Systematic bibliometric analysis of research hotspots and trends on the application of premium IOLs in the past 2 decades.

AIM: To analysis of research hotspots and trends on the application of premium intraocular lens (PIOLs) in the past 2 decades. METHODS: The literature search was performed on the Web of Science and included PIOLs studies published between January 2000 and December 2022. The retrieved literature was collated and analyzed by R-tool's Bibliometrix package, CitNetExplorer, CiteSpace and other software. RESULTS: A total of 1801 articles about PIOLs were obtained, most of which were published in Spain and the United States. The organization that published the most articles was the University of Valencia in Spain. Alió JL, and Montés-Micó R, from Spain were the most influential authors in this field. The Journal of Cataract and Refractive Surgery and Journal of Refractive Surgery were the core journals for this field; the top 10 cited articles mainly focus on postoperative satisfaction with multifocal intraocular lens (IOLs) and postoperative results of toric IOLs. Through the keyword analysis, we found that trifocal IOLs, astigmatism and extended depth of focus (EDoF) IOLs are the most discussed topics at present, and the importance of astigmatism and the clinical application of the new generation of PIOLs are the emerging research trends. CONCLUSION: Bibliometric analysis can effectively help to identify multilevel concerns in PIOLs research and the prevailing research trends in the realm of PIOLs encompass the adoption of EDoF IOLs, trifocal IOLs, and their respective Toric models.

Analysis of the Molecular Mechanism of Xueshuantong in the Treatment of Wet Age-Related Macular Degeneration (AMD) Using GEO Datasets, Network Pharmacology, and Molecular Docking.

At present, the main treatment method for wet AMD is single anti-VEGF therapy, which can require multiple injections, is costly and may have poor efficacy. Studies and clinical experiments have shown that the oral Chinese medicine Xueshuantong combined with anti-VEGF therapy is more effective, and this study aims to explore the molecular mechanism. The TCMSP database was used to identify the main Xueshuantong components. The PubChem database and SWISS Target Prediction data were used to find the SMILES molecular formulas of compounds and corresponding target genes and disease-related genes were searched using the GEO, DisGeNET, and GeneCards databases. Venny was used to identify the intersecting wet AMD-related genes and Xueshuantong targets and Cytoscape software was used to construct direct links between the drug components and disease targets. Then, PPI networks were constructed using the STRING website. R software was used for GO and KEGG enrichment analyses. Cytoscape software was used for topological analyses, and AutoDock Vina v.1.1.2 software was used for molecular docking. 64 compounds corresponding to four drugs were found by the TCMSP database, 1001 total drug targets were found by the PubChem database, 607 wet AMD target genes were found by the GEO, DisGeNET, and GeneCards databases, and 87 Xueshuantong target genes for wet AMD were obtained. Then, by constructing the drug component and disease target network and PPI network, we found that the components closely interacted with VEGF, TNF, caspase 3, CXCL8, and AKT1, which suggested that the therapeutic effects might be related to the inhibition of neovascularization, inflammation, and AKT pathway. Then, GO enrichment analysis showed that the biological processes response to hypoxia, positive regulation of angiogenesis, and inflammatory response were enriched. KEGG enrichment results showed that the HIF-1 and pi3k-akt pathways may mediate the inhibition of wet AMD by Xueshuantong. Topological analysis results identified 10 key proteins, including VEGF, TNF, AKT1, and TLR4. The results of molecular docking also confirmed their strong binding to their respective compounds. In this study, it was confirmed that Xueshuantong could inhibit wet AMD by targeting VEGF, TNF, TLR4, and AKT1, multichannel HIF-1, and the PI3K-AKT pathway, which further proved the therapeutic effects of Xueshuantong combined with single anti-VEGF therapy on wet AMD and provided new insights into the study of novel molecular drug targets for the treatment of wet AMD.

Comparison of the accuracy of 9 intraocular lens power calculation formulas after SMILE in Chinese myopic eyes.

As of 2021, over 2.8 million small-incision lenticule extraction (SMILE) procedures have been performed in China. However, knowledge regarding the selection of intraocular lens (IOL) power calculation formula for post-SMILE cataract patients remains limited. This study included 52 eyes of 26 myopic patients from northern China who underwent SMILE at Tianjin Eye Hospital from September 2022 to February 2023 to investigate the suitability of multiple IOL calculation formulas in post-SMILE patients using a theoretical surgical model. We compared the postoperative results obtained from three artificial intelligence (AI)-based formulas and six conventional formulas provided by the American Society of Cataract and Refractive Surgery (ASCRS). These formulas were applied to calculate IOL power using both total keratometry (TK) and keratometry (K) values, and the results were compared to the preoperative results obtained from the Barrett Universal II (BUII) formula for the SMILE patients. Among the evaluated formulas, the results obtained from the Emmetropia Verifying Optical 2.0 Formula with TK (EVO-TK) (0.40 ± 0.29 D, range 0-1.23 D), Barrett True K with K formula (BTK-K, 0.41 ± 0.26 D, range 0.01-1.19 D), and Masket with K formula (Masket-K, 0.44 ± 0.33 D, range 0.02-1.39 D) demonstrated the closest proximity to BUII. Notably, the highest proportion of prediction errors within 0.5 D was observed with the BTK-K (71.15%), EVO-TK (69.23%), and Masket-K (67.31%), with the BTK-K showing a significantly higher proportion than the Masket-K (p < 0.001). Our research indicates that in post-SMILE patients, the EVO-TK, BTK-K, and Masket-K may yield more accurate calculation results. At their current stage in development, AI-based formulas do not demonstrate significant advantages over conventional formulas. However, the application of historical data can enhance the performance of these formulas.

