Celastrol alleviates subconjunctival fibrosis induced by silicone implants mimicking glaucoma surgery.

Subconjunctival fibrosis is critical to the outcomes of several ophthalmic conditions or procedures, such as glaucoma filtering surgery. This study aimed to investigate the anti-fibrotic effect of celastrol on subconjunctival fibrosis and to further reveal the underlying mechanisms. Given the toxicity and poor water solubility of celastrol, we fabricated celastrol-loaded nanomicelles hydrogel hybrid to attenuate subconjunctival fibrosis around silicone implant. The results in vitro demonstrated that celastrol-nanodrug suppressed TGF-ß1-induced fibroblast activation and extracellular matrix deposition in human pterygium fibroblasts by inhibiting the TGF-ß1/Smad2/3-YAP/TAZ signaling. Further, the results in vivo showed that the celastrol-nanodrug reduced subconjunctival fibrosis in the rabbit model of silicone implantation. These findings suggested that celastrol could serve as a promising therapy for controlling subconjunctival fibrosis. This study aimed to investigate the anti-fibrotic effect of celastrol on subconjunctival fibrosis and to further reveal the underlying mechanisms. We used celastrol-loaded nanomicelles hydrogel hybrid as a sustained-release drug. A rabbit model of subconjunctival fibrosis following silicone implantation was used for in vivo study and TGF-ß1-induced human pterygium fibroblast (HPF) activation as an in vitro model. The effects of celastrol on inhibiting TGF-ß1-induced migration and proliferation of HPFs were evaluated by scratch wound assay and CCK-8, respectively. Immunofluorescence and western blotting were used to examine the effect of celastrol on the expression of α-SMA, collagen I, fibronectin, and the targets of the Hippo signaling pathway. We found that in vivo celastrol treatment reduced the expression of YAP and TAZ in subconjunctival tissue. Moreover, celastrol alleviated collagen deposition and subconjunctival fibrosis at 8weeks. No obvious tissue toxicity was observed in the rabbit models. Mechanistically, celastrol significantly inhibited TGF-ß1-induced proliferation and migration of HPFs. Pretreatment of HPFs with celastrol also suppressed the TGF-ß1-induced protein expression of α-SMA, collagen I, fibronectin, TGF-ßRII, phosphorylated Smad2/3, YAP, TAZ, and TEAD1. In conclusion, celastrol effectively prevented subconjunctival fibrosis through inhibiting TGF- ß1/Smad2/3-YAP/TAZ pathway. Celastrol could serve as a promising therapy for subconjunctival fibrosis.

An injectable thermoresponsive-hydrogel for lamellar keratoplasty: In-situ releases celastrol and hampers corneal scars.

Corneal stromal fibrosis is a common cause of visual impairment resulting from corneal injury, inflammation and surgery. Therefore, there is an unmet need for inhibiting corneal stromal fibrosis. However, bioavailability of topical eye drops is very low due to the tear and corneal barriers. In situ delivery offers a unique alternative to improve efficacy and minimize systemic toxicity. Herein, a drug delivery platform based on thermoresponsive injectable hydrogel/nano-micelles composite with in situ drug-controlled release and long-acting features is developed to prevent corneal scarring and reduce corneal stromal fibrosis in lamellar keratoplasty. The in-situ gelation hydrogels enabled direct delivery of celastrol to the corneal stroma. In vivo evaluation with a rabbit anterior lamellar keratoplasty model showed that hydrogel/micelles platform could effectively inhibit corneal stromal fibrosis. This strategy achieves controlled and prolonged release of celastrol in the corneal stroma of rabbit. Following a single corneal interlamellar injection, celastrol effectively alleviated fibrosis via mTORC1 signal promoting autophagy and inhibiting TGF-ß1/Smad2/3 signaling pathway. Overall, this strategy demonstrates promise for the clinical application of celastrol in preventing corneal scarring and reducing corneal stromal fibrosis post-lamellar keratoplasty, highlighting the potential benefits of targeted drug delivery systems in ocular therapeutics.

M2 macrophages promote subconjunctival fibrosis through YAP/TAZ signalling.

