Uric acid-driven NLRP3 inflammasome activation triggers lens epithelial cell senescence and cataract formation.

Excessive uric acid (UA) is associated with age-related cataract. A previous study showed that a high UA level in the aqueous humor stimulated the senescence of lens epithelial cells (LECs), leading to cataract progression. To better understand the underlying mechanisms, we investigated UA-driven senescence in human lens tissue samples obtained during surgery, rat lens organ cultures, and in vivo experiments, using senescence-associated ß-galactosidase (SA-ß-gal) staining, electronic microscopy, Western blotting, and histological analyses. Initially, we identified markedly higher expressions of NLRP3 and caspase-1 in the lens capsules of hyper-uricemic patients compared to normo-uricemic patients. This increase was accompanied by a significant rise in the SA-ß-gal positive rate. We next built a cataract model in which rat lenses in an organ culture system were treated with an increasing dosage of UA. Notably, opacification was apparent in the lenses treated with 800 µM of UA starting on the fifth day. Mechanistically, UA treatment not only significantly induced the expression of NLRP3, caspase-1, and IL-1ß, but also upregulated the levels of SA-ß-gal and the senescence regulators p53 and p21. These effects were fully reversed, and lens opacification was ameliorated by the addition of MCC950, a selective NLRP3 antagonist. Moreover, an in vivo model showed that intravitreal UA injection rapidly induced cataract phenotypes within 21 days, an effect significantly mitigated by co-injection with MCC950. Together, our findings suggest that targeting the UA-induced NLRP3 inflammasome with MCC950 could be a promising strategy for preventing cataract formation associated with inflammageing.

Design and experiment of high-field asymmetric waveform ion mobility spectrometry chip based on an integrated temperature control printed circuit board structure.

RATIONALE: During the detection of volatile organic compounds (VOC) using high-field asymmetric waveform ion mobility spectrometry (FAIMS), the ambient temperature significantly impacts the accuracy of planar FAIMS. To mitigate the influence of ambient temperature on detection accuracy and enhance resolution, a FAIMS system based on the inner impedance characteristics of a printed circuit board (PCB) was designed for temperature control. METHODS: This study, conducted under standard atmospheric pressure, aimed to assess the signal stability of a planar FAIMS instrument with and without temperature control, and the effect of temperature change on the detection ability of acetone, ethanol, and their mixture was studied using PCB self-heating. RESULTS: Experimental results demonstrated that the base noise in FAIMS with temperature control was 0.2 pA, whereas that in FAIMS without temperature control was 1.8 pA. Notably, with increasing temperature, the detection ability of FAIMS changes accordingly. The optimal relative detection ability of acetone was observed when the electrode plate was heated to 45°C under an electric field of 15 kV/cm. CONCLUSIONS: This study provides a novel approach to improve the resolving power of FAIMS systems and their signal-to-noise ratio. The utilization of a PCB-based temperature control proved effective in stabilizing FAIMS signal characteristics and optimizing detection capabilities, particularly for VOCs such as acetone. These findings have significant implications for improving the accuracy and resolving power of FAIMS systems in VOC detection applications.

ELEVATED LEVEL OF URIC ACID, BUT NOT GLUCOSE, IN AQUEOUS HUMOR AS A RISK FACTOR FOR DIABETIC MACULAR EDEMA IN PATIENTS WITH TYPE 2 DIABETES.

PURPOSE: To determine the association of uric acid (UA) and glucose in aqueous humor with diabetic macular edema (DME) in patients with Type 2 diabetes. METHODS: Patients with DME or diabetes mellitus without retinopathy were enrolled from August 2016 to December 2020. Nondiabetic patients with age-related cataract or age-related macular degeneration were included as controls. RESULTS: A total of 585 eyes from 585 patients were included for this study. Statistical analysis showed that aqueous UA was associated with central retinal thickness (r = 0.39, P < 0.0001), with higher levels of UA in severe DME and lower levels in mild DME, suggesting an ocular source of UA from the diabetic retina. Aqueous UA {odds ratio (OR), 6.88 (95% confidence interval [CI], 2.61-18.12)}, but not aqueous glucose (0.95 [95% CI, 0.73-1.23]) or serum UA (0.90 [95% CI, 0.66-1.23]), was a stronger predictor for DME than the duration of DM (1.26 [95% CI, 1.12-1.42]) or hemoglobin A1c (1.35 [95% CI, 0.99-1.83]). If aqueous UA (<2.46 mg/dL) and aqueous glucose (<6.43 mmol/L) were used as reference, high UA (≥2.46 mg/dL) alone was associated with 5.83-fold increase in risk of DME, but high glucose (≥6.43 mg/dL) alone was not associated with DME. CONCLUSION: Increased aqueous UA, but not glucose, is an independent risk factor for DME. These data suggest that an intravitreal UA-lowering therapy could be beneficial for DME.