Comparative analysis of IOL power calculations in postoperative refractive surgery patients: a theoretical surgical model for FS-LASIK and SMILE procedures.

BACKGROUND: As the two most prevalent refractive surgeries in China, there is a substantial number of patients who have undergone Femtosecond Laser-assisted In Situ Keratomileusis (FS-LASIK) and Small Incision Lenticule Extraction (SMILE) procedures. However, there is still limited knowledge regarding the selection of intraocular lens (IOL) power calculation formulas for these patients with a history of FS-LASIK or SMILE. METHODS: A total of 100 eyes from 50 postoperative refractive surgery patients were included in this prospective cohort study, with 25 individuals (50 eyes) having undergone FS-LASIK and 25 individuals (50 eyes) having undergone SMILE. We utilized a theoretical surgical model to simulate the IOL implantation process in postoperative FS-LASIK and SMILE patients. Subsequently, we performed comprehensive biological measurements both before and after the surgeries, encompassing demographic information, corneal biometric parameters, and axial length. Various formulas, including the Barrett Universal II (BUII) formula, as a baseline, were employed to calculate IOL power for the patients. RESULTS: The Barrett True K (BTK) formula, demonstrated an mean absolute error (AE) within 0.5 D for both FS-LASIK and SMILE groups (0.28 ± 0.25 D and 0.36 ± 0.24 D, respectively). Notably, the FS-LASIK group showed 82% of results differing by less than 0.25 D compared to preoperative BUII results. The Barrett True K No History (BTKNH) formula, which also incorporates measured posterior corneal curvature, performed similarly to BTK in both groups. Additionally, the Masket formula, relying on refractive changes based on empirical experience, displayed promising potential for IOL calculations in SMILE patients compared with BTK (p = 0.411). CONCLUSION: The study reveals the accuracy and stability of the BTK and BTKNH formulas for IOL power calculations in myopic FS-LASIK/SMILE patients. Moreover, the Masket formula shows encouraging results in SMILE patients. These findings contribute to enhancing the predictability and success of IOL power calculations in patients with a history of refractive surgery, providing valuable insights for clinical practice. Further research and larger sample sizes are warranted to validate and optimize the identified formulas for better patient outcomes.

Clinical characteristics and the prognosis of diabetic foot in Tibet: A single center, retrospective study.

The objective of this study was to explore the clinical characteristics and prognosis of diabetic foot in hospitalized patients with diabetes in Tibet. To achieve that, patients hospitalized in People's Hospital of Tibet Autonomous Region and diagnosed with diabetic foot ulcer (DFU) from January 1, 2016 to December 31, 2020 were enrolled in the study, and DFU cases of Peking University First Hospital were collected as control group. Analysis and comparison of clinical characteristics of DFU in plateau and plain areas were conducted. Normal distribution data or non-normal distribution data between groups were analyzed by t-test analysis or the nonparametric Mann-Whitney U test, and categorical variants were compared by Chi-square of Pearson. A total of 54 DFU cases were enrolled in the study in the People's Hospital of Tibet Autonomous Region (Tibet group for short). Males accounted for 83.3% (45 cases) in Tibet group, which was higher than that of Peking University First Hospital (Beijing group for short), which accounted for 67.0%. Compared with the DFU patients in the Beijing group, the Tibet group was younger (58.11 ± 12.25 years vs 64.18 ± 11.37 years, P < 0.05), with a shorter disease duration (7.00 years vs 12.00 years, P < 0.05). In contrast, alcohol consumption was higher in the Tibet group (44.4 vs 27.4%, P < 0.05), and the number of patients with smoking habit was higher in the Beijing group (29.6 vs 43.7%, P < 0.05). The Tibet group had higher HbA1c (10.2 vs 8.7%, P < 0.05) and lower DFU proportion (22.2 vs 44.2%, P < 0.05). There was no statistically significant difference in the proportion of moderate to severe infections between the two groups (58.5 vs 59.6%, P = 0.887). Leukocytes (6.75 × 109/L vs 8.72 × 109/L, P < 0.05) and neutrophils (4.07 × 109/L vs 6.26 × 109/L, P < 0.05) in Tibet group were lower. Although the DFU amputation rate in the Tibet group was lower than that in the Beijing group (9.3 vs 29.8%, P < 0.05), there was no statistically significant difference between the two groups in terms of treatment cost, hospital stay, and mortality. In conclusion, patients with DFU in Tibet had a smaller age, shorter duration of diabetes, and more male predominance. The proportions of gangrene and amputation were lower in Tibet, with gangrene accounting for 80% of all amputees.

