Multifunctional Cerium Oxide Nanozyme for Synergistic Dry Eye Disease Therapy.

Dry eye disease (DED) is a chronic multifactorial ocular surface disease mainly caused by the instability of tear film, characterized by a series of ocular discomforts and even visual disorders. Oxidative stress has been recognized as an upstream factor in DED development. Diquafosol sodium (DQS) is an agonist of the P2Y2 receptor to restore the integrity/stability of the tear film. With the ability to alternate between Ce3+ and Ce4+, cerium oxide nanozymes could scavenge overexpressed reactive oxygen species (ROS). Hence, a DQS-loaded cerium oxide nanozyme was designed to boost the synergistic treatment of DED. Cerium oxide with branched polyethylenimine-graft-poly(ethylene glycol) as nucleating agent and dispersant was fabricated followed with DQS immobilization via a dynamic phenylborate ester bond, obtaining the DQS-loaded cerium oxide nanozyme (defined as Ce@PBD). Because of the ability to mimic the cascade processes of superoxide dismutase and catalase, Ce@PBD could scavenge excessive accumulated ROS, showing strong antioxidant and anti-inflammatory properties. Meanwhile, the P2Y2 receptors in the conjunctival cells could be stimulated by DQS in Ce@PBD, which can relieve the incompleteness and instability of the tear film. The animal experiments demonstrated that Ce@PBD significantly restored the defect of the corneal epithelium and increased the number of goblet cells, with the promotion of tear secretion, which was the best among commercial DQS ophthalmic solutions.

Multifunctional cerium oxide nanozymes with high ocular surface retention for dry eye disease treatment achieved by restoring redox balance.

Dry eye disease (DED) is a kind of multifactorial ocular surface disease that displays ocular discomfort, visual disturbance, and tear film instability. Oxidative stress is a fundamental pathogenesis in DED. An imbalance between the reactive oxygen species (ROS) level and protective enzyme action will lead to oxidative stress, cell dysfunction, tear hyperosmolarity, and inflammation. Herein, a multifunctional cerium oxide nanozyme with high ocular surface retention property was designed to neutralize over-accumulated ROS and restore redox balance. Cerium oxide nanozymes were fabricated via branched polyethylenimine-graft-poly (ethylene glycol) nucleation and dispersion, followed by phenylboronic acid (PBA) functionalization (defined as Ce@PB). Due to the dynamic chemical bonding formation between the PBA segment and the cis-diol groups in the mucin layer of the tear film, Ce@PB nanozymes possess good adhesive capability to the ocular surface, thus extending the drug's retention time. On the other hand, Ce@PB nanozymes could mimic the cascade processes of superoxide dismutase and catalase to maintain intracellular redox balance. In vitro and in vivo studies suggest that such multifunctional nanozymes possess good biocompatibility and hemocompatibility. More importantly, Ce@PB nanozymes treatment in the animal model could repair corneal epithelial defect, increase the number of goblet cells and promote tear secretion, thus achieving an effective treatment for DED. STATEMENT OF SIGNIFICANCE.

Refractive index adjustable intraocular lens design to achieve diopter control for improving the treatment of ametropia after cataract surgery.

Intraocular lens (IOL) implantation is currently the most effective clinical treatment for cataracts. Nevertheless, due to the growth of the eye axis in patients with congenital cataracts during the process of growth and development, the progressive incapacity of an IOL with a fixed focus does not meet the demands of practical usage, leading to the occurrence of ametropia. This work describes an innovative class of an IOL bulk material that offers good biosafety and light-controlled refractive index adjustment. Acrylate materials were synthesized for the preparation of IOLs by free radical polymerization of ethylene glycol phenyl ether methacrylate (EGPEMA), hydrophilic monomer 2-(2-ethoxyethoxy) ethyl acrylate (EA), and functional monomer hydroxymethyl coumarin methacrylate (CMA). Under 365/254 nm ultraviolet (UV) irradiation, the coumarin group could adjust the polymer material's refractive index through reversible photoinduced dimerization/depolymerization. Meanwhile, the potential for the IOL use is enabled by its satisfactory biosafety. Such a light-induced diopter adjustable IOL will be more appropriate for implantation during cataract surgery since it will not require the correction needed for ametropia and will offer more accurate and humane treatment. STATEMENT OF SIGNIFICANCE.

