Comparison of rotational stability of the Implantable Collamer Lens after using a vertical or horizontal implanting orientation.

PURPOSE: To compare rotational stability of the Implantable Collamer Lens (ICL) between horizontal and vertical implantation. SETTING: Zhongshan Ophthalmic Center, China. DESIGN: Prospective 1:1 matched design. METHODS: 94 cases (185 eyes with a vertical elliptical ciliary sulcus) were included with a 1:1 matched design based on ciliary sulcus morphology, preset deviation angle, and vault. Follow-ups at 4 days, 1 month, 3 months, and 6 months post-surgery measured rotational angles using slit-lamp photography. Latent class trajectory modeling was employed to investigate the postoperative rotational angle trajectories. RESULTS: Six months after surgery, both groups exhibited similar visual acuity and refractive outcomes. The horizontal group had a significantly greater rotation angle than the vertical group (F group = 13.638, P < 0.001). Additionally, a statistically significant difference (P = 0.004) in the average trajectories of rotational angles was observed. The vertical group displayed a greater presence in the low-stable trajectory subgroup while demonstrating a reduced presence in the moderate-increase and high-fluctuation trajectory subgroups compared to the horizontal group. The horizontal group had a 3.750 times higher risk of rotation angle ≥3° compared to the vertical group, which represented a statistically significant difference (95% CI: 1.346∼10.446). In both groups, a positive correlation between the preset deviation angle and the rotation angle was observed, with correlation coefficients of 0.320 (P = 0.030) and 0.371 (P = 0.011), respectively. CONCLUSIONS: Vertical ICL implantation showed better rotational stability than horizontal implantation in eyes with a vertical elliptical ciliary sulcus, offering guidance for ICL surgery.

Rotational Stability, Footplate Position, and Visual Outcomes of Toric Implantable Collamer Lenses in Eyes With Low Vault.

PURPOSE: To evaluate the clinical outcomes, rotational stability, and footplate position of the toric Implantable Collamer Lens (TICL) (STAAR Surgical) in eyes with low vault and analyze factors related to rotational stability. METHODS: This prospective observational study included 59 eyes of 59 patients with insufficient vault (< 250 µm). Postoperative rotation was defined as the difference between the achieved angle and the intraoperative fixation angle, and assessed with a digital anterior segment photograph after full mydriasis at 1 week and 1, 3, and 6 months postoperatively. Ultrasound biomicroscopy was used to determine the ciliary body morphology and position of the footplate. Correlation analysis was employed to identify the risk factors associated with TICL rotation at 6 months postoperatively. RESULTS: At 6 months postoperatively, the mean central vault was 137.4 ± 61.0 µm (range: 40 to 236 µm), and the mean efficacy and safety indices were 1.04 and 1.15, respectively. The mean manifest refractive astigmatism decreased from -1.67 ± 0.82 diopters (D) preoperatively to -0.43 ± 0.33 D postoperatively, and the mean absolute rotation was 4.50 ± 3.08 degrees (range: 0 to 12.50 degrees). The angle of rotation was correlated with the preoperative spherical power (r = -0.318, P = .014), the average value of TICL footplates position (r = 0.284, P = .029), and postoperative astigmatism (r = -.469, P⩽ .001). CONCLUSIONS: TICL implantation is predictable, safe, and effective in correcting myopic astigmatism in eyes with low vault. The rotational stability was acceptable and related to the malposition of the footplate and preoperative spherical power. [J Refract Surg. 2024;40(7):e460-e467.].

Design, synthesis and biological evaluation of 1-aryldonepezil analogues as anti-Alzheimer's disease agents.

Aim: To design and synthesize a novel series of 1-aryldonepezil analogues. Materials & methods: The 1-aryldonepezil analogues were synthesized through palladium/PCy3-catalyzed Suzuki reaction and were evaluated for cholinesterase inhibitory activities and neuroprotective effects. In silico docking of the most effective compound was conducted. Results: The 4-tert-butylphenyl analogue exhibited good inhibitory potency against acetylcholinesterase and butyrylcholinesterase and had a favorable neuroprotective effect on H2O2-induced SH-SY5Y cell injury. Conclusion: The 4-tert-butylphenyl derivative is a promising lead compound for anti-Alzheimer's disease drug development.

[Box: see text].

Rethinking therapeutic strategies of dual-target drugs: An update on pharmacological small-molecule compounds in cancer.

