Revealing the Mechanisms of Byu dMar 25 in the Treatment of Alzheimer's Disease through Network Pharmacology, Molecular Docking, and In Vivo Experiment.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease, severely reducing the cognitive level and life quality of patients. Byu dMar 25 (BM25) has been proved to have a therapeutic effect on AD. However, the pharmacological mechanism is still unclear. Therefore, this study aims to reveal the potential mechanism of BM25 affecting AD from the perspective of network pharmacology and experimental validation. METHODS: The potential active ingredients of BM25 were obtained from the TCMSP database and literature. Possible targets were predicted using SwissTargetPrediction tools. AD-related genes were identified by using GeneCards, OMIM, DisGeNET, and Drugbank databases. The candidate genes were obtained by extraction of the intersection network. Additionally, the "drug-target-disease" network was constructed by Cytoscape 3.7.2 for visualization. The PPI network was constructed by the STRING database, and the core network modules were filtered by Cytoscape 3.7.2. Enrichment analysis of GO and KEGG was carried out in the Metascape platform. Ledock software was used to dock the critical components with the core target. Furthermore, protein levels were evaluated by immunohistochemistry. RESULTS: In this study, 112 active components, 1112 disease candidate genes, 3084 GO functions, and 277 KEGG pathways were obtained. Molecular docking showed that the effective components of BM25 in treating AD were ß-asarone and hydroxysafflor yellow A. The most important targets were APP, PIK3R1, and PIK3CA. Enrichment analysis indicated that the Golgi genetic regulation, peroxidase activity regulation, phosphatidylinositol 3-kinase complex IA, 5-hydroxytryptamine receptor complexes, cancer pathways, and neuroactive ligand-receptor interactions played vital roles against AD. The rat experiment verified that BM25 affected PI3K-Akt pathway activation in AD. CONCLUSIONS: This study reveals the mechanism of BM25 in treating AD with network pharmacology, which provides a foundation for further study on the molecular mechanism of AD treatment.

Spin-Coating-Based Facile Annular Photodynamic Intraocular Lens Fabrication for Efficient and Safer Posterior Capsular Opacification Prevention.

Posterior capsular opacification (PCO) is the most common complication after cataract surgery, which is primarily caused by the proliferation of the residual lens epithelial cells (LECs) in the lens capsule. Previous studies have demonstrated that a drug-eluting intraocular lens (IOL), aimed to in situ eliminate LECs, are an effective and promising way to prevent PCO. However, because of the potential toxicities of the antiproliferative drugs to the adjacent tissues, the safety of such drug-eluting IOLs is still a highly important issue to be solved. In this investigation, a facile photodynamic coating-modified IOL was developed for effective and safer PCO prevention. An annular poly(lactide-co-glycolic acid) (PLGA) coating loaded with photosensitizer chlorin e6 (Ce6) was prepared by a spin-coating technique. The optical property investigations showed that the Ce6@PLGA coating was particularly suitable for the IOL surface modification. The in vitro cell culture investigation showed that Ce6@PLGA coating-modified IOLs effectively eliminated LECs when treated with light illumination, whereas it appeared to have good cytocompatibility without irradiation. The investigation of the cell elimination mechanism showed that the apoptosis of HLECs may be associated with the cytomembrane disruption induced by ROS, which is generated by the photodynamic coating during light illumination. The in vivo implantation experiments confirmed the desired PCO prevention effect, as well as the safety to and biocompatibility with the surrounding tissues. Thus, the facile Ce6@PLGA coating will provide an effective yet safe alternative of IOL surface modification for PCO prevention.

Centrifugally concentric ring-patterned drug-loaded polymeric coating as an intraocular lens surface modification for efficient prevention of posterior capsular opacification.