PURPOSE: To evaluate the role of M2 macrophages in subconjunctival fibrosis after silicone implantation (SI) and investigate the underlying mechanisms. MATERIALS AND METHODS: A model of subconjunctival fibrosis was established by SI surgery in rabbit eyes. M2 distribution and collagen deposition were evaluated by histopathology. The effects of M2 cells on the migration (using wound-scratch assay) and activation (by immunofluorescence and western blotting) of human Tenon's fibroblasts (HTFs) were investigated. RESULTS: There were more M2 macrophages (CD68+/CD206+ cells) occurring in tissue samples around silicone implant at 2 weeks postoperatively. Dense collagen deposition was observed at 8 weeks after SI. In vitro experiment showed M2 expressed high level of CD206 and transforming growth factor-ß1 (TGF-ß1). The M2-conditioned medium promoted HTFs migration and the synthesis of collagen I and fibronectin. Meanwhile, M2-conditioned medium increased the protein levels of TGF-ß1, TGF-ßR II, p-Smad2/3, yes-associated protein (YAP), and transcriptional coactivator with PDZ-binding motif (TAZ). Verteporfin, a YAP inhibitor, suppressedTGF-ß1/Smad2/3-YAP/TAZ pathway and attenuated M2-induced extracellular matrix deposition by HTFs. CONCLUSIONS: TGF-ß1/Smad2/3-YAP/TAZ signalling may be involved in M2-induced fibrotic activities in HTFs. M2 plays a key role in promoting subconjunctival fibrosis and can serve as an attractive target for anti-fibrotic therapeutics.

Antibiotic Delivery System for Treating Bacteria-Induced Anterior Blepharitis.

The eyelid-related disease of blepharitis remains a tricky ocular disorder and affects patient compliance. However, there is no available and effective treatment, making it extremely challenging. Herein, an antibacterial system based on antibiotic delivery was developed and applied in a blepharitis model induced by bacteria. The antibacterial tests against Staphylococcus aureus both in vitro and in vivo demonstrated that the system shows a favorable bactericidal effect. Then, histological evaluation indicated that the system shows both antibacterial and anti-inflammatory effects. This facile design provided an effective ocular infection management, which displays a promising prospect while addressing other complex ocular disorders.

Multifunctional Biotemplated Micromotors for In Situ Decontamination of Antibiotics and Heavy Metals in Soil and Groundwater.

The ubiquitous pollution by antibiotics and heavy metal ions has posed great threats to human health and the ecological environment. Therefore, we developed a self-propelled tubular micromotor based on natural fibers as an active heterogeneous catalyst for antibiotic degradation and adsorbent for heavy metal ions in soil/water. The prepared micromotors can move in the presence of hydrogen peroxide (H2O2) through a bubble recoil mechanism. The MnO2 NPs and MnFe2O4 NPs loaded on the hollow fibers not only enabled self-driven motion and magnetic control but also served as activators of peroxymononsulfate (PMS) and H2O2 to produce active free radicals SO4•- and •OH. Benefiting from the self-propulsion and bubble generation, the micromotors can effectively overcome the disadvantage of low diffusivity of traditional heterogeneous catalysts, achieving the degradation of more than 90% TC in soil within 30 min. Meanwhile, due to the large specific surface area, abundant active sites, and strong negative zeta potential, the micromotors can effectively adsorb heavy metal ions in the water environment. In 120 min, self-propelled micromotors removed more than 94% of lead ions, an increase of 47% compared to static micromotors, illustrating the advantages of on-the-fly capture. The prepared micromotors with excellent catalytic performance and adsorption capacity can simultaneously degrade antibiotics and adsorb heavy metal ions. Moreover, the magnetic response enabled the micromotors to be effectively separated from the system after completion of the task, avoiding the problem of secondary pollution. Overall, the proposed micromotors provide a new approach to the utilization of natural materials in environmental applications.

Novel technique for amniotic membrane transplantation for acute Stevens-Johnson syndrome/toxic epidermal necrolysis patients.