Influences of Heider Balance on Knowledge, Attitude, Practice, and Quality of Life in Bladder Cancer Patients after Urinary Diversion.

Objective: To explore the influences of Heider balance on knowledge, attitude, practice (KAP), and quality of life in bladder cancer patients after urinary diversion. Methods: A set of bladder cancer patients after urinary diversion in our hospital from January 2016 to December 2020 were included in this study. Patients who received out-hospital intervention based on Heider balance were included in the observation group (85 cases). Meanwhile, patients who received routine out-hospital intervention were included in the control group (85 cases), and these patients matched with the observation group by gender, age, and education level. The scores of KAP, WHO quality of life-100 (WHOQOL-100) before discharge and at 6 months after discharge, and the rate of complications were compared in the two groups. Results: At 6 months after discharge, the score of these items of KAP including basic knowledge of disease, procedure of pouch replacement, dealing with pouch leakage, skin care of stoma, purchase and storage of pouch, dealing with stoma complications, optimistic mentality for disease, optimistic mentality for stoma, trust in medical staff, willingness to correct bad habits, confidence in maintaining health behavior, maintaining in health dietary habit, maintaining in health behavior, learning from relevant books, learning from relevant videos, experienced in pouch replacement, and experienced in care of stoma of the observation group were significantly higher than those of the control group (t = 6.144, 9.366, 3.129, 3.809, 4.173, 5.923, 2.788, 8.871, 3.291, 10.797, 7.067, 7.805, 3.828, 9.454, 2.827, 4.059, and 8.662, respectively, all P < 0.05). The scores of 16 items of WHOQOL-100 such as energy and fatigue, sleep and rest, positive feelings, thinking, learning, memory and concentration, self-esteem, body image and appearance, negative feelings, mobility, activities of daily living, dependence on medical support, personal relationships, social support, health and social care: availability and quality, opportunities to get new information/skills, opportunities for recreation and leisure, and quality of life from viewpoint in the observation group were significantly higher than those in the control group (t = 2.666, 2.571, 2.961, 3.453, 4.279, 2.781, 3.775, 4.807, 5.850, 4.194, 3.324, 3.873, 5.118, 3.244, 2.956, and 4.218, respectively, all P < 0.05). The rate of complications of the observation group was significantly lower than that of the control group (x 2 = 5.829, P < 0.05). Conclusion: The Heider balance can help to reduce the rate of complications, improve knowledge, attitude, practice, and quality of life in urinary diversion patients. These merits make it an attractive approach in guidance of out-hospital intervention.

Regenerative cerium oxide nanozymes alleviate oxidative stress for efficient dry eye disease treatment.

Dry eye disease (DED) is the most common eye disease in ophthalmic consultation except for refractive errors. Therefore, an exploration of valid and alternative therapeutic interventions is essential to feed the urgent medical need. It has been demonstrated that oxidative stress causes multiple adverse effects in the pathogenesis of DED, thence alleviating oxidative stress is an effective therapeutic strategy for the DED treatment. Herein, we developed a cerium oxide nanozyme combined with branched poly(ethylene imine)-graft-poly(ethylene glycol) (bPEI-g-PEG). Owing to its stable hydrophilic chains on the surface reducing the cytotoxicity and loads of amines groups that be combined with cerium ions through coordination bonds, the modified nanozymes (referred to as CNP@bPEI-g-PEG) are water soluble and highly biocompatible. Meanwhile, due to its excellent antioxidant activity, CNP@bPEI-g-PEG nanozymes can mimic the activity of superoxide dismutase and catalase to scavenge intracellular reactive oxygen species (ROS). Experimental studies firmly demonstrated that the modified nanozymes were auto-regenerative and more active in scavenging excessive ROS and alleviating oxidative stress by cerium-element valence state recycling, recovering the morphology of corneal, conjunctival epithelium and the number of goblet cells. The advanced combination may offer a superior therapeutic strategy to deal with oxidative stress for effective treatment of DED.