Cardiovascular safety of celecoxib in rheumatoid arthritis and osteoarthritis patients: A systematic review and meta-analysis.

OBJECTIVE: To assess the cardiovascular safety of celecoxib compared to non-selective non-steroid anti-inflammatory drugs or placebo. METHODS: We included randomized controlled trials of oral celecoxib compared with a non-selective NSAID or placebo in rheumatoid arthritis and osteoarthritis patients. We conducted searches in EMBASE, Cochrane CENTRAL, MEDLINE, China National Knowledge Infrastructure, VIP, Wanfang, and Chinese Biomedical Literature Database. Study selection and data extraction were done by two authors independently. The risk of bias was assessed using Cochrane's risk-of-bias Tool for Randomized Trials. The effect size was presented as a risk ratio with their 95% confidence interval. RESULTS: Until July 22nd, 2021, our search identified 6279 records from which, after exclusions, 21 trials were included in the meta-analysis. The overall pooled risk ratio for Antiplatelet Trialists Collaboration cardiovascular events for celecoxib compared with any non-selective non-steroid anti-inflammatory drugs was 0.89 (95% confidence interval: 0.80-1.00). The pooled risk ratio for all-cause mortality for celecoxib compared with non-selective non-steroid anti-inflammatory drugs was 0.81 (95% confidence interval: 0.66-0.98). The cardiovascular mortality rate of celecoxib was lower than non-selective non-steroid anti-inflammatory drugs (risk ratio: 0.75, 95% confidence interval: 0.57-0.99). There was no significant difference between celecoxib and non-selective non-steroid anti-inflammatory drugs or placebo in the risk of other cardiovascular events. CONCLUSION: Celecoxib is relatively safe in rheumatoid arthritis and osteoarthritis patients, independent of dose or duration. But it remains uncertain whether this would remain the same in patients treated with aspirin and patients with established cardiovascular diseases.

Epigallocatechin-3-gallate increases autophagic activity attenuating TGF-ß1-induced transformation of human Tenon's fibroblasts.

We previously found that epigallocatechin-3-gallate (EGCG) could inhibit the myofibroblast transformation of human Tenon's fibroblasts, however, the underlying mechanism remained unclear. We therefore investigated whether the autophagic regulation involved in the anti-fibrotic function of EGCG. The fibroblasts were subjected to transforming growth factor beta-1 (TGF-ß1) induction followed by EGCG treatments. The autophagic flux was examined by transmission electron microscopy and autophagic flux analysis. The levels of autophagy-related proteins (LC3ß and p62) and alpha-smooth muscle actin (α-SMA) were measured by Western blot and immunofluorescence. Results showed that TGF-ß1 partially inhibited the autophagic function of Tenon's fibroblasts. But this inhibition effect was rescued by LY2157299, a TGF-ßR1 selective inhibitor. Compared with the cells treated with TGF-ß1 alone, EGCG treatments increased the amount of autophagosomes and autolysosomes, evaluated the ratio of LC3-II to LC3-I and decreased p62 level. Our results indicated that EGCG could recover the activity of autophagy in the TGF-ß1-treated cells. Moreover, treatments with EGCG significantly decreased the α-SMA expression. Taken together, these findings revealed that autophagic regulation involved in the action of EGCG against TGF-ß1-induced transformation of Tenon's fibroblasts. Through increasing intracellular autophagy, EGCG could be a potential anti-fibrotic reagent for preventing subconjunctival fibrosis after glaucoma filtration surgery.

Admission blood cell counts are predictive of stroke-associated infection in acute ischemic stroke patients treated with endovascular therapy.