Purpose: To report a novel technique to facilitate amniotic membrane transplantation (AMT) for acute stage Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Design: Laboratory investigation and retrospective, single-center case series. Methods: The polylactic acid (PLA) amniotic fornical ring (AFR) have been successfully manufactured by three-dimensional (3D) printing technology for AMT. This study retrospectively analyzed the medical records of 5 SJS/TEN patients at the acute stage between 2019 and 2023. Patients were surgically treated with AFR or sutured amniotic membrane transplant (SAMT). Epidemiology, best-corrected visual acuity (BCVA), acute ocular severity score, operative duration, epithelial healing time, amniotic dissolution and follow-up time were evaluated. Results: Of all five patients, three patients (6 eyes) received AFR/AMT (Group A), and 2 patients (4 eyes) received SAMT (Group B). There were no significant differences between two groups in the mean preoperative days and vision changes. The mean operation duration was 11.7 ± 3.8 mins in group A. Compared with the SAMT (48.8 ± 5.3 mins), the operation duration was reduced by 76.02%. The mean times for epithelial healing were 32.5 ± 29.2 days in group A and 12.0 ± 0.0 days in group B. In addition, there were no significant side effects of 3D-printed sterile AFR on the eyes. Conclusions: 3D-printed PLA scaffolds could be used as an AFR device for acute SJS/TEN. In addition, personalized 3D-printed AFR is superior to conventional SAMT in operation duration.

Carboxymethyl chitosan regulates macrophages polarization to inhibit early subconjunctival inflammation in conjunctival injury.

Persistent subconjunctival inflammation leads to subconjunctival fibrosis and eventual visual impairment. There is an unmet need for how to effectively inhibit subconjunctival inflammation. Herein, the effect of carboxymethyl chitosan (CMCS) on subconjunctival inflammation was investigated and the mechanism was involved. The evaluation of cytocompatibility demonstrated that CMCS had good biocompatibility. The in vitro results showed that CMCS inhibited secretions of pro-inflammatory cytokines (IL-6, TNF-α, IL-8 and IFN-γ) and chemokines (MCP-1), and downregulated TLR4/MyD88/NF-κB pathway in M1. The in vivo results displayed that CMCS alleviated conjunctival edema and congestion, and improved conjunctival epithelial reconstruction significantly. Both in vitro and in vivo results demonstrated that CMCS inhibited the infiltration of macrophages and reduced the expressions of iNOS, IL-6, IL-8 and TNF-α in the conjunctiva. Given that CMCS indicated the activities of inhibiting M1 polarization, NF-κB pathway, and subconjunctival inflammation, which may be employed as a potent treatment for subconjunctival inflammation.

A chitosan-based self-healing hydrogel for accelerating infected wound healing.

Wound infection causes irregular tissue closure, often with prolonged healing. Traditional therapies based on antibiotic delivery have resulted in reduced therapeutic efficiency and drug resistance. Such features make it highly desirable to develop an antibiotic-free material for wound infection in clinical applications. Herein, a self-healing antibacterial hydrogel was designed to realize the treatment of S. aureus-infected wounds. The design of the dynamic imine bond endows hydrogels with self-healing and adaptive properties, which could cover the irregular wound and improve the safety of administration. In addition, benefiting from quaternized chitosan, the designed hydrogels also present fascinating antimicrobial properties and favorable biocompatibility. The evaluation in a rat skin wound infection model indicates that the fascinating antimicrobial effect accelerates wound healing by the designed hydrogels. This facile design of an antibiotic-free material allows effective wound infection management, which may be promising in coping with other complex wound healings.

Peroxidase-like MoS2/Ag nanosheets with synergistically enhanced NIR-responsive antibacterial activities.

Pathogenic microbial infections have been threatening public health all over the world, which makes it highly desirable to develop an antibiotics-free material for bacterial infection. In this paper, molybdenum disulfide (MoS2) nanosheets loaded with silver nanoparticles (Ag NPs) were constructed to inactive bacteria rapidly and efficiently in a short period under a near infrared (NIR) laser (660 nm) in the presence of H2O2. The designed material presented favorable features of peroxidase-like ability and photodynamic property, which endowed it with fascinating antimicrobial capacity. Compared with free MoS2 nanosheets, the MoS2/Ag nanosheets (denoted as MoS2/Ag NSs) exhibited better antibacterial performance against Staphylococcus aureus by the generated reactive oxygen species (ROS) from both peroxidase-like catalysis and photodynamic, and the antibacterial efficiency of MoS2/Ag NSs could be further improved by increasing the amount of Ag. Results from cell culture tests proved that MoS2/Ag3 nanosheets had a negligible impact on cell growth. This work provided new insight into a promising method for eliminating bacteria without using antibiotics, and could serve as a candidate strategy for efficient disinfection to treat other bacterial infections.