Type I Collagen-Adhesive and ROS-Scavenging Nanoreactors Enhanced Retinal Ganglion Cell Survival in an Experimental Optic Nerve Crush Model.

Traumatic optic neuropathy (TON) is a severe condition characterized by retinal ganglion cell (RGC) death, often leading to irreversible vision loss, and the death of RGCs is closely associated with oxidative stress. Unfortunately, effective treatment options for TON are lacking. To address this, catalase (CAT) is encapsulated in a tannic acid (TA)/poly(ethylenimine)-crosslinked hollow nanoreactor (CAT@PTP), which exhibited enhanced anchoring in the retina due to TA-collagen adhesion. The antioxidative activity of both CAT and TA synergistically eliminated reactive oxygen species (ROS) to save RGCs in the retina, thereby treating TON. In vitro experiments demonstrated that the nanoreactors preserve the enzymatic activity of CAT and exhibit high adhesion to type I collagen. The combination of CAT and TA-based nanoreactors enhanced ROS elimination while maintaining high biocompatibility. In an optic nerve crush rat model, CAT@PTP is effectively anchored to the retina via TA-collagen adhesion after a single vitreous injection, and RGCs are significantly preserved without adverse events. CAT@PTP exhibited a protective effect on retinal function. Given the abundance of collagen that exists in ocular tissues, these findings may contribute to the further application of this multifunctional nanoreactor in ocular diseases to improve therapeutic efficacy and reduce adverse effects.

Arginase-1 promotes lens epithelial-to-mesenchymal transition in different models of anterior subcapsular cataract.

BACKGROUND: Arginase-1 (ARG1) promotes collagen synthesis and cell proliferation. ARG1 is highly expressed in various tumour cells. The mechanisms of ARG1 in epithelial-to-mesenchymal transition (EMT)-associated cataracts were studied herein. METHODS: C57BL/6 mice, a human lens epithelial cell line (HLEC-SRA01/04), and human lens capsule samples were used in this study. The right lens anterior capsule of the mouse eye was punctured through the central cornea with a 26-gauge hypodermic needle. Human lens epithelial cells (HLECs) were transfected with ARG1-targeted (siARG1) or negative control siRNA (siNC). For gene overexpression, HLECs were transfected with a plasmid bearing the ARG1 coding sequence or an empty vector. Medium containing 0.2% serum with or without transforming growth factor beta-2 (TGF-ß2) was added for 6 or 24 h to detect mRNA or protein, respectively. The expression of related genes was measured by quantitative real-time polymerase chain reaction (RT-qPCR), western blotting, and immunohistochemical staining. Transwell assays and wound healing assays were used to determine cell migration. Cell proliferation, superoxide levels, nitric oxide (NO) levels, and arginase activity were estimated using Cell Counting Kit-8 assays, a superoxide assay kit, an NO assay kit, and an arginase activity kit. RESULTS: ARG1, alpha-smooth muscle actin (α-SMA), fibronectin, and Ki67 expression increased after lens capsular injury, while zonula occludens-1 (ZO-1) expression decreased. Fibronectin and collagen type I alpha1 chain (collagen 1A1) expression increased, and cell migration increased significantly in ARG1-overexpressing HLECs compared with those transfected with an empty vector after TGF-ß2 treatment. These effects were reversed by ARG1 knockdown. The arginase-related pathway plays an important role in EMT. mRNAs of enzymes of the arginase-related pathway were highly expressed after ARG1 overexpression. ARG1 knockdown suppressed these expression changes. Numidargistat (CB-1158) dihydrochloride (CB-1158), an ARG1 inhibitor, suppressed TGF-ß2-induced anterior subcapsular cataract (ASC) by reducing the proliferation of lens epithelial cells (LECs) and decreasing fibronectin, α-SMA, collagen 1A1, and vimentin expression. Compared with that in nonanterior subcapsular cataract (non-ASC) patients, the expression of ARG1, collagen 1A1, vimentin, fibronectin, and Ki67 was markedly increased in ASC patients. CONCLUSIONS: ARG1 can regulate EMT in EMT-associated cataracts. Based on the pathogenesis of ASC, these findings are expected to provide new therapeutic strategies for patients.