Oncogenes and tumor suppressors are well-known to orchestrate several signaling cascades, regulate extracellular and intracellular stimuli, and ultimately control the fate of cancer cells. Accumulating evidence has recently revealed that perturbation of these key modulators by mutations or abnormal protein expressions are closely associated with drug resistance in cancer therapy; however, the inherent drug resistance or compensatory mechanism remains to be clarified for targeted drug discovery. Thus, dual-target drug development has been widely reported to be a promising therapeutic strategy for improving drug efficiency or overcoming resistance mechanisms. In this review, we provide an overview of the therapeutic strategies of dual-target drugs, especially focusing on pharmacological small-molecule compounds in cancer, including small molecules targeting mutation resistance, compensatory mechanisms, synthetic lethality, synergistic effects, and other new emerging strategies. Together, these therapeutic strategies of dual-target drugs would shed light on discovering more novel candidate small-molecule drugs for the future cancer treatment.

Corneal Stroma Analysis and Related Ocular Manifestations in Recovered COVID-19 Patients.

Purpose: The purpose of this study was to assess the impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) on corneal stroma characteristics, ocular manifestations, and post-recovery refractive surgery outcomes after varying recovery durations. Methods: Fresh corneal lenticules from patients with post-coronavirus disease 2019 (COVID-19; recovered within 135 days) and healthy controls (HCs) after small incision lenticule extraction (SMILE) surgery were obtained for experimental validation of SARS-CoV-2 susceptibility, morphological changes, and immune response of the corneal stroma. Corneal optical density (CD) was measured using the Pentacam HR. Corneal epithelium thickness (ET) and endothelium parameters were evaluated by wide-field optical coherence tomography (OCT) and non-contact specular microscopy (SP-1P), respectively. All the patients were assessed after SMILE surgery until 3 month of follow-up. Results: The cornea was susceptible to SARS-CoV-2 with the presence of SARS-CoV-2 receptors (CD147 and ACE2) and spike protein remnants (4 out of 58) in post-recovery corneal lenticules. Moreover, SARS-CoV-2 infection triggered immune responses in the corneal stroma, with elevated IL-6 levels observed between 45 and 75 days post-recovery, which were then lower at around day 105. Concurrently, corneal mid-stromal nerve length and branching were initially higher in the 60D to 75D group and returned to control levels by day 135. A similar trend was observed in CD within zones 0 to 2 and 2 to 6 and in the hexagonal cells (HEX) ratio in endothelial cells, whereas ET remained consistent. Notably, these changes did not affect the efficacy, safety, or predictability of post-recovery SMILE surgery. Conclusions: SARS-CoV-2 induces temporal alterations in corneal stromal morphology and function post-recovery. These findings provided a theoretical basis for corneal health and refractive surgery management in the post-COVID-19 milieu.

Ocular features in myopic eyes with longer horizontal ciliary sulcus diameters for intended implantable collamer lens surgery.

PURPOSE: To assess the ocular anterior segment characteristics in myopic eyes intended for ICL surgery with horizontal ciliary sulcus-to-sulcus (STS) diameters being greater than vertical STS diameters. METHODS: This retrospective, comparative case study included 1230 eyes of patients who underwent ICL implantation for the treatment of myopia or myopic astigmatism at the Zhongshan Ophthalmic Center from September 2020 to November 2021. The myopic eyes were divided into two groups according to the relatively long diameter of the ciliary sulcus. General parameters and anterior chamber parameters were compared between the two groups. RESULTS: 1230 eyes of 694 patients were included. The proportion of myopic eyes with longer horizontal STS diameters was 4.63%. Horizontal STS distances exceeding vertical meridians in these eyes were mainly attributed to the shortening of vertical STS distances (horizontal STS: P = 0.112; vertical STS: P < 0.001). Eyes with longer horizontal meridians of the ciliary sulcus displayed larger steep keratometry value (P = 0.001), larger corneal volume (P = 0.002), larger corneal astigmatism (P < 0.001), larger ocular residual astigmatism (P = 0.017), worse visual acuity (logMAR UDVA: P = 0.021; logMAR CDVA: P = 0.001), and more iridociliary cysts (P = 0.017) compared to eyes with vertically oval shapes. CONCLUSION: Myopic eyes with longer horizontal STS diameters are commonly accompanied by a change in corneal morphology and more iridociliary cysts. The anatomical features of the ciliary sulcus should be given sufficient consideration to ICL size and placement selection, contributing to more personalized and precise surgery.

Lithium Chloride Exerts Anti-Inflammatory and Neuroprotective Effects by Inhibiting Microglial Activation in LPS-Induced Retinal Injury.