Stroke-associated infection (SAI) is a major medical complication in acute ischemic stroke patients (AIS) treated with endovascular therapy (EVT). Three hundred thirty-three consecutive patients with AIS caused by a large vessel occlusion in the anterior circulation who received EVT (142 (42.6%) of them were given IV tPA as bridging therapy) and 337 AIS patients who received IV tPA only (non-EVT) were enrolled in the study and evaluated to determine the association of inflammatory factors on admission with SAI. Among the 333 AIS patients undergoing EVT, SAI occurred in 219 (65.8%) patients. Patients with SAI had higher baseline National Institutes of Health Stroke Scale (NIHSS) total scores, white blood cell (WBC) and neutrophil counts, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) than those without SAI (P < 0.05). The multivariable logistic regression analyses showed that older age in addition to higher diastolic blood pressure (DBP), NIHSS score, fasting blood glucose, WBC and neutrophil counts, NLR, and PLR were significantly associated with SAI (P < 0.05). However, these associations were not revealed in 337 non-EVT AIS patients. Furthermore, based on the inflammatory markers, we developed a nomogram that provided the opportunity for more accurate predictions (compared with conventional factors) and appeared a better prognostic tool for SAI according to the decision curve analysis. In summary, if proven externally valid, our nomogram that included WBC count, NLR, and PLR may be a useful tool for SAI prediction in clinical practice.

Comparisons of Ocular Anatomic Differences of Lens-Subluxated Eye with or without Acute Angle Closure: A Retrospective Study.

PURPOSE: To compare ocular anatomy differences of lens subluxation between eyes with or without acute angle closure (AAC). METHODS: This is a retrospective and case-control study. Sixty cases with mild lens subluxation were recruited. Among them, 30 eyes with acute angle closure were assigned to the AAC group and 30 eyes without AAC were assigned to the non-AAC group. The anterior segment was quantitatively evaluated by ultrasound biomicroscopy (UBM). The axial length (AL) was measured with IOL Master. All patients underwent lens extraction surgery and were followed up for six months. RESULTS: The history of blunt trauma accounted for 22 (73.3%) cases in the AAC group and 21 (70%) cases in the non-AAC group. Fifteen (50%) patients in the AAC group had iridotomy history, and high intraocular pressure recurred. The UBM analysis showed that the average central chamber depth of the affected eyes in the AAC group was 1.82 mm, which was significantly shallower than that in the fellow eyes (2.58 mm, P < 0.05) or both eyes in the non-AAC group.Both eyes in the AAC group presented a shorter AL and shallower anterior chamber than the eyes in the non-AAC group. CONCLUSIONS: An asymmetrical anterior chamber between bilateral eyes is an important feature in lens subluxation-induced AAC. The crowded anterior chamber and shorter AL might be the anatomic basis for the eye with lens subluxation-induced AAC.

Elevated level of uric acid in aqueous humour is associated with posterior subcapsular cataract in human lens.

IMPORTANCE: Age-related cataract is the leading cause of blindness worldwide. The pathological mechanisms causing this disease remain elusive. BACKGROUND: To examine the involvement of uric acid (UA) in the pathogenesis of posterior subcapsular cataract (PSC). DESIGN: Retrospective study and experimental investigation. PARTICIPANTS: A total of 180 patients with PSC or non-PSC were included. METHODS: Samples obtained from the patients were used to analyse content of UA and for histochemical examinations. The effects of UA on human lens epithelial cells were also investigated. MAIN OUTCOME MEASURES: Aqueous humour UA and urate deposits. RESULTS: The results showed a significant increase of aqueous humour UA in patients with PSC. After adjustment for potential confounders, elevated aqueous humour UA (odds ratio [OR] = 1.45) showed a stronger association with PSC than serum UA (OR = 1.10). Gomori methenamine silver staining revealed in PSC an intense deposit of urates in the lens fibres in equatorial regions, and in subcapsular fibres in posterior regions of the lens. Such staining was not detected in the lens with non-PSC. Treatment with UA-induced senescence and apoptosis in human lens epithelial cells in a dose dependent manner. Our results suggest that the elevated level of UA in aqueous humour causes a deposition of urates in human lens epithelium, which could possibly lead to dysfunction of these cells that generates opacification in PSC. CONCLUSIONS AND RELEVANCE: These findings indicate the local action of excessive UA in the pathogenesis of PSC. Control of serum UA level could delay the progression of PSC.

Epigallocatechin-3-gallate (EGCG) inhibits myofibroblast transformation of human Tenon's fibroblasts.

Myofibroblast transformation of human Tenon's fibroblasts severely challenges the outcome of glaucoma filtration surgery. epigallocatechin-3-gallate (EGCG) is considered as