of AC tears after the initial 100 procedures.

Conclusion: The most common causes of incomplete capsulotomies were eye tilt and air bubbles or ocular secretions at the interface. Secondary capsulorhexis after incomplete capsulotomy is the main risk factor for AC tears. There was a steep learning curve for laser capsulotomy in the first 100 operated eyes, as evidenced by the higher complication rate, but this stabilised after 200 procedures.
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http://dx.doi.org/10.1136/bjophthalmol-2021-320842DOI Listing
February 2022

Comparison Study of Anterior Capsule Contraction of Hydrophilic and Hydrophobic Intraocular Lenses Under the Same Size Capsulotomy.

Transl Vis Sci Technol 2022 01;11(1):24

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

Purpose: To compare anterior capsule contraction of two kinds of hydrophilic and hydrophobic acrylic intraocular lenses (IOLs) under the same size capsulotomy with femtosecond laser-assisted cataract surgery (FLACS).

Methods: A total of 320 eyes in 320 patients who underwent FLACS were included. The patients were scheduled to have hydrophilic acrylic IOLs (MI60, 509M) and hydrophobic acrylic IOLs (iSert250, ZCB00) implanted. Visual acuity and anterior segment photography using a slit lamp microscope were performed at postoperative one week, one month, three months, and one year.

Results: The contraction of the anterior capsule opening area (mm2) and circumference (mm) in the hydrophilic group were larger than that of the hydrophobic group from postoperative one week to one year (P < 0.001, P < 0.001, respectively). The postoperative contraction of the capsule opening area in MI60 was larger than in 509M (P < 0.001) and larger in 509M than in iSert250 and ZCB00 (P = 0.008, P = 0.019, respectively), but no difference was observed between iSert250 and ZCB00 (P = 0.867). During postoperative one to three months, all groups had the maximum capsule contraction (P < 0.001).

Conclusions: Under the same size capsulotomy with FLACS, the postoperative anterior capsule contraction induced by hydrophobic IOLs was less than that induced by hydrophilic IOLs. Among the four IOLs, the capsule contraction was largest in MI60, followed by 509M, and least in iSert250 and ZCB00, which was time-dependent.

Translational Relevance: Our findings implied that patients with a high risk of ACC should choose hydrophobic IOLs, as well as nonsteroidal anti-inflammatory drugs may be used for a longer period in patients with high risk of capsule contraction syndrome.
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http://dx.doi.org/10.1167/tvst.11.1.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764210PMC
January 2022

Intraocular Lens with Mussel-Inspired Coating for Preventing Posterior Capsule Opacification via Photothermal Effect.

ACS Appl Bio Mater 2021 04 19;4(4):3579-3586. Epub 2021 Mar 19.

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

Phacoemulsification with implantation of intraocular lens (IOLs) has been widely applied as a standard treatment for cataract, which is the leading cause of vision impairment. However, it still remains a critical challenge to prevent posterior capsule opacification (PCO) in terms of postoperative visual quality. Herein, we report IOLs with mussel-inspired coatings for inhibiting lens epithelial cells and then preventing PCO through photothermal conversion effect. The mussel-inspired coatings are deposited on the nonoptical surface areas of IOLs, endowing the modified IOLs with efficient photothermal conversion property. The temperature can be facilely raised to 50-60 °C for the photothermal IOLs (PT-IOLs) by near-infrared (NIR) laser irradiation at a safe intensity of 0.3 W/cm. These PT-IOLs display high capability of inhibiting lens epithelial cells (LECs) . Therefore, under routine NIR laser irradiation, New Zealand white rabbits implanted with the PT-IOLs demonstrate significantly lower evaluation of PCO (EPCO) scores than the control groups. The overall results indicate that our PT-IOLs provide a promising choice for the clinical prevention of PCO, thus opening a way to maintain the postoperative visual qualities for cataract patients.
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http://dx.doi.org/10.1021/acsabm.1c00089DOI Listing
April 2021

Cupriferous Silver Peroxysulfite Superpyramids as a Universal and Long-Lasting Agent to Eradicate Multidrug-Resistant Bacteria and Promote Wound Healing.

ACS Appl Bio Mater 2021 05 27;4(5):3729-3738. Epub 2020 Oct 27.

The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, China.