Correction: Design of foldable, responsively drug-eluting polyacrylic intraocular lens bulk materials for prevention of postoperative complications.

Correction for 'Design of foldable, responsively drug-eluting polyacrylic intraocular lens bulk materials for prevention of postoperative complications' by Yueze Hong et al., J. Mater. Chem. B, 2022, DOI: https://doi.org/10.1039/d2tb01974d.

Design of foldable, responsively drug-eluting polyacrylic intraocular lens bulk materials for prevention of postoperative complications.

Posterior capsular opacification (PCO), resulting from undesired intracapsular cell proliferation, is the most common complication of intraocular lens (IOL) implantation after cataract surgery. In recent years, IOLs have been developed into a drug delivery platform. Compared with traditional eye drops, drug-loaded IOLs have the characteristics of independent patient compliance and no other operation except surgical implantation. In this work, a series of poly(glycidyl methacrylate-co-2-(2-ethoxyethoxy)ethyl acrylate) (PGE) acrylic intraocular lens materials were synthesized as drug delivery platforms. The PGE synthesized with 10% crosslinking agent has excellent optical, foldable, and thermomechanical properties. An aldehyde group was subsequently introduced into the PGE chains, and an antiproliferative drug (doxorubicin) was immobilized onto the PGE chains via an H+-sensitive imine bond. The IOL exhibits H+-dependent Dox release behavior in a simulated pathological environment. The in vitro and in vivo systematical evaluations indicate that such a responsively drug-eluting PGE IOL can effectively prevent PCO.

Aberrant miR-339-5p/neuronatin signaling causes prodromal neuronal calcium dyshomeostasis in mutant presenilin mice.

Mushroom spine loss and calcium dyshomeostasis are early hallmark events of age-related neurodegeneration, such as Alzheimer's disease (AD), that are connected with neuronal hyperactivity in early pathology of cognitive brain areas. However, it remains elusive how these key events are triggered at the molecular level for the neuronal abnormality that occurs at the initial stage of disease. Here, we identify downregulated miR-339-5p and its upregulated target protein, neuronatin (Nnat), in cortex neurons from the presenilin-1 M146V knockin (PSEN1-M146V KI) mouse model of familial AD (FAD). Inhibition of miR-339-5p or overexpression of Nnat recapitulates spine loss and endoplasmic reticulum calcium overload in cortical neurons with the PSEN1 mutation. Conversely, either overexpression of miR-339-5p or knockdown of Nnat restores spine morphogenesis and calcium homeostasis. We used fiber photometry recording during the object-cognitive process to further demonstrate that the PSEN1 mutant causes defective habituation in neuronal reaction in the retrosplenial cortex and that this can be rescued by restoring the miR-339-5p/Nnat pathway. Our findings thus reveal crucial roles of the miR-339-5p/Nnat pathway in FAD that may serve as potential diagnostic and therapeutic targets for early pathogenesis.

MiR-4652-5p Targets RND1 to Regulate Cell Adhesion and Promote Lung Squamous Cell Carcinoma Progression.

