Beneficial mechanisms of dimethyl fumarate in autoimmune uveitis: insights from single-cell RNA sequencing.

BACKGROUND: Dimethyl fumarate (DMF) is a fumaric acid ester that exhibits immunoregulatory and anti-inflammatory properties. However, the function of DMF in autoimmune uveitis (AU) is incompletely understood, and studies comprehensively exploring the impact of DMF on immune cells are still lacking. METHODS: To explore the function of DMF in uveitis and its underlying mechanisms, we conducted single-cell RNA sequencing (scRNA-seq) on the cervical draining lymph node (CDLN) cells of normal, experimental autoimmune uveitis (EAU), and DMF-treated EAU mice. Additionally, we integrated scRNA-seq data of the retina and CDLNs to identify the potential impact of DMF on ocular immune cell infiltration. Flow cytometry was conducted to verify the potential target molecules of DMF. RESULTS: Our study showed that DMF treatment effectively ameliorated EAU symptoms. The proportional and transcriptional alterations in each immune cell type during EAU were reversed by DMF treatment. Bioinformatics analysis in our study indicated that the enhanced expression of Pim1 and Cxcr4 in EAU was reversed by DMF treatment. Further experiments demonstrated that DMF restored the balance between effector T (Teff) /regulatory T (Treg) cells through inhibiting the pathway of PIM1-protein kinase B (AKT)-Forkhead box O1 (FOXO1). By incorporating the scRNA-seq data of the retina from EAU mice into analysis, our study identified that T cells highly expressing Pim1 and Cxcr4 were enriched in the retina. DMF repressed the ocular infiltration of Teff cells, and this effect might depend on its inhibition of PIM1 and CXCR4 expression. Additionally, our study indicated that DMF might reduce the proportion of plasma cells by inhibiting PIM1 expression in B cells. CONCLUSIONS: DMF effectively attenuated EAU symptoms. During EAU, DMF reversed the Teff/Treg cell imbalance and suppressed the ocular infiltration of Teff cells by inhibiting PIM1 and CXCR4 expression. Thus, DMF may act as a new drug option for the treatment of AU.

Associated risk factors of postoperative pain after glaucoma surgery: a prospective study.

PURPOSE: This study aimed to determine degree of postoperative pain and the incidence of serious postoperative pain after glaucoma surgery and further to identify the associated risk factors. METHODS: A total of 194 consecutive patients who were diagnosed with glaucoma and underwent glaucoma surgery were enrolled in this study. The intensity of postoperative pain was evaluated using numerical rating scale (NRS) within 24 h after surgery; NRS ≥ 5 was considered as clinically significant postoperative pain. Risk factors associated with the development of postoperative pain were analyzed by multivariate logistic regression analysis. RESULTS: Clinically significant postoperative pain was experienced at any time after glaucoma surgery in 41.75% of the patients, which peak at 2 h. 27.8% of the patients requested analgesic medication within 24 h after surgery. According to multivariate logistic regression analysis, preoperative anxiety (OR = 4.13 [1.29-13.2], p = 0.017), cyclophotocoagulation (OR = 30.9 [3.47-375.1], p = 0.002), and phacotrabeculectomy combined with or without intraocular lens implantation (OR = 30.0 [2.69-335.6], p = 0.006) were associated with increased clinically significant postoperative pain. Interestingly, patients with diabetes and/or hypertension were associated with less postoperative pain after glaucoma surgery (OR = 0.23 [0.08-0.64], p = 0.005). CONCLUSION: Patients undergoing glaucoma surgery tend to experience postoperative pain in the early postoperative period. Anxiety level and surgery types of cyclophotocoagulation and phacotrabeculectomy are risk factors for postoperative pain. Patients with diabetes and/or hypertension are less likely to develop postoperative pain.

Risk factors for persistent epiphora following successful canalicular laceration repair.

AIM: To identify the risk factors of epiphora in patients with anatomical patency after surgical repair of canalicular laceration. METHODS: This retrospective case series included 178 cases of canalicular laceration repair from 2005 to 2012. Demographic data collected from each patient included age, sex, type of injury, distance from the distal lacerated end of the canaliculus to the punctum, the severity score for the structural abnormity of the medial canthus, the duration of stent placement, and the timing of surgery. The risk factors for epiphora were evaluated using Logistic regression models. RESULTS: Among the 178 cases, 45 (25.3%) with lacrimal patency after irrigation had symptomatic epiphora at the final follow-up. Patients' sex, age, type of injury, duration of stent placement, timing of surgery, and concurrent trauma were not found to be significantly associated with symptomatic epiphora after surgical repair of the lacerated canaliculus (P>0.05). A distance of more than 5 mm from the distal cut end to the punctum was closely and significantly associated with symptomatic epiphora after surgical repair of the lacerated canaliculus (P<0.01). Symptomatic epiphora was significantly more frequent in patients with higher severity scores for structural abnormities of the medial canthus (P<0.01). CONCLUSION: Our results indicate that the risk factors for postoperative symptomatic epiphora include a further distance between the distal cut end and the lacrimal punctum and a higher severity score for structural abnormities of the medial canthus. These findings could be used to prognosticate postoperative symptomatic epiphora.