Fibrotic cataracts can be classified as anterior subcapsular cataract or posterior capsular opacification depending on where fibrosis occurs. The mechanism of fibrotic cataracts is not fully understood. Fibrotic opacities induced by trauma, inflammation, or radiation can accumulate underneath the anterior lens capsule, causing anterior subcapsular cataract. Posterior capsular opacification is one of the most common complications of phacoemulsification with intraocular lens implantation, with a high incidence in young patients. We show for the first time that ARG1 can regulate EMT in fibrotic cataracts. TGF-ß2 is the main cause of fibrosis in LECs. The expression of ARG1 and fibronectin in LECs increased after TGF-ß2 treatment or mouse lens capsular injury. We investigated the specific molecular mechanisms by which ARG1 regulates EMT in fibrotic cataracts. The mRNA expression of enzymes of the arginase-related pathway was decreased due to knockdown of ARG1 expression in HLECs. These effects were reversed by ARG1 overexpression. Additionally, knockdown of ARG1 decreased collagen 1A1, fibronectin, and vimentin expression; superoxide levels; and cell migration and increased NO levels. These effects were reversed by ARG1 overexpression. Pharmacological blockade of the ARG1 pathway with CB-1158 reduced the proliferation of LECs and decreased fibronectin, α-SMA, collagen 1A1, and vimentin expression in mouse lenses. We believe that ARG1 promotes the production of collagen 1A1 by directly activating the arginase pathway and leads to lens fibrosis by reducing NO production and increasing superoxide levels, providing a new mechanism for the prevention and treatment of fibrotic cataracts. Video Abstract.

Bibliometric analysis of the Vogt‒Koyanagi‒Harada disease literature.

PURPOSE: As an autoimmune disease, Vogt‒Koyanagi‒Harada disease (VKHD) is a main type of uveitis in many countries and regions, significantly impacting patient vision. At present, information regarding VKHD is still limited, and further research is needed. We conducted a bibliometric analysis to characterize the overall status, current trends, and current focus of VKHD research. METHOD: Literature published from 1975 to 2022 was obtained from the Web of Science core collection and analysed with the R-language packages Bibliometrix, VOSviewer, and CiteSpace software. RESULTS: A total of 1050 papers on VKHD were retrieved from 261 journals, and 16,084 references were obtained from the papers in the original search. The average annual number of published articles was approximately 21.9, and the number of publications rapidly increased after 2004. The journal Ocular Immunology and Inflammation published the most papers on VKHD, while the American Journal of Ophthalmology has the highest citation frequency. The leading countries were Japan, China (PRC), and the United States of America (USA). Yang PZ from Chongqing Medical University was the most prolific and cited author. The most frequently cited study discussed revision of VKHD diagnostic criteria. An analysis of the highest frequency keywords showed that most research focused on the treatment, diagnosis, and pathogenesis of VKHD and its relationship with other related diseases. At present, the most urgent research direction is in the relationship between COVID-19 or COVID-19 vaccines and VKHD and the corresponding mechanisms underlying it. CONCLUSION: Utilizing dynamic and visualization tools, bibliometrics provides a clear depiction of the research history, development trends, and research hotspots in VKHD It serves as a valuable tool for identifying research gaps and areas that necessitate further exploration. Our study revealed potential directions for future VKHD research, including investigating specific molecular mechanisms underlying the disease, exploring the clinical utility of optical coherence tomography angiography and other diagnostic techniques, and conducting clinical research on novel therapeutic drugs.

Changes of dysfunctional lens index before and after implantable collamer lens V4c implantation in patients with moderate-to-high myopia.

BACKGROUND: Dysfunctional lens index (DLI) changing is rarely reported after implantable collamer lens (ICL) implantation. In the current research, we hope to investigate the changes of DLI by ray-tracing aberrometry before and after implantation of the posterior chamber phakic implantable collamer lens with a central artificial hole for patients with moderate-to-high myopia. METHODS: This retrospective, observational case series included 206 eyes of 104 patients with moderate-to-high myopia who underwent ICL V4c implantation. Data were collected on ocular indicators preoperatively and at 1 day, 1, 3, and 6 months postoperatively. The i-Trace Visual Functional Analyzer was used to assess the DLI measurement. RESULTS: The overall values of safety index and efficacy index were both more than 1. Preoperatively, the mean spherical equivalent (SE) of included 206 eyes was - 10.77 ± 3.46 diopter (D). Then at 1-day postoperation, the mean SE was - 0.22 ± 0.55 D, and barely changed from 1 day to 6 months postoperatively. Although the endothelial parameters had no significant differences between preoperation and postoperation, the mean loss of endothelial cells was 0.74 ± 0.98% at 6 months. Regarding the vault, there was a significant difference between each time of follow-up (P < 0.001). The mean of the vault decreased 109.6 ± 13.5 µm from 1-day post-op to 6 months post-op. The DLI values were 3.70, 9.26, 10.00, and 9.68 at baseline, 1, 3, and 6 months, respectively (P < 0.001), but no significant differences were found between 1, 3, and 6 months postoperatively (P > 0.05). The preoperative lnDLI showed a significant positive linear correlation (r = 0.621, P < 0.001) with the preoperative spherical equivalent (SE). The lnDLI was negatively correlated with the axial length (r = - 0.462, P < 0.001), corneal thickness (r = - 0.207, P = 0.003), preoperative LogMAR UDVA (r = - 0.189, P = 0.006), and preoperative LogMAR CDVA (r = - 0.306, P < 0.001). CONCLUSIONS: The postoperative refractive parameters were confirmed excellent in efficacy, predictability, and stability in half a year. The DLI was significantly improved after the ICL V4c implantation in patients with moderate-to-high myopia and showed good stability during the follow-up periods. The DLI deserves a more comprehensive understanding and application in clinical services.

