Topical Application of Cell-Penetrating Peptide Modified Anti-VEGF Drug Alleviated Choroidal Neovascularization in Mice.

Background: Age-related macular degeneration (AMD) stands as the foremost cause of irreversible central vision impairment, marked by choroidal neovascularization (CNV). The prevailing clinical approach to AMD treatment relies on intravitreal injections of anti-vascular endothelial growth factor (VEGF) drugs. However, this method is encumbered by diverse complications, prompting exploration of non-invasive alternatives such as ocular administration via eye drops for anti-VEGF therapy. Methods: Two complexes, 5-FITC-CPP-Ranibizumab (5-FCR) and 5-FITC-CPP-Conbercept (5-FCC), were synthesized by incorporating the anti-VEGF drugs Ranibizumab (RBZ) or Conbercept (CBC) with cell-penetrating peptide (CPP). Circular dichroism spectrum (CD) facilitated complexes characterization. Eye drops was utilized to address laser-induced CNV in mice. Fluorescein fundus angiography (FFA) observe the CNV lesion, while FITC-dextran and IB4 dual fluorescent staining, along with hematoxylin-eosin (HE) staining, assessed in lesion size. Tissue immunofluorescence examined CD31 and VEGF expression in choroidal/retinal pigment epithelial (RPE) tissues. Biocompatibility and biosafety of 5-FCR and 5-FCC was evaluated through histological examination of various organs or cell experiments. Results: Both 5-FCR and 5-FCC exhibited favorable biocompatibility and safety profiles. VEGF-induced migration of Human umbilical vein endothelial cells (HUVECs) significantly decreased post-5-FCR/5-FCC treatment. Additionally, both complexes suppressed VEGF-induced tube formation in HUVECs. FFA results revealed a significant improvement in retinal exudation in mice. Histological examination unveiled the lesion areas in the 5-FCR and 5-FCC groups showed a significant reduction compared to the control group. Similar outcomes were observed in histological sections of the RPE-choroid-sclera flat mounts. Conclusion: In this study, utilizing the properties of CPP and two anti-VEGF drugs, we successfully synthesized two complexes, 5-FCR and 5-FCC, through a straightforward approach. Effectively delivering the anti-VEGF drugs to the target area in a non-invasive manner, suppressing the progression of laser-induced CNV. This offers a novel approach for the treatment of wet AMD.

Synthesis of a Tetrahedral Metal-Organic Supramolecular Cage with Dendritic Carbazole Arms.

In recent years, incredible endeavors have been devoted to the design and self-assembly of discrete metal-organic cages (MOCs) with expanding intricacy and functionality. The controlled synthesis of metal-organic supramolecular cages with large branched chains remains an interesting and challenging work in supramolecular chemistry. Herein, a tetrahedral metal-organic supramolecular cage (ZnII4L4) containing 12 dendritic carbazole arms is unprecedentedly constructed through coordination-driven subcomponent self-assembly and characterized in different ways. Interestingly, tetrahedral supramolecular Cage-1 exhibited the potential for aggregation-induced emission (AIE) performance and stimulus-responsive luminescence features, and it achieved color-tunable photoluminescence due to the introduction of dendritic carbazole arms. Crucially, owing to the great photophysical properties of Cage-1 in solution, Cage-1 was enabled to act as a fluorescent ink for the vapor-responsive recording and wiping of information.

Cu(II)-Catalyzed N-Directed Distal C(sp3)-H Heteroarylation of Aliphatic N-Fluorosulfonamides.

A copper-catalyzed δ-regioselective C(sp3)-H heteroarylation of N-fluorosulfonamides has been developed. A broad range of heteroarenes were well tolerated and reacted with various N-fluorosulfonamides to give the corresponding heteroarylated amides in good yields. Notably, all types (1°, 2°, and 3°) of δ-C(sp3)-H bonds in the N-fluorosulfonamides could be regioselectively activated through the 1,5-HAT process. This protocol provides a practical strategy for the functionalization of heteroarenes and amides via forging a C(sp3)-C(sp2) bond.