Lung squamous cell carcinoma (LUSC) is one subtype of non-small-cell lung cancer, whose pathogenesis has not been fully understood. Exploring molecular mechanisms of LUSC helps a lot with the development of LUSC novel therapy. Hence, our study aims to investigate novel molecular mechanisms. Differentially expressed miRNAs and mRNAs were acquired from The Cancer Genome Atlas database. A series of assays were applied to test cell functions, including qRT-PCR to analyze RND1 and miR-4652-5p expression, dual-luciferase reporter gene assay to verify the targeting relationship between these two genes, cell counting kit-8 and colony formation assays to evaluate the ability of LUSC cells to proliferate, transwell to examine the migratory and invasive abilities, and western blot to test expression of RND1 and cell adhesion-related proteins. RND1 was lowly expressed while miR-4652-5p was highly expressed in LUSC cells. The correlation between these two genes was significantly negative and miR-4652-5p could downregulate RND1 expression. Additionally, cellular function assays validated that RND1 suppressed LUSC cells to proliferate, migrate, and invade. Besides, this gene might also affect cell adhesion. Furthermore, rescue assay suggested that miR-4652-5p downregulated RND1 expression to promote the progression of LUSC cells. Together, miR-4652-5p targeted RND1 to modulate cell adhesion and the progression of LUSC cells.

ABCDEF pulmonary rehabilitation program can improve the mid-term lung function of lung cancer patients after thoracoscopic surgery: A randomized controlled study.

Background Pulmonary rehabilitation is recommended for most patients with lung diseases. However, some previous studies have shown that pulmonary rehabilitation has no obvious effect on short-term lung function in patients with lung cancer. Objective The purpose of this study was to evaluate the effect of the ABCDEF pulmonary rehabilitation program on lung cancer patients who have undergone surgery. Design This was a randomized controlled trial with repeated measures. Settings The study was conducted in the Cardiothoracic Surgery Department of a 4000-bed comprising training and research hospital from 2019 to 2020. Participants A total of 90 patients who underwent thoracoscopic pneumonectomy were divided into two groups of 45, using a completely randomized model. Methods Patients in the experimental group participated in an ABCDEF program (Acapella positive vibration pressure training, breathing exercise, cycling training, dance in the square, education, and follow-up) after surgery. In contrast, the regular care provided to the control group focused on breathing and expectoration guidance. The study outcomes were the first second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, 6 min walking distance, Borg score, incidence of postoperative complications, length of indwelling chest tube, and length of postoperative stay. Generalized estimating equation models were used to compare the changes in the outcomes between the groups over time. Results The ABCDEF pulmonary rehabilitation program for patients who underwent thoracoscopic pneumonectomy was found to be more effective in increasing lung function at 3 months after discharge (p<0.05). However, there was no statistically significant difference on the day of discharge (p>0.05). Exercise tolerance was different at both time points (p<0.05). The incidence of postoperative complications in the experimental group was lower than that in the control group (p<0.05). The length of postoperative stay in the experimental group was also shorter (p<0.05), however, the length of the indwelling chest tube was not significantly different between the intervention and control groups (p>0.05). Conclusions This study showed that the ABCDEF pulmonary rehabilitation program could effectively improve mid-term lung function and exercise tolerance in patients after thoracoscopic pneumonectomy, and reduce the incidence of postoperative complications along with the length of postoperative hospital stay.

Mathematical Analysis of Application of a Three-Dimensional Printing Fixator in the Fracture of Multiple Ribs.

Data were obtained from 66 clinical patients. The patients were divided into a non-3D printing group (control group) and a 3D printing group (intervention group) in a 1 : 1 ratio, with 33 patients in each group. The information including gender, age, incision length, number of surgical roots, bleeding volume, operation time, and intraoperative blood transfusion was collected for SPSS analysis. The results showed the following: (1) The paired t-test was used to test the difference of experimental data. There was a significant difference of 0.01 between the incision length/surgical root number in the intervention group and the incision length/surgical root number in the control group. The incision length/surgical root number in the intervention group was significantly lower than that in the control group. (2) Surgical time, intraoperative blood transfusion, age, and incision length/surgical root number in the intervention group had a significant positive impact on the amount of bleeding. Gender did not affect the amount of bleeding. (3) A total of 1 item of operation time in the intervention group had a significant positive impact on intraoperative blood transfusion. (4) The incision length/number of surgical roots in the intervention group had a noteworthy negative impact on blood transfusion during the operation.