Because of the emergent evolution of multidrug-resistant (MDR) bacteria, resistance to traditional antibiotics has been increasingly causing public health concerns that it can rapidly overcome the development of antibacterial agents. Here, we demonstrated a facile electrodeposition method to prepare silver peroxysulfite (AgOHSO, AOHS) superpyramids on band-aids with extraordinary antibacterial performance. The porous structure and the sharp apex of AOHS superpyramids could facilitate the release of high-valence silver ions, which possess highly efficient MDR bacteria-killing effect and keep long-term antibacterial activity (>99% killing efficiency, recycle at least 4 times) because of their superior destruction capability of the membrane of the bacteria. A layer of copper was further evaporated onto the AOHS pyramids decorated on a band-aid, which could promote wound tissue angiogenesis and prohibit bacterial infection simultaneously, and finally accelerate the healing process in MDR bacteria-infected wound in vivo. The simple and low-cost fabrication process, as well as the outstanding antibacterial performance, make AOHS pyramids have promising applications in bacterial infection and practical sterilization fields, especially toward multidrug-resistant bacteria.
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http://dx.doi.org/10.1021/acsabm.0c00889DOI Listing
May 2021

Multivariate Classification of Brain Blood-Oxygen Signal Complexity for the Diagnosis of Children with Tourette Syndrome.

Mol Neurobiol 2022 Feb 3;59(2):1249-1261. Epub 2022 Jan 3.

Center for Psychological Sciences, Zhejiang University, Hangzhou, 310027, China.

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by the presence of multiple motor and vocal tics. Because of its varied clinical expressions and lack of reliable diagnostic biomarker, present TS diagnosis still depends on qualitative descriptions of symptoms. Our study aimed to investigate whether the complexity of resting state brain activity can serve as a potential biomarker for TS diagnosis, since it has been used successfully in various neuropsychiatric disorders, including two common TS comorbidities: attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). In the current study, we used both univariate analysis and multivariate searchlight analysis with both linear and non-linear classification methods to explore the group differences in the complexity of resting state brain blood oxygen level-dependent (BOLD) signals between 25 TS boys without comorbidity and 25 sex, age and educational years matched healthy controls (HCs). We also investigated the relation between symptom severity in TS patients (YGTSS scores) and complexity indices derived from different analysis methods. We found: i) univariate analysis revealed reduced complexity in TS patients in the left cerebellum, left superior frontal gyrus, and left medial frontal gyrus; ii) multivariate analysis with non-linear classification method achieved the highest performance (accuracy: 0.94, sensitivity: 0.96, specificity: 0.92, AUC: 0.95) in bilateral supplementary motor areas; iii) significant correlations were found between complexity index derived from multivariate analysis with non-linear classification method and Tic severity (YGTSS scores) in the left cerebellum (r = 0.523, with YGTSS phonic) and in the right supplementary motor area (r = 0.767, with YGTSS motor). Taken together, these results suggested that complexity of resting state BOLD activity is a highly effective index for differentiating TS patients from normal controls. It has a good potential to be a quantitative biomarker for TS diagnosis.
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http://dx.doi.org/10.1007/s12035-021-02707-0DOI Listing
February 2022

Development of a Species-Specific SCAR-PCR Assay for Direct Detection of Sugar Beet Cyst Nematode () from Infected Roots and Soil Samples.

Life (Basel) 2021 Dec 7;11(12). Epub 2021 Dec 7.

State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China.

Sugar beet cyst nematode (SBCN, ) is an important nematode that causes significant yield losses of 25-50% or more in most areas of sugar beet production worldwide. Rapid and accurate identification of this species is essential to support decisions on pest management. However, the difference between and other spp. based on morphology is a challenging task. In the present study, a SCAR-PCR assay was developed to identify and differentiate in infected root and soil samples. -species-specific SCAR-PCR primers OPA06-HsF and OPA06-HsR were designed from the randomly amplified polymorphic DNA (RAPD) marker amplified with random primer OPA06. The developed primers specifically amplify a 922-bp fragment from the target populations but did not amplify DNA from non-target cyst nematodes including , , , and other related species tested in this study. The sensitivity detection indicated that 5 × 10 of a single cyst, 1/320 of a single second-stage juvenile (J2), or 10 pg of genomic DNA could be detected. The assay accurately identifies the different stages of in sugar beet and oilseed rape roots as well as a single J2 in 10 g of soil. Finally, the SCAR-PCR assay detected in seven samples out of the fifteen field samples. The assay will not only be useful for differentiating from mixed populations of spp. but also for effective detection of the species directly from infested samples. The assay also requires no expertise in the taxonomy and morphology of the species but serves to improve the diagnosis of in infested fields.
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http://dx.doi.org/10.3390/life11121358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8708203PMC
December 2021

Modulation of Sirt1-mTORC1 Pathway in Microglia Attenuates Retinal Ganglion Cell Loss After Optic Nerve Injury.

J Inflamm Res 2021 14;14:6857-6869. Epub 2021 Dec 14.

Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.