MicroRNA-27a Promotes Oxidative-Induced RPE Cell Death through Targeting FOXO1.

Age-related macular degeneration (AMD) is a multifactor disease, which is primarily characterized by retinal pigment epithelium (RPE) cell loss. Since the retina is the most metabolically active tissue, RPE cells are exposed to consistent oxidative environment. So, oxidation-induced RPE cell death has long been considered a contributor to the onset of AMD. Here, we applied a retinal degeneration (RD) rat model induced by blue light-emitting diode (LED) and a cell model constructed by H2O2 stimulus to mimic the prooxidant environment of the retina. We detected that the expression of miR-27a was upregulated and the expression of FOXO1 was downregulated in both models. So, we furtherly investigated the role of miR-27a-FOXO1 axis in RPE in protesting against oxidants. Lentivirus-mediated RNA was injected intravitreally into rats to modulate the miR-27a-FOXO1 axis. Retinal function and histopathological changes were evaluated by electroretinography (ERG) analysis and hematoxylin and eosin (H&E) staining, respectively. Massive photoreceptor and RPE cell death were examined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). The damage to the retina was aggravated in the FOXO1 gene-knockdown and miR-27a-overexpression groups after exposure to LED but was alleviated in the FOXO1 gene-overexpression or miR-27a-knockdown groups. Dual luciferase assay was used to detect the binding site of miR-27a and FOXO1. Upregulated miR-27a inhibited the expression of FOXO1 by directly binding to the FOXO1 mRNA 3'UTR and decreased the autophagy activity of ARPE-19 cells, resulting in the accumulation of reactive oxygen species (ROS) and decrease of cell viability. The results suggest that miR-27a is a negative regulator of FOXO1. Also, our data emphasize the prominent role of miR-27a/FOXO1 axis in modulating ROS accumulation and cell death in RPE cell model under oxidative stress and influencing the retinal function in the LED-induced RD rat model.

NaOH-Mediated Direct Synthesis of Quinoxalines from o-Nitroanilines and Alcohols via a Hydrogen-Transfer Strategy.

A NaOH-mediated sustainable synthesis of functionalized quinoxalines is disclosed via redox condensation of o-nitroamines with diols and α-hydroxy ketones. Under optimized conditions, various o-nitroamines and alcohols are well tolerated to generate the desired products in 44-99% yields without transition metals and external redox additives.

Effectiveness and Safety of Trabeculectomy along with Amniotic Membrane Transplantation on Glaucoma: A Systematic Review.

PURPOSE: To determine the effectiveness and safety of trabeculectomy along with amniotic membrane transplantation (AMT) for glaucoma. METHODS: This systematic review was performed using RevMan 5.3. We searched PubMed, EMBASE, and the Cochrane Library and included studies published until September 2019. The treatment group included patients with AMT and trabeculectomy (group A), and the control group had only trabeculectomy (group B). We only included randomized controlled trials. The outcomes were intraocular pressure (IOP), complete success rate, number of antiglaucoma medications, and complications. RESULTS: Five studies, including 174 eyes (87 eyes in the AMT group and 87 eyes in the control group), were eligible in this review. The parameters had no significant difference in heterogeneity between the AMT and control groups preoperatively. In the AMT group, the mean IOP was significantly lower at 3 and 12 months after operation (P < 0.0001 and P = 0.02, respectively), while the number of complete successes in the AMT group was significantly higher at 6 and 12 months (P = 0.02 and P = 0.003, respectively) compared with the control group. Complications, including a flat anterior chamber and hyphema, appeared to be decreased in the AMT group compared to the control group (P = 0.02 and P = 0.02, respectively). No differences were observed in the number of antiglaucoma medications, hypotony, encapsulated bleb, or choroidal detachment. CONCLUSION: Compared with only trabeculectomy, it is more efficient and safer to add AMT to trabeculectomy during glaucoma filtering surgery.