A positive feedback cycle between the alarmin S100A8/A9 and NLRP3 inflammasome-GSDMD signalling reinforces the innate immune response in Candida albicans keratitis.

OBJECTIVE: Fungal keratitis is a severe sight-threatening ocular infection, without effective treatment strategies available now. Calprotectin S100A8/A9 has recently attracted great attention as a critical alarmin modulating the innate immune response against microbial challenges. However, the unique role of S100A8/A9 in fungal keratitis is poorly understood. METHODS: Experimental fungal keratitis was established in wild-type and gene knockout (TLR4-/- and GSDMD-/-) mice by infecting mouse corneas with Candida albicans. The degree of mouse cornea injuries was evaluated by clinical scoring. To interrogate the molecular mechanism in vitro, macrophage RAW264.7 cell line was challenged with Candida albicans or recombinant S100A8/A9 protein. Label-free quantitative proteomics, quantitative real-time PCR, Western blotting, and immunohistochemistry were conducted in this research. RESULTS: Herein, we characterized the proteome of mouse corneas infected with Candida albicans and found that S100A8/A9 was robustly expressed at the early stage of the disease. S100A8/A9 significantly enhanced disease progression by promoting NLRP3 inflammasome activation and Caspase-1 maturation, accompanied by increased accumulation of macrophages in infected corneas. In response to Candida albicans infection, toll-like receptor 4 (TLR4) sensed extracellular S100A8/A9 and acted as a bridge between S100A8/A9 and NLRP3 inflammasome activation in mouse corneas. Furthermore, the deletion of TLR4 resulted in noticeable improvement in fungal keratitis. Remarkably, NLRP3/GSDMD-mediated macrophage pyroptosis in turn facilitates S100A8/A9 secretion during Candida albicans keratitis, thus forming a positive feedback cycle that amplifies the proinflammatory response in corneas. CONCLUSIONS: The present study is the first to reveal the critical roles of the alarmin S100A8/A9 in the immunopathology of Candida albicans keratitis, highlighting a promising approach for therapeutic intervention in the future.

Fine-tuning the sequential drug release of nano-formulated mutual prodrugs dictates the combination effects.

The maintenance of robust ratiometric loading of dual therapeutic agents and fine-tuning release kinetics for consistent in vitro and in vivo optimization of combination effects is vital for discovering new anticancer drug combinations and remains challenging. Smart nanomedicine strategies have been investigated for this purpose, but most of the reported strategies focus either on ratiometric delivery or on unimodal sequential release of the two different agents, which hampers effective optimization of combination effects. Herein we report a sequential drug release system based on nanoformulated mutual prodrugs constructed by the formation of ketal linkages with different acid sensitivities, thus enabling the acid-triggered release of two anticancer drugs, paclitaxel and gemcitabine, in various sequences. We found that in several cell lines, the sequence of drug release substantially affected the combination effects; specifically, in A549 cells, time-staggered release profiles showed enhanced synergistic effects relative to those of a simultaneous release profile. Moreover, in vivo assessment of the antitumor efficacy of the nanoformulations in A549 xenograft models indicated that the best therapeutic effects were obtained with time-staggered release profiles, which was consistent with the in vitro results. Our strategy for precisely controlled sequential drug release can be expected to facilitate the screening of optimal drug combinations and maximize combination effects both in vitro and in vivo.

Effects of intraocular lens anterior edge design on anterior capsule morphology changes following femtosecond laser-assisted capsulotomy.

PURPOSE: To compare morphological changes in the anterior capsule of two intraocular lenses (IOLs) with different anterior edge designs 6 months after femtosecond laser-assisted capsulotomy surgery (FLACs). METHODS: This study included 168 eyes from168 patients undergoing FLACs. Group A included 74 eyes from 74 patients who had an Acrysof IQ Restor SN6AD3 IOL implantation with a flat anterior edge and Group B included 94 eyes of 94 patients with a TECNIS Multifocal ZMB00 IOL implantation and a "peak-like" anterior edge. All patients were followed up for 6 months. We assessed anterior capsule morphological changes including variation of anterior opening diameters and lens epithelial cell (LEC) proliferation in four directions, variation of anterior opening area, and the level of anterior capsule opacification (ACO). RESULTS: Variation of anterior opening diameters in 4 directions were significantly lower in Group B (P < 0.05). Obvious shrinkage ratio of anterior opening diameters and contraction of anterior opening area (P < 0.05) appeared in Group A. LEC proliferation was along the "peak" in Group B, while it spread to the edge of anterior capsule in Group A. ACO grades 6 months after operation in Groups A and B were as follows: grade I in 28.38% and 82.98% of eyes, grade II in 51.35% and 17.02% of eyes, and grade III in 20.27% and 0% of eyes, respectively. CONCLUSIONS: These findings suggest that a "peak-like" IOL anterior edge design played an important role in maintaining the morphology of anterior capsule in the early postoperative stage.