Posterior capsular opacification (PCO) is the main postoperative complication after intraocular lens (IOL) implantation in cataract surgery, because of the proliferation of the residual lens epithelial cells (LECs) in the lens capsule. Drug-eluting IOLs, aimed to develop an in situ drug delivery device, are the promising concept in recent years. As IOLs are optical devices other than implants, the feasibility and applicability remain a challenge for drug-eluting coatings. In this investigation, a centrifugally concentric ring-patterned drug-loaded poly(lactide-co-glycolic acid) (PLGA) coating was designed and fabricated by the spin coating technique. The concentric ring-patterned morphologies and the drug loading and release properties were carefully investigated, and the spin coating parameters were optimized. A concentric annular coating with a thin center and thick periphery was obtained, which was particularly suitable for the surface modification of IOLs, as the visual pathway of the intraocular light transmission greatly requires good light transmittance of the IOLs. IOLs with the immunosuppressant cyclosporin A (CsA)-loaded coating (CsA @ PLGA) modification were then fabricated for PCO prevention. The in vitro LECs culture results showed that the CsA @ PLGA coating-modified IOLs significantly inhibited cell proliferation and induced cell death. Western blot analysis showed that the efficient cell inhibition behavior of CsA was due to the autophagy-mediated cell death pathway. The in vivo intraocular implantation results confirmed the desired PCO inhibition effect. Thus, the centrifugally concentric ring-patterned drug-loaded PLGA coating obtained by the spin coating technique provides a simple yet effective alternative of IOL modification for PCO prevention. STATEMENT OF SIGNIFICANCE: • Concentric ring-patterned polymer coating, specifically for drug-eluting IOL fabrication, was developed by the spin coating technique. • The immunosuppressant CsA inhibited LEC proliferation through the autophagy-mediated cell death pathway. • Concentric ring-patterned CsA-eluting IOLs exhibited reliable in vivo PCO prevention. • The drug-eluting IOLs fabricated by the simple and economical spin coating technique have a great potential in clinical translation.

Facile multifunctional IOL surface modification via poly(PEGMA-co-GMA) grafting for posterior capsular opacification inhibition.

Posterior capsule opacification (PCO) is a significant complication of intraocular lens (IOL) implantation in cataract surgery, in which the adhesion and proliferation of lens epithelial cells (LECs) on the implanted IOL surface play an important role. The surface modification of IOL to prevent LEC adhesion and proliferation is a practical way to reduce the incidence of PCO. In this study, a multifunctional binary copolymer of poly(ethylene glycol) methacrylate (PEGMA) and glycidyl methacrylate (GMA) was synthesized (poly(PEGMA-co-GMA), PPG) and chemically grafted onto the aminolyzed IOL surface, utilizing the coupling reaction of epoxy and amino groups. Doxorubicin (DOX) was subsequently immobilized on the surface coating via the reaction of epoxy and amino groups as well. Taking advantages of the hydrophilicity of the PEG segments in the copolymer coating and the anti-proliferative effects of the DOX, a multifunctional surface coating was easily established by the synthesized copolymer PPG. Such anti-proliferative drug immobilized hydrophilic coating modification may effectively reduce the cell adhesion and proliferation and thus it is hypothesized to have great potential in PCO inhibition. The synthesis of PPG was confirmed by proton nuclear magnetic resonance spectroscopy (1H-NMR) and Fourier transform infrared spectroscopy (FTIR). The surface coating immobilization was demonstrated by X-ray photoelectron spectroscopy (XPS). The in vitro drug release profiles and the cell behaviors were also investigated to validate the multifunctional coating inhibition effect on cellular adhesion and antiproliferation. Finally, the in vivo ocular implantation was carried out on rabbit eyes to evaluate the effect of the coating modified IOL on the inhibition of postoperative PCO. It followed that such multifunctional coating modification can effectively inhibit the adhesion and proliferation of LECs and significantly reduce the incidence of PCO. All these results reveal that such PPG copolymer modification provides a facile yet effective way to inhibit PCO formation after IOL implantation.

"Kill-release" antibacterial polysaccharides multilayer coating based therapeutic contact lens for effective bacterial keratitis treatment.

Contact lenses (CLs) are an important medical device for ophthalmic disease treatment. They can be used not only to correct refractive errors, such as myopia, but also can serve as a drug carrier for ocular surface disease treatment. In this study, a therapeutic CL was designed for bacterial keratitis treatment by constructing an antibacterial surface coating via a layer-by-layer (LbL) electrostatic self-assembly method. Vancomycin-incorporated chitosan nanoparticles were firstly prepared by ionic condensation of sodium tripolyphosphate (abbreviated as CTVNP). The positively charged CTVNP were then used for LbL deposition with negatively charged heparin (HEP), obtaining a (HEP/CTVNP) n polyelectrolyte multilayer on the CL surface. It is shown that such antibiotic incorporated surface coating doesn't influence the light transmittance of the CL, so it should not affect the patients' visual acuity when wearing them. The in vitro bacteriostatic effect evaluation was performed via live and dead bacteria staining and scanning electron microscope (SEM), which demonstrated the effective antibacterial property of such a surface. The fabricated therapeutic CL was then used to treat bacterial keratitis on a rabbit model. The results showed that such CL could effectively control the development of the bacteria-infected cornea and had a significant therapeutic effect.