Risk factors of cerebrospinal fluid leakage after neuroendoscopic transsphenoidal pituitary adenoma resection: a systematic review and meta-analysis.

Introduction: Cerebro spinal fluid (CSF) leakage is common and might lead to severe postoperative complications after endoscopic transsphenoidal pituitary adenoma resection. However, the risk factors of postoperative CSF leakage are still controversial. This article presents a systematic review to explore the explicit risk factors of CSF leakage after endoscopic transsphenoidal pituitary adenomere section. Methods: PRISMA and AMSTAR guidelines were followed to assess the methodological quality of the systematic review. PubMed, Medline, Embase, Web of Science, Cochrane, Clinical Trails, CNKI, CBM, Wan Fang, and VIP databases were searched for all studies on postoperative CSF leak risk factors. The quality of the included studies was assessed by the Newcastle-Ottawa scale. Review Manager 5.4 software was used to calculate the pooled effect size of potential factors with statistical significance. Results: A total of 6775 patients with pituitary adenoma across 18 articles were included, containing 482 cases of postoperative CSF leakage (accounting for 7.11%). All of the articles had a quality score > 5, indicating good quality. Meta-analysis showed that an increased risk of CSF leak was found for higher levels of BMI (MD=1.91, 95% CI (0.86,2.96), bigger tumor size [OR=4.93, 95% CI (1.41,17.26)], greater tumor invasion (OR=3.01, 95% CI (1.71, 5.31), the harder texture of tumor [OR=2.65, 95% CI (1.95,3.62)], intraoperative cerebrospinal fluid leakage [OR=5.61, 95% CI (3.53,8.90)], multiple operations [OR=2.27, 95% CI (1.60,3.23)]. Conclusion: BMI, multiple operations, tumor size, tumor invasion, hard texture, and intraoperative cerebrospinal fluid leakage are the risk factors of postoperative CSF leakage. Clinical doctors should pay attention to these risk factors, and conduct strict skull base reconstruction and careful postoperative management.

A plasma-image-assisted method for matrix effect correction in laser-induced breakdown spectroscopy.

The matrix effect is one of the main bottlenecks for the laser-induced breakdown spectroscopy (LIBS) technique. In this work, image-assisted, laser-induced breakdown spectroscopy (IA-LIBS) based on the Lomakin-Scherbe formula was put forward as a correction to the matrix effect. The brightness and area information in the plasma image was extracted to correct the spectral line intensities among which the brightness information characterizes the plasma temperature, and the area information characterizes the ablative mass. To verify the feasibility of this method, the experiment was conducted on metal samples and pressed samples. The method was applied for quantitative analysis of copper (Cu), magnesium (Mg) in metal samples and chromium (Cr), manganese (Mn) in pressed samples. For the metal samples, after correcting the matrix effect by IA-LIBS, the determination coefficient R squared (R2) of Cu I 510.55 nm and Mg I 518.36 nm calibration curves were increased from 0.726 to 0.942 to 0.992 and 0.988, respectively. The root-mean-square-error of cross-validation (RMSECV) and the average relative error (ARE) decreased by 75.10% and 77.18%, respectively. For the pressed samples, R2 of Cr I 520.84 nm and Mn I 403.07 nm calibration curves corrected by IA-LIBS increased from 0.364 to 0.098 to 0.975 and 0.980; and RMSECV and ARE decreased by 77.88% and 83.83%, respectively. The experimental results showed that IA-LIBS had an obvious improvement on elimination of the matrix effect for the different samples and the different elements. Therefore, IA-LIBS will become a promising technology and will greatly promote the development of LIBS in various fields.