Long-acting acid-sensitive ketal-linked dexamethasone microcrystals for treating experimental autoimmune uveitis.

Corticosteroids have for some time been used as first-line drugs for the topical treatment of noninfectious uveitis, but poor ocular bioavailability and the rapid clearance of eye drops necessitate frequent dosing, reducing patient compliance. In this study, we used an acid-sensitive stearoxyl-ketal-dexamethasone pro-drug microcrystals (SKD MCs), which is consistently safe and effective in the control of uveitis inflammation in rats. We used a rat model of experimental autoimmune uveitis (EAU) to evaluate the effects of SKD MCs in terms of clinical manifestations, molecular biology, pathological histology, and visual electrophysiology compared to dexamethasone sodium phosphate injection or phosphate-buffered saline. SKD MCs significantly reduced inflammation in EAU, improved the ability to suppress inflammatory cytokines and to protect retinal function, and significantly reduced retinal microglia activation, with no increase in intraocular pressure throughout the treatment. Our results indicate that the SKD MCs formulation holds promise as a new strategy for the treatment of noninfectious uveitis and potentially other ocular inflammatory diseases.

Microcrystals of Ketal-Linked Paliperidone Prodrugs for Long-Acting Antipsychotics.

Intramuscularly injectable long-acting prodrug-based microcrystals (MCs) are of particular interest for chronic disease management. Nevertheless, current prevalently used linkers degraded by enzymes have the potential drawback of substantial differences in enzyme levels between individuals. Here, we reported the synthesis of a stearyl-modified paliperidone prodrug (SKP) with an acid-sensitive ketal linker for developing long-acting MC antipsychotics. SKP-MCs of three different sizes were prepared and systematically examined. We found that paliperidone exposure in SKP-MC-treated rats was prolonged compared with that in rats treated with the commercial antipsychotic Invega Sustenna and that the drug release rate decreased with increasing MC size. In inflammation-inhibition-model rats, paliperidone release from the SKP-MCs was considerably decreased, indicating that the immune-mediated foreign-body response after intramuscular administration boosted paliperidone release. Our findings will provide valuable insights into in vivo drug release from prodrug-based MC formulations. The ketal-linked prodrug strategy might be a new solution for developing long-acting prodrug formulations of hydroxyl-group-bearing drugs.

Roles of pattern recognition receptors in response to fungal keratitis.

Fungal keratitis is one of the leading causes of blindness worldwide, which has become an increasingly serious threat to public ocular health, but no effective treatment strategies are available now. Pattern recognition receptors (PRRs) of the innate immune system are the first line of host defense against fungal infections. They could recognize pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) and trigger an array of inflammatory responses. Over the last decades, research has resulted in significant progress regarding the roles of PRRs in fungal keratitis. This review will highlight the importance of several pattern recognition receptors (C-type lectin-like receptors, Toll-like receptors, and NOD-like receptors) in regulating the innate immunity under fungal keratitis and describe the crosstalk and collaboration in PRRs contributing to disease pathology. Meanwhile, some potential therapy-based PRRs against corneal fungal infections are discussed.

Risk Factors for Diabetic Peripheral Neuropathy, Peripheral Artery Disease, and Foot Deformity Among the Population With Diabetes in Beijing, China: A Multicenter, Cross-Sectional Study.

Diabetic peripheral neuropathy (DPN), peripheral artery disease (PAD), and foot deformity are the most common causes of diabetic foot, which can considerably worsen the patient's quality of life. In this study, we aimed to investigate the prevalence and risk factors associated with DPN, PAD, and foot deformity among patients with diabetes living in Beijing, China. In total, 3,898 diabetes patients from 11 hospitals in Beijing were evaluated using questionnaires and physical examinations, and 3,758 patients were included in the analysis. We compared the demographic, clinical, biological characteristics, and comorbidities of patients with and without DPN, PAD, or foot deformity, and used binary logistic regression analysis to identify potential factors associated with these outcomes. Overall, 882 patients (23.5%) had DPN, 437 patients (11.6%) had PAD, and 1,117 patients (29.7%) had foot deformities, including callus. The risk factors for DPN included: age ≥40 years, a ≥10+year duration of diabetes, a body mass index of <18.5 kg/m2 or ≥24 kg/m2, a systolic blood pressure (SBP) of ≥140 mm Hg, a hemoglobin A1c (HbA1c) level of ≥7%, chronic kidney disease, and cerebrovascular disease. The risk factors for PAD included: a 15+ year diabetes duration, a body mass index of <18.5 kg/m2, a SBP of ≥140 mm Hg, a HbA1c level of ≥7%, chronic kidney disease, coronary heart disease, and cerebrovascular disease. The risk factors for skeletal foot deformities included: women, age ≥40 years, a SBP ≥140 mm Hg, and hyperlipidemia. The risk factors for callus formation included: women, a SBP ≥140 mm Hg, and hyperlipidemia. In conclusion, the prevalence of foot deformities was higher than DPN and PAD in patients with diabetes. Managing the risk factors for DPN, PAD, and foot deformity is important for reducing the risk of diabetic foot.