Intravenous anti-VEGF agents with RGD peptide-targeted core cross-linked star (CCS) polymers modified with indocyanine green for imaging and treatment of laser-induced choroidal neovascularization.

Age-related macular degeneration (AMD) is a leading cause of irreversible visual loss among elderly persons, of which wet AMD is characterized by choroidal neovascularization (CNV). We herein developed nanoparticles with good biosafety for effective treatment of choroidal neovascularization (CNV). S-PEG-ICG-RGD-RBZ NPs were synthesized and characterized by ZP, DLS, UV-Vis, TEM and Coomassie Brilliant Blue staining analyses. In our study, the S-PEG-ICG-RGD-RBZ NPs exhibited good biocompatibility in vitro and in vivo. There was no cellular toxicity, dead cells, apoptosis or genotoxicity in the studied concentration range in vitro; meanwhile, intravenous injection of the designed NPs did not cause histological damage or apoptosis in the organs in vivo, including the heart, liver, spleen, lung, kidneys and brain. The designed NPs inhibited VEGF-induced proliferation, cell migration, tube formation and expression of CD31 and VEGF in vitro. Meanwhile, in vivo studies also indicated the inhibition of CNV development by NPs. What's more, the CNV area was imaged after intravenous injection of NPs modified with indocyanine green. The NPs were mainly targeted to CNV areas and did not remain in the other organs. In summary, S-PEG modified with RGD was designed as a powerful carrier to deliver anti-VEGF agents to CNV areas. The smart NPs, which have good cellular compatibility, hold great potential for drug delivery in CNV treatment.

NAD+ inhibits the metabolic reprogramming of RPE cells in early AMD by upregulating mitophagy.

Age-related macular degeneration (AMD) is a leading cause of blindness and is becoming a global crisis, with the number of affected people expected to reach 288 million by 2040 worldwide. Retinal pigment epithelium (RPE) performs a number of highly diverse functions that are essential to maintaining the normal health and function of the retina. Alterations to retinal metabolism and remodeling are an early feature of AMD. The pathology of AMD is associated with mitochondrial dysfunction. Mitophagy is vital to promote a metabolic shift towards glycolysis that is required for cell differentiation. Nicotinamide adenine dinucleotide (NAD+) acts as a central metabolic cofactor, plays a pivotal role in regulating cellular metabolism and energy homeostasis, and may aid disease treatment. Therefore, we hypothesized that NAD+ may restore homeostasis by inducing mitophagy in AMD, thereby reducing the damage caused by metabolic reprogramming. Since NAD+ has shown promise as a novel and inexpensive cytoprotective agent in the treatment of oxidative stress-related disease, patients with AMD may benefit from NAD+ treatment.

Quercetin inhibits transforming growth factor ß1-induced epithelial-mesenchymal transition in human retinal pigment epithelial cells via the Smad pathway.

PURPOSE: The purpose of this study was to evaluate the effect and mechanism of quercetin on TGF-ß1-induced retinal pigment epithelial (RPE) cell proliferation, migration, and extracellular matrix secretion. MATERIALS AND METHODS: Cell counting kit-8, transwell, wound-healing assays, and ELISA were used to assess viability, migration, and collagen I secretion, respectively. Western blot analysis and qPCR were employed to detect mRNA and protein expression levels, respectively. RESULTS: Quercetin suppressed TGF-ß1-induced cell proliferation, migration, and collagen I secretion. The results also showed that mRNA and protein expression of epithelial-mesenchymal transition (EMT)-related markers such as alpha-smooth muscle actin and N-cadherin was downregulated by quercetin in TGF-ß1-treated RPE cells; conversely, quercetin upregulated the expression of E-cadherin and tight junction protein 1 (ZO-1). In addition, quercetin could inhibit mRNA and protein expression of matrix metalloproteinases. Quercetin may reverse the progression of EMT via the Smad2/3 pathway. CONCLUSION: Our results demonstrate the protective effects of quercetin on RPE cell EMT, revealing a potential therapeutic agent for proliferative vitreoretinopathy treatment.