"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.

Gene Therapy for Hepatocellular Carcinoma Using Adenoviral Vectors Delivering a Gene Encoding IL-17A-Neutralizing Antibody Fragments.

High interleukin 17A (IL-17A) expression in hepatocellular carcinoma (HCC) tissue promotes HCC development. This study explores a method to inhibit HCC growth by neutralizing IL-17A in the HCC microenvironment. A novel type 5 adenoviral vector (Ad5) that carries DNA sequences encoding specific neutralizing IL-17A recombinant antibody fragments was developed in this research. After locally injecting into tumor tissues, the Ad5 transduced into tumor cells. This leads to the expression of the anti-IL-17A recombinant antibody fragments in the HCC tissue and consequently to an inhibition of HCC growth by neutralizing IL-17A. The stability of the antibody fragments was optimized by different structures design. Stable HCC cell lines that secrete IL-17A continuously were constructed, which showed stronger invasion and migration ability than control HCC cell lines. In addition, the enhanced migration and invasion ability were partially reversed by applying the adenoviral vectors. These results suggest that IL-17A might promote HCC growth by enhancing the invasion and migration ability of hepatoma cells. The antibody fragments from Ad5 neutralized IL-17A locally, in turn inhibiting the growth of HCC tumors. In conclusion, the local administration of Ad5 vectors encoding IL-17A-neutralizing antibody fragments provides a new option for HCC immunotherapy.

Anti-tumor activity and the mechanism of a green tea (Camellia sinensis) polysaccharide on prostate cancer.

In this study, a homogeneous polysaccharide (GTP), with a molecular weight of 7.0 × 104 Da, was isolated from Green tea, which was only composed of glucose. The antitumor effects of GTP on prostate cancer (PC) cell line along with the possible mechanism was examined. First, we investigate the potential role of microRNA-93 (miR-93) in PC progression. Our results showed that miR-93 was significantly upregulated in human PC tissues and several PC cell lines, and its overexpression was correlated with poor survival in PC patients. Furthermore, functional analysis showed that miR-93 overexpression promoted the migration, invasion and proliferation of PC-3 cells transfected with miR-93 mimics, while its knockdown displayed an opposite result in DU145 cells following miR-93 inhibitor transfection. Additionally, in vivo tumorigenic studies on nude mice confirmed that miR-93 mimic treatment accelerated the growth of PC-3 xenograft tumors. As expected, GTP (25, 50 and 100 µg/ml) inhibited growth of PC-3 cells via inducing apoptosis, which was achieved by elevation of bax/bcl-2 ratio and caspae-3 protein expression, as well as a decrease of miR-93. Thus, miR-93 may be a potential therapeutic target by GTP for PC therapy.

MiR-93 functions as a tumor promoter in prostate cancer by targeting disabled homolog 2 (DAB2) and an antitumor polysaccharide from green tea (Camellia sinensis) on their expression.

Our previous work has demonstrated that the role of miR-93 in prostate cancer (PC) progression. The aim of this study was to determine the downstream gene regulated by miR-93 and the molecular mechanisms underlying its roles in PC. Bioinformatics analysis and luciferase reporter assays predicted disabled homolog 2 (DAB2) as a direct target gene of miR-93. Real time quantitative polymerase chain reaction (qRT-PCR) and Western blot analysis revealed that DAB2 was tumor repressor in PC cells, and its mRNA expression was negatively correlated with miR-93 in PC tissues. Gain and loss of function experiments also indicated DAB2 overexpression significantly suppressed PC cells proliferation, invasion and migration, while knockdown of its expression came to the opposite effect. Furthermore, a rescue experiment indicated miR-93 directly regulated PC cell growth and migration, as well as AKT and ERK activation by targeting DAB2. Additionally, antitumor effect of a Green tea polysaccharide (GTP) on PC-3 cells could be achieved by increasing DAB2 protein expression and inactivating AKT and ERK1/2 signaling. Our study suggests that miR-93 promoted PC progression and metastasis by repressing DAB2 to activate Akt/ERK1/2 pathway, and elevation of DAB2 and inactivation of Akt/ERK1/2 might be a potential therapeutic target for PC by GTP.