Purpose: Optic nerve injury (ONI) causes neuroinflammation and neurodegeneration leading to visual deficits. The response of microglia has emerged as an impactful component of etiology in neurodegeneration. This study aimed to investigate the effect of SIRT1-mTORC1 signaling pathway in microglia regulation after ONI.

Methods: Cx3Cr1-Cre/ and Cx3Cr1-Cre/ mice were used to delete and in microglia, respectively. Optic nerve crush (ONC) model was established to mimic ONI. PLX5622, a highly specific inhibitor of the colony-stimulating factor 1 receptor (CSF1R), is used to eliminate microglia in optic nerve. Ionized calcium binding adaptor molecule 1 (Iba1) immunostaining was used to detect microglial activation. Retinal ganglion cells (RGCs) were quantified by Nissl staining and retinal whole-mount immunostaining with RNA-binding protein with multiple splicing (RBPMS). Axonal damage was valued by transmission electron microscopy (TEM).

Results: Microglial activation emerged on day 3 post ONC and was earlier than RGCs loss which occurred at day 5 after injury. Depleting microglia with PLX5622 could attenuate the loss of RGCs and axon damage after ONC. Gain- and loss-of-function studies revealed that SIRT1 determined the activation of microglia in optic nerve. In addition, microglia-specific deletion of resulted in decreased microglial activation. Interestingly, activating mTORC1 with CCT007093 could reverse the function of SIRT1 in regulating the process of microglial activation mediated RGCs loss.

Conclusion: Our study reveals a potential novel mechanism of SIRT1-mTORC1 pathway in microglia regulation, and indicates a therapeutic potential for the protection of RGCs in ONI.
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http://dx.doi.org/10.2147/JIR.S338815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684404PMC
December 2021

Exosomes-loaded thermosensitive hydrogels for corneal epithelium and stroma regeneration.

Biomaterials 2022 01 11;280:121320. Epub 2021 Dec 11.

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

Corneal damage forms scar tissue and manifests as permanent corneal opacity, which is the main cause of visual impairment caused by corneal diseases. To treat these diseases, herein, we developed a novel approach based on the exosome derived from induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) combined with a thermosensitive hydrogel, which reduces scar formation and accelerates the healing process. We found that a thermosensitive chitosan-based hydrogels (CHI hydrogel) sustained-release iPSC-MSC exosomes can effectively promote the repair of damaged corneal epithelium and stromal layer, downregulating mRNA expression coding for the three most enriched collagens (collagen type I alpha 1, collagen type V alpha 1 and collagen type V alpha 2) in corneal stroma and reducing scar formation in vivo. Furthermore, iPSC-MSCs secrete exosomes that contain miR-432-5p, which suppresses translocation-associated membrane protein 2 (TRAM2), a vital modulator of the collagen biosynthesis in the corneal stromal stem cells to avert the deposition of extracellular matrix (ECM). Our findings indicate that iPSC-MSCs secrete miRNA-containing exosomes to promote corneal epithelium and stroma regeneration, and that miR-432-5p can prevent ECM deposition via a mechanism most probably linked to direct repression of its target gene TRAM2. Overall, our exosomes-based thermosensitive CHI hydrogel, is a promising technology for clinical therapy of various corneal diseases.
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http://dx.doi.org/10.1016/j.biomaterials.2021.121320DOI Listing
January 2022

CD82 protects against glaucomatous axonal transport deficits via mTORC1 activation in mice.

Cell Death Dis 2021 12 11;12(12):1149. Epub 2021 Dec 11.

Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

Glaucoma is a leading cause of irreversible blindness worldwide and is characterized by progressive optic nerve degeneration and retinal ganglion cell loss. Axonal transport deficits have been demonstrated to be the earliest crucial pathophysiological changes underlying axonal degeneration in glaucoma. Here, we explored the role of the tetraspanin superfamily member CD82 in an acute ocular hypertension model. We found a transient downregulation of CD82 after acute IOP elevation, with parallel emergence of axonal transport deficits. The overexpression of CD82 with an AAV2/9 vector in the mouse retina improved optic nerve axonal transport and ameliorated subsequent axon degeneration. Moreover, the CD82 overexpression stimulated optic nerve regeneration and restored vision in a mouse optic nerve crush model. CD82 exerted a protective effect through the upregulation of TRAF2, which is an E3 ubiquitin ligase, and activated mTORC1 through K63-linked ubiquitylation and intracellular repositioning of Raptor. Therefore, our study offers deeper insight into the tetraspanin superfamily and demonstrates a potential neuroprotective strategy in glaucoma treatment.
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http://dx.doi.org/10.1038/s41419-021-04445-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8665930PMC
December 2021
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