Incidence and Risk Factors of Moderate to Severe Postoperative Pain Following the Placement of Primary and Secondary Orbital Implants: A Prospective Observational Study.

PURPOSE: To prospectively explore the incidence and risk factors of moderate to severe pain after primary and secondary orbital implantation following evisceration or enucleation surgery. METHODS: One hundred eighteen patients under general anesthesia for orbital implantation were enrolled in this study. In 91 patients, primary orbital implantation followed evisceration, and in 27 patients, the implantation was secondary after previous evisceration or enucleation surgery. Medical interventions for all participants were followed by standardized surgical, anesthetic, and analgesic protocols. Postoperative pain (POP) intensity was quantified by an 11-point numerical rating scale within 72 hours after the surgery, numerical rating scale ≥4 was considered moderate to severe POP. Multivariate logistic regression was utilized to identify the risk factors related to the development of POP. RESULTS: Thirty-five patients (29.7%) displayed moderate to severe POP, particularly within 6 to 24 hours after surgery, which peaked at 24 hours. Of these patients, 26 patients who were unable to tolerate the pain received additional doses of analgesics during in-hospital stay. Logistic regression model revealed that preoperative anxiety (odds ratios = 4.890; p = 0.002), congenital microphthalmia (odds ratios = 14.602; p = 0.038), and surgical time longer than 60 minutes (odds ratios = 5.586; p = 0.001) were significantly associated with moderate to severe POP after orbital implantation. CONCLUSIONS: Orbital implantation after evisceration or enucleation surgery is likely to cause moderate to severe pain intensity in the early postoperative period. Preoperative anxiety, prolonged surgical time, and congenital microphthalmia were the risk factors.

Laquinimod Inhibits Inflammation-Induced Angiogenesis in the Cornea.

Background: Inflammation-induced angiogenesis plays a critical role in many eye diseases, and abnormal angiogenesis inhibition is regarded as a therapeutic approach. Here, we examined the effects of laquinimod on inflammatory corneal angiogenesis. Methods: Mouse model of corneal neovascularization was induced by NaOH. Laquinimod or control vehicle were topically applied to alkali-treated eyes twice a day for 10 days. Corneal neovascularization, infiltrating inflammatory cells, and the levels of chemokines, pro-inflammatory cytokines were assessed. RAW cells and human umbilical vein endothelial cells were used in vitro to further explore the underlying mechanisms of the effects of laquinimod on inflammation-induced angiogenesis. Results: Topical administration of laquinimod to the injured corneas dramatically inhibited alkali-induced corneal neovascularization and decreased inflammatory cell (such as macrophage) infiltration in a corneal injury mouse model. Laquinimod significantly downregulated the expression of chemokines (monocyte chemotactic protein-1 and macrophage inflammatory protein-1), pro-inflammatory cytokines (interleukin-1ß and tumor necrosis factor-alpha), vascular endothelial growth factor, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 and apoptosis-associated speck-like protein containing C-terminal caspase-recruitment domain adaptor protein in both injured corneas and RAW cells. In vitro, laquinimod also dramatically inhibited the proliferation, migration and tube formation of human umbilical vein endothelial cells. Conclusion: Laquinimod inhibits inflammation-induced angiogenesis in the cornea. These results suggest that laquinimod is a potential new therapeutic option for corneal neovascularization and other angiogenesis-associated diseases.

Effect of congenital blepharoptosis on corneal biomechanical properties and changes after ptosis surgery.

OBJECTIVES: We studied the difference in the corneal biomechanical parameters of ptotic and fellow eyes in patients with congenital blepharoptosis. The correlations between corneal biomechanical parameters and demographic or ocular parameters, and the changes after surgery were also researched. METHODS: The corneal biomechanical parameters were measured by Corvis ST tonometry. The central corneal thickness (CCT), axial length (AL) and keratometry measurements were performed with LenStar LS900, and intraocular pressure (IOP) by non-contact applanation tonometry. The parameters were evaluated for the effect of ptosis and the relationship of corneal biomechanical parameters. These examinations were repeated 6 months after blepharoptosis surgery. RESULTS: Twenty-nine patients were enroled. The Corvis ST parameters (Deformation amplitude [DA], A1 times, and A1 velocity), CCT, IOP with NCT, IOP with corrected, differed significantly between ptotic and fellow eyes. CCT was significantly positively correlated with Length A1 and IOP with Corvis, and negatively correlated with IOP corrected by Corvis of the ptotic eyes. The same tendency was found in the fellow eyes. Six months after the ptosis surgery, the differences in corneal biomechanics parameters between ptotic eyes and fellow eyes were not significantly changed. CONCLUSIONS: Congenital blepharoptosis causes significant corneal biomechanical changes measured by Corvis ST. The ptotic eyes had thicker and less deformable corneas. The differences in corneal biomechanics between ptotic eyes and fellow eyes were mostly related to CCT changes. Six months after surgery, these differences in corneal biomechanics did not change significantly.