MicroRNA-122-3p inhibits tumor cell proliferation and induces apoptosis by targeting Forkhead box O in A549 cells.

The imbalance between cell proliferation and apoptosis was implicated to serve key roles in cancer pathogenesis. The characteristics of microRNAs (miRNAs/miRs) have attracted much attention in research focusing on cancer pathogenesis in recent years. miR-122-3p has been reported to be associated with a number of disease processes and pathogenesis, including lung cancer. The present study aimed to investigate the association of miR-122-3p expression level with cell proliferation and apoptosis in a lung cancer cell line. A549 cells were transfected with miR-122-3p to interrupt the expression of miR-122-3p. Subsequently, MTT and BrdU assay, and western blot were used to analyze the influence of miR-122-3p on lung cancer cell proliferation, cell viability and its underlying mechanism. The present study revealed that, by targeting p27, overexpression of miR-122-3p inhibited cell proliferation in lung cancer. Furthermore, the cell apoptosis analysis suggested that overexpression of miR-122-3p was able to inhibit cell apoptosis by targeting Forkhead box O. These findings suggest that miR-122-3p may be associated with the pathology and progression of lung cancer and be a new therapeutic target for this disease.

Hedgehog signaling pathway affects the sensitivity of hepatoma cells to drug therapy through the ABCC1 transporter.

The poor response to drug therapy often seen in hepatocellular carcinoma requires insight into the molecular interplay responsible for intrinsic or acquired drug resistance. We previously demonstrated that the CD133-/EpCAM- subpopulation of the Huh-7 hepatoma cell line features aberrant activation of the hedgehog signaling (Hh) pathway and chemoresistance. The prevailing hypothesis of the present study is that hedgehog signaling may govern expression of ATP-binding cassette (ABC) transporters, which are responsible for drug resistance in the CD133-/EpCAM- subpopulation. Our aim is to reveal the molecular interplay in the mediation of drug resistance with a newly established Huh-7 subpopulation featuring high Hh signaling activity and drug resistance. In this study, chemoresistance was determined in a newly established Huh-7-DN subpopulation featuring the CD133-/EpCAM- surface marker profile, aberrant expression of Hh pathway, and epithelial-mesenchymal transition (EMT). Expression of ABC transporter proteins (ABCB1, ABCC1, and ABCG2) and Hh transcription factor Gli-1/2 was evaluated with and without Hh signaling antagonists LDE225 or itraconazole. We found that hedgehog signaling activity as determined by transfection with a Gli-Lux reporter cassette and gene expression levels tended to increase from Huh-7 CD133+/EpCAM+ to CD133-/EpCAM-, and the highest levels were found in Huh-7-DN cells. The Huh-7-DN subpopulation exhibited characteristics of EMT as evidenced by increased expression of vimentin and loss of E-cadherin. Sorafenib significantly inhibited the viability of all subpopulations except the Huh-7-DN subpopulation. Compared with other sorafenib-sensitive subpopulations, the Huh-7-DN subpopulation showed enhanced expression of Hh transcription factor Gli-2 and ABCC1 transporter protein. Silencing Gli-2 by lentivirus harboring shRNA against Gli-2 or LDE225 significantly suppressed expression of Gli-2 and ABCC1 genes in Huh-7-DN subpopulation. In conclusion, aberrant hedgehog signaling activation is linked to poor differentiation, epithelial-mesenchymal transition, and chemoresistance in the Huh-7-DN subpopulation. Hedgehog signaling transcription factor Gli-2 appears to be the primary regulator for drug sensitivity of hepatoma through the ABCC1 transporter.