Purpose: To explore the anti-inflammatory and neuroprotective effects of lithium chloride (LiCl) in LPS-induced retinal injury. Methods: In vitro, primary retinal microglia were pretreated with LiCl and stimulated with lipopolysaccharide (LPS). Pro-inflammatory cytokine production, microglial morphological changes, and inflammation-associated signaling pathways were measured by real-time PCR (RT-PCR), western blotting, and immunofluorescence. Primary retinal neurons were cultured with microglial-derived conditioned medium in the absence or presence of LiCl. Neurotoxicity was evaluated by Cell Counting Kit-8 (CCK-8), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, and γ-H2AX detection. In vivo, an endotoxin-induced uveitis mice model was established, and each animal was given intraperitoneal injection of LiCl or vehicle. The retinal inflammatory response was measured by hematoxylin and eosin and fluorescent staining, RT-PCR, western blotting, and TUNEL assay. Retinal thickness and function were evaluated by spectral-domain optical coherence tomography and electroretinography. Results: In vitro, LiCl exerted no obvious toxic effects on microglia and significantly decreased proinflammatory factor (inducible nitric oxide synthase, tumor necrosis factor α, interleukin 6) production, inhibited microglial activation in morphology, and suppressed nuclear factor kappa B (NF-κB), Akt, and phosphatidylinositol 3-kinase (PI3K) phosphorylation. Moreover, LiCl promoted retinal neuron survival and reduced cell apoptosis and the expression of γ-H2AX. In vivo, LiCl reduced inflammatory infiltrating cells in the vitreous cavity and decreased proinflammatory cytokine expression in retinas. LiCl suppressed LPS-induced microglial activation, proliferation, and migration. Additionally, LiCl reduced LPS-induced apoptosis of ganglion cells and retinal edema and rescued retinal functional damage. Conclusions: This study demonstrates that LiCl exerts anti-inflammatory and neuroprotective effects by inhibiting microglial activation via the PI3K/Akt/NF-κB pathway in LPS-induced retinal injury. LiCl provides a novel and promising option to treat retinal inflammatory diseases.

Palladium-Catalyzed Synthesis, Acetylcholinesterase Inhibition, and Neuroprotective Activities of N-Aryl Galantamine Analogues.

A series of new N-aryl galantamine analogues (5a-5x) were designed and synthesized by modification of galantamine, using Pd-catalyzed Buchwald-Hartwig cross-coupling reaction in good to excellent yields. The cholinesterase inhibitory and neuroprotective activities of N-aryl derivatives of galantamine were evaluated. Among the synthesized compounds, the 4-methoxylpyridine-galantamine derivative (5q) (IC50 = 0.19 µM) exhibited excellent acetylcholinesterase inhibition activity, as well as significant neuroprotective effect against H2O2-induced injury in SH-SY5Y cells. Molecular docking, staining, and Western blotting analyses were performed to demonstrate the mechanism of action of 5q. Derivative 5q would be a promising multifunctional lead compound for the treatment of Alzheimer's disease.

Additive-controlled asymmetric iodocyclization enables enantioselective access to both α- and ß-nucleosides.

ß-Nucleosides and their analogs are dominant clinically-used antiviral and antitumor drugs. α-Nucleosides, the anomers of ß-nucleosides, exist in nature and have significant potential as drugs or drug carriers. Currently, the most widely used methods for synthesizing ß- and α-nucleosides are via N-glycosylation and pentose aminooxazoline, respectively. However, the stereoselectivities of both methods highly depend on the assisting group at the C2' position. Herein, we report an additive-controlled stereodivergent iodocyclization method for the selective synthesis of α- or ß-nucleosides. The stereoselectivity at the anomeric carbon is controlled by the additive (NaI for ß-nucleosides; PPh3S for α-nucleosides). A series of ß- and α-nucleosides are prepared in high yields (up to 95%) and stereoselectivities (ß:α up to 66:1, α:ß up to 70:1). Notably, the introduced iodine at the C2' position of the nucleoside is readily functionalized, leading to multiple structurally diverse nucleoside analogs, including stavudine, an FDA-approved anti-HIV agent, and molnupiravir, an FDA-approved anti-SARS-CoV-2 agent.

Transcriptome Sequencing Reveals Tgf-ß-Mediated Noncoding RNA Regulatory Mechanisms Involved in DNA Damage in the 661W Photoreceptor Cell Line.