Improved glycaemic control and weight benefit with iGlarLixi versus insulin glargine 100 U/mL in Chinese people with type 2 diabetes advancing their therapy from basal insulin plus oral antihyperglycaemic drugs: Results from the LixiLan-L-CN randomized controlled trial.

AIMS: To evaluate the efficacy and safety of iGlarLixi compared with iGlar in Chinese adults with type 2 diabetes advancing therapy from basal insulin ± oral antihyperglycaemic drugs. MATERIALS AND METHODS: LixiLan-L-CN (NCT03798080) was a 30-week randomized, active-controlled, open-label, parallel-group, multicentre study. Participants were randomized 1:1 to iGlarLixi or iGlar. The primary objective was to show the superiority of iGlarLixi over iGlar in glycated haemoglobin (HbA1c) change from baseline to Week 30. RESULTS: In total, 426 participants were randomized to iGlarLixi (n = 212) or iGlar (n = 214). Mean age was 58 years, 67% had a body mass index ≥24 kg/m2 , corresponding to overweight/obesity, and the mean diabetes duration was 12.3 years. From mean baseline HbA1c of 8.1% in both groups, greater decreases were seen with iGlarLixi versus iGlar [least squares mean difference: -0.7 (95% confidence interval: -0.9, -0.6)%; p < .0001] to final HbA1c of 6.7% and 7.4%, respectively. HbA1c <7.0% achievement was greater with iGlarLixi (63.3%) versus iGlar (29.9%; p < .0001). Mean body weight decreased with iGlarLixi and increased with iGlar [least squares mean difference: -0.9 (95% confidence interval: -1.4, -0.5) kg; p = .0001]. Hypoglycaemia incidence was similar between groups. Few gastrointestinal adverse events occurred (rated mild/moderate) with a slightly higher incidence with iGlarLixi than iGlar. CONCLUSIONS: iGlarLixi provided better glycaemic control and facilitated more participants to reach glycaemic targets alongside beneficial effects on body weight, no additional risk of hypoglycaemia, and few gastrointestinal AEs, supporting iGlarLixi use as an efficacious and well tolerated therapy option in Chinese people with long-standing T2D advancing therapy from basal insulin.

AIP1 suppresses neovascularization by inhibiting the NOX4-induced NLRP3/NLRP6 imbalance in a murine corneal alkali burn model.

BACKGROUND: Apoptosis signal-regulating kinase 1-interacting protein 1 (AIP1) participates in inflammatory neovascularization induction. NADPH oxidase 4 (NOX4) produces reactive oxygen species (ROS), leading to an imbalance in nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) and NLR family pyrin domain containing 6 (NLRP6) expression. The mechanisms of AIP1, NOX4, ROS and inflammasomes in corneal neovascularization were studied herein. METHODS: C57BL/6 and AIP1-knockout mice were used in this study. The alkali burn procedure was performed on the right eye. Adenovirus encoding AIP1 plus green fluorescence protein (GFP) (Ad-AIP1-GFP) or GFP alone was injected into the right anterior chamber, GLX351322 was applied as a NOX4 inhibitor, and then corneal neovascularization was scored. The expression of related genes was measured by quantitative real-time polymerase chain reaction, western blotting and immunofluorescence staining. 2',7'-Dichlorofluorescin diacetate staining was used to determine the ROS levels. RESULTS: The expression of AIP1 was decreased, while that of cleaved interleukin-1ß (clv-IL-1ß) and vascular endothelial growth factor A (VEGFa) was increased after alkali burn injury. NOX4 expression was increased, the imbalance in NLRP3/NLRP6 was exacerbated, and corneal neovascularization was increased significantly in AIP1-knockout mice compared with those in C57BL/6 mice after alkali burns. These effects were reversed by AIP1 overexpression. NLRP3/NLRP6 expression was imbalanced after alkali burns. GLX351322 reversed the imbalance in NLRP3/NLRP6 by reducing the ROS levels. This treatment also reduced the expression of clv-IL-1ß and VEGFa, suppressing neovascularization. CONCLUSIONS: AIP1 and NOX4 can regulate corneal inflammation and neovascularization after alkali burn injury. Based on the pathogenesis of corneal neovascularization, these findings are expected to provide new therapeutic strategies for patients. Corneal alkali burn injury is a common type of ocular injury that is difficult to treat in the clinic. The cornea is a clear and avascular tissue. Corneal neovascularization after alkali burn injury is a serious complication; it not only seriously affects the patient's vision but also is the main reason for failed corneal transplantation. Corneal neovascularization affects approximately 1.4 million patients a year. We show for the first time that AIP1 and NOX4 can regulate corneal inflammation and neovascularization after alkali burns. The expression of AIP1 was decreased, while that of clv-IL-1ß and VEGFa was increased after alkali burns. We tried to elucidate the specific molecular mechanisms by which AIP1 regulates corneal neovascularization. NOX4 activation was due to decreased AIP1 expression in murine corneas with alkali burns. NOX4 expression was increased, the imbalance in NLRP3/NLRP6 was exacerbated, and corneal neovascularization was increased significantly in AIP1-knockout mice compared with those in C57BL/6 mice after alkali burns. These effects were reversed by AIP1 overexpression. Additionally, NLRP3/NLRP6 expression was unbalanced, with NLRP3 activation and NLRP6 suppression in the corneal alkali burn murine model. Eye drops containing GLX351322, a NOX4 inhibitor, reversed the imbalance in NLRP3/NLRP6 by reducing ROS expression. This treatment also reduced the expression of clv-IL-1ß and VEGFa, reducing neovascularization. Therefore, we provide new gene therapeutic strategies for patients. With the development of neovascularization therapy, we believe that in addition to corneal transplantation, new drug or gene therapies can achieve better results. Video Abstract.

NLRP3 Inflammasome-Mediated Pyroptosis Pathway Contributes to the Pathogenesis of Candida albicans Keratitis.

Purpose: Fungal keratitis is a sight-threatening corneal infection caused by fungal pathogens, and the pathogenic mechanisms have not been fully elucidated. The aim of this study was to determine whether NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis contributes to Candida albicans (C. albicans) keratitis and explore the underlying mechanism. Methods: An in vivo mouse model of C. albicans keratitis and an in vitro culture model of human corneal epithelial cells (HCECs) challenged with heat-killed C. albicans (HKCA) were established in this study. The degree of corneal infection was evaluated by clinical scoring. Gene expression was assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis or immunofluorescence staining was performed to evaluate protein expression. TdT-mediated dUTP nick end labeling (TUNEL) staining was performed to examine the pyroptotic cell death. A lactate dehydrogenase (LDH) release assay was performed to assess cytotoxicity. Results: Compared with the mock-infected group, we observed that the mRNA levels of NLRP3, caspase-1 (CASP1), interleukin (IL)-1ß and gasdermin-D (GSDMD) in C. albicans-infected mice cornea was significantly increased. Our data also demonstrated that the protein expression of NLRP3 and the pyroptosis-related markers apoptosis-associated speck-like protein containing a CARD (ASC), cleaved CASP1, N-GSDMD, cleaved IL-1ß and cleaved IL-18 as well as pyroptotic cell death were dramatically elevated in the mouse model of C. albicans keratitis. More importantly, NLRP3 knockdown markedly alleviated pyroptosis and consequently reduced corneal inflammatory reaction in C. albicans keratitis. In vitro, the presence of activated NLRP3 inflammasome and pyroptotic cell death were validated in HCECs exposed to HKCA. Furthermore, the potassium (K+) channel inhibitor glyburide decreased LDH release and suppressed NLRP3 inflammasome activation and pyroptosis in HCECs exposed to HKCA. Conclusion: In conclusion, the current study revealed for the first time that NLRP3 inflammasome activation and pyroptosis occur in C. albicans-infected mouse corneas and HCECs. Moreover, NLRP3 inflammasome-mediated pyroptosis signaling is involved in the disease severity of C. albicans keratitis. Therefore, This NLRP3 inflammasome-dependent pathway may be an attractive target for the treatment of fungal keratitis.

NLRP3 and NLRP6 expression in pterygium and normal conjunctiva and their relationship with pterygium formation and recurrence.

PURPOSE: This study aimed to explore the pterygium formation and recurrence, by detecting the expression of Nod-like receptor pyrin domain 3 (NLRP3) and Nod-like receptor pyrin domain 6 (NLRP6) in pterygium and evaluate the correlation between NLRP3 and NLRP6 in pterygium. METHODS: In this prospective study, the expression levels of NLRP3 and NLRP6, with their related effectors, were evaluated in primary pterygium (n = 40) and recurrent pterygium (n = 32) tissue samples and compared with normal conjunctiva (n = 11) tissue samples by immunohistochemistry. RESULTS: Compared to the normal conjunctiva group, the expression levels of NLRP3, caspase-1, IL-18, and IL-1ß, were significantly higher, and NLRP6 showed an expression that was significantly lower in pterygium tissue samples (P < 0.05, respectively). Compared to the primary pterygium group, the expression levels of NLRP3, caspase-1, IL-18 and IL-1ß were significantly higher, and NLRP6 showed an expression that was significantly lower in recurrent pterygium tissue samples (P < 0.05, respectively).There was a negative correlation between NLRP3 expression and NLRP6 expression in normal conjunctival (r = -0.739, P = 0.009) and pterygium (r = -0.533, P = 0.000). CONCLUSIONS: NLRP3 and NLRP6 may be involved in the formation and recurrence of pterygium. NLRP6 may play an anti-inflammatory role in normal conjunctival tissue to maintain conjunctival homeostasis.