Metformin inhibits the proliferation and metastasis of osteosarcoma cells by suppressing the phosphorylation of Akt.

Metformin (Met) is a therapeutic agent for the treatment of type 2 diabetes mellitus. There is evidence that Met may reduce the risk of cancer in patients with type 2 diabetes mellitus by inhibiting tumor cell growth, prolonging the overall survival time in patients with various types of malignancy. However, the function and mechanism of Met have not been fully elucidated in osteosarcoma (OS). The present study evaluated the anti-proliferative effect of Met on MG63 and U2OS OS cells, identifying that it acted in a dose- and time-dependent manner. Met also inhibited OS cell migration and invasion, potentially by regulating the epithelial-mesenchymal transition in OS cells. Mechanistically, Met was demonstrated to partly exert these functions through the suppression of Akt phosphorylation, which was associated with increased phosphatase and tensin (PTEN) expression. Silencing PTEN prevented the Met-induced inhibition of the growth and metastasis of OS cells. As Met has anti-proliferative and anti-metastatic effects on OS cells it is a potential candidate, in combination with other chemotherapeutic agents, for use in the treatment of OS.

microRNA-21a-5p/PDCD4 axis regulates mesenchymal stem cell-induced neuroprotection in acute glaucoma.

Mesenchymal stem cells (MSCs) have been demonstrated to have promising therapeutic benefits for a variety of neurological diseases; however, the underlying mechanisms are poorly understood. Here, we showed that intravitreal infusion of MSCs promoted retinal ganglion cell (RGC) survival in a mouse model of acute glaucoma, with significant inhibition of microglial activation, production of TNF-α, IL-1ß, and reactive oxygen species, as well as caspase-8 and caspase-3 activation. In vitro, MSCs inhibited both caspase-8-mediated RGC apoptosis and microglial activation, partly via the action of stanniocalcin 1 (STC1). Furthermore, we found that microRNA-21a-5p (miR-21) and its target, PDCD4, were essential for STC1 production and the neuroprotective property of MSCs in vitro and in vivo. Importantly, miR-21 overexpression or PDCD4 knockdown augmented MSC-mediated neuroprotective effects on acute glaucoma. These data highlight a previously unrecognized neuroprotective mechanism by which the miR-21/PDCD4 axis induces MSCs to secrete STC1 and other factors that exert neuroprotective effects. Therefore, modulating the miR-21/PDCD4 axis might be a promising strategy for clinical treatment of acute glaucoma and other neurological diseases.

Clinical Outcomes of FP-7/8 Ahmed Glaucoma Valves in the Management of Refractory Glaucoma in the Mainland Chinese Population.

BACKGROUND: To evaluate the efficacy and safety of the Ahmed glaucoma valve (AGV) and the risk factors associated with AGV implantation failure in a population of Chinese patients with refractory glaucoma. METHOD: In total, 79 eyes with refractory glaucoma from 79 patients treated in our institution from November 2007 to November 2010 were enrolled in this retrospective study. The demographic data, preoperative and postoperative intraocular pressures (IOPs), best corrected visual acuity (BCVA), number of anti-glaucoma medications used, completed and qualified surgery success rates and postoperative complications were recorded to evaluate the outcomes of AGV implantation. Factors that were associated with implant failure were determined using Cox proportional hazard regression model analysis and multiple linear regression analysis. PRINCIPLE FINDINGS: The average follow-up time was 12.7±5.8 months (mean±SD). We observed a significant reduction in the mean IOP from 39.9±12.6 mm Hg before surgery to 19.3±9.6 mm Hg at the final follow-up. The complete success rate was 59.5%, and the qualified success rate was 83.5%. The number of previous surgeries was negatively correlated with qualified success rate (P<0.05, OR=0.736, 95% CI 0.547-0.99). Patients with previous trabeculectomy were more likely to use multiple anti-glaucoma drugs to control IOP (P<0.01). The primary complication was determined to be a flat anterior chamber (AC). CONCLUSION: AGV implantation was safe and effective for the management of refractory glaucoma. Patients with a greater number of previous surgeries were more likely to experience surgical failure, and patients with previous trabeculectomy were more likely to use multiple anti-glaucoma drugs to control postoperative IOP.