Transforming growth factor ß (Tgf-ß), a pleiotropic cytokine, can enhance DNA repair in various cells, including cancer cells and neurons. The noncoding regulatory system plays an important role in Tgf-ß-mediated biological activities, whereas few studies have explored its role in DNA damage and repair. In this study, we suggested that Tgf-ß improved while its inhibitor LSKL impaired DNA repair and cell viability in UV-irradiated 661W cells. Moreover, RNA-seq was carried out, and a total of 106 differentially expressed (DE)-mRNAs and 7 DE-lncRNAs were identified between UV/LSKL and UV/ctrl 661W cells. Gene ontology and Reactome analysis confirmed that the DE-mRNAs were enriched in multiple DNA damaged- and repair-related biological functions and pathways. We then constructed a ceRNA network that included 3 lncRNAs, 19 miRNAs, and 29 mRNAs with a bioinformatics prediction. Through RT-qPCR and further functional verification, 2 Tgf-ß-mediated ceRNA axes (Gm20559-miR-361-5p-Oas2/Gbp7) were further identified. Gm20559 knockout or miR-361-5p mimics markedly impaired DNA repair and cell viability in UV-irradiated 661W cells, which confirms the bioinformatics results. In summary, this study revealed that Tgf-ß could reduce DNA damage in 661W cells, provided a Tgf-ß-associated ceRNA network for DNA damage and repair, and suggested that the molecular signatures may be useful candidates as targets of treatment for photoreceptor pathology.

Bioinformatics Analysis and Experimental Identification of Immune-Related Genes and Immune Cells in the Progression of Retinoblastoma.

Purpose: Retinoblastoma (RB) is the most common type of aggressive intraocular malignancy in children. The alteration of immunity during RB progression and invasion has not yet been well defined. This study investigated significantly altered immune-associated genes and cells related to RB invasion. Methods: The differentially expressed immune-related genes (IRGs) in noninvasive RB and invasive RB were identified by analysis of two microarray datasets (GSE97508 and GSE110811). Hub IRGs were further identified by real time PCR. The single-sample gene set enrichment analysis algorithm and Pearson correlation analysis were used to define immune cell infiltration and the relationships between hub IRGs and immune cells. Cell viability and migration were evaluated by CCK-8 and Transwell assays. A xenograft mouse model was used to verify the relationship between Src homology 3 (SH3) domain GRB2-like 2 (SH3GL2) expression and myeloid-derived suppressor cells (MDSCs). Results: Eight upregulated genes and six downregulated IRGs were identified in invasive RB. Seven IRGs were confirmed by real-time PCR. Moreover, the proportions of MDSCs were higher in invasive RB tissues than in noninvasive RB tissues. Furthermore, correlation analysis of altered immune genes and cells suggested that SH3GL2, Langerhans cell protein 1 (LCP1) and transmembrane immune signaling adaptor TYROBP have strong connections with MDSCs. Specifically, decreased SH3GL2 expression promoted the migration of RB cells in vitro, increased the tumor size and weight, and increased the numbers of MDSCs in the tumor and spleen in vivo. Conclusions: This study indicated that SH3GL2 and MDSCs play a critical role in RB progression and invasion and provide candidate targets for the treatment of RB.

Pd-Catalyzed Direct Diversification of Natural Anti-Alzheimer's Disease Drug: Synthesis and Biological Evaluation of N-Aryl Huperzine A Analogues.

The first systematic direct diversification of a complex natural product by metal-catalyzed N-H functionalization was carried out. A new series of N-(hetero)aryl analogues (1-32) of the natural anti-Alzheimer's disease drug huperzine A (HPA) was prepared via palladium-catalyzed Buchwald-Hartwig cross-coupling reactions of HPA with various aryl bromides in good yields. Most of the N-aryl-huperzine A (N-aryl-HPA) analogues showed good acetylcholinesterase (AChE) inhibitory activity in in vitro experiments. Three arylated huperzine A analogues (14, 19, and 30) exhibited stronger anti-AChE activity than HPA. The 5-methoxy-2-pyridyl analogue (30) displayed the most potent AChE inhibition activity, with an IC50 value of 1.5 µM, which was 7.6-fold more active than HPA. Compound 30 also exhibited better neuroprotective activity for H2O2-induced damage in SH-SY5Y cells than HPA. Structure-activity relationship analysis suggested that the electron density of the installed aromatic ring or heteroaromatic ring played a significant role in inducing the AChE inhibition activity. Overall, compound 30 showed the advantages of easy synthesis, high potency and selectivity, and improved neuroprotection, making it a potential huperzine-type lead compound for Alzheimer's disease drug development.

Iron-Catalyzed Skeletal Conversion of Lathyrane to Premyrsinane Euphorbia Diterpenes and Their Cytotoxic Activities.

Two new premyrsinane-type diterpenes (2 and 3) as diastereomers were synthesized from lathyrane-type diterpene euphorbia factor L3 (1) for the first time via an efficient Fe(acac)3-catalyzed skeleton conversion process. This conversion features a biogenetically inspired strategy that relies on a concise reductive olefin coupling involving intramolecular Michael addition with free radicals. The structures of 2 and 3 were elucidated by a combination of the interpretation of their spectroscopic data and single-crystal X-ray diffraction analysis. The premyrsinane diterpenes 2 and 3 exhibited cytotoxic activity against the 4T1 breast cancer cell line, while the parent compound euphorbia factor L3 (1) was inactive. The current results not only confirmed the biogenetic relationship between lathyranes and premyrsinanes for the first time but also suggested a novel method for the preparation of naturally rare premyrsinane diterpenes with high bioactivity from the more abundant natural lathyrane diterpenes.

Attenuated Salmonella engineered with an apoptosis-inducing factor (AIF) eukaryotic expressing system enhances its anti-tumor effect in melanoma in vitro and in vivo.

VNP20009, an attenuated mutant of Salmonella, is potentially applied for tumor therapy due to its specific accumulation and proliferation in the hypoxic zone of tumor. However, studies have shown that human immunity system and the associated toxicities of attenuated Salmonella evidently alleviated the anti-tumor effect when tumor is reduced. As apoptosis-inducing factor (AIF) can directly induce nuclear apoptosis in the absence of caspases to avoid unwished apoptosis in normal cells, therefore, a eukaryotic expressing VNP20009-AbVec-Igκ-AIF (V-A-AIF) strain was constructed in the present study, and its anti-melanoma effects were evaluated in vitro and in vivo. The results showed that AIF expressed by the V-A-AIF strain significantly enhanced the apoptosis of B16F10 cells in vitro, seen as remarkable decrease of tumor volume, formation of larger necrotic areas, and prolongation of the lifespan in a melanoma-bearing mouse model. Furthermore, we observed that the colonization of the V-A-AIF strain and the massive expression of AIF in tumors significantly promoted apoptosis of tumor cells by upregulating the expression ratio of Bcl-2-associated X protein/B cell lymphoma-2 (Bax/Bcl-2), suppressed the inflammatory response by downregulating toll-like receptor-4/nuclear factor kappa-B (TLR-4/NFκB) signaling pathway, seen as reduction of the expressions of phosphorylated phosphoinositide 3 kinase (PI3K) and protein kinase B (AKT), and decrease of the production of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). Our study demonstrated that the colonization of the V-A-AIF strain in tumor triggers a decent anti-tumor effect in vivo and in vitro, suggesting that the engineered strain may provide a potential reagent for cancer therapy.

Hydroxypropyl­ß­cyclodextrin attenuates the epithelial­to­mesenchymal transition via endoplasmic reticulum stress in MDA­MB­231 breast cancer cells.

The epithelial­to­mesenchymal transition (EMT) has been reported to serve vital roles in regulating the progress of cancer metastasis. In addition, lipid rafts enriched in sphingolipids and cholesterol serve important roles in physiological and biochemical processes as a signaling platform. The present study explored the effects of hydroxypropyl­ß­cyclodextrin (HP­ß­CD), a cholesterol­depleting agent of lipid rafts, on the transforming growth factor (TGF)­ß/Smad signaling pathway and endoplasmic reticulum (ER) stress in mediating EMT in MDA­MB­231 breast cancer cells. HP­ß­CD treatment inhibited TGF­ß1­induced EMT, based on increased expression of E­cadherin and decreased expression of vimentin. HP­ß­CD reduced the expression of the TGF receptor TßRI and blocked the phosphorylation of Smad2. In addition, HP­ß­CD increased the expression of ER stress­related proteins (binding immunoglobulin protein and activating transcription factor 6), but TGF­ß1 could reverse these changes. Sodium 4­phenylbutyrate, an inhibitor of ER stress, suppressed these effects of HP­ß­CD on EMT and TGF­ß/Smad signaling pathway inhibition in breast cancer cells. Thus, HP­ß­CD can block the TGF­ß/Smad signaling pathway via diminishing the expression of TßRI which helps to activate ER stress and attenuate EMT in MDA­MB­231 cells, highlighting a potential target of lipid rafts for breast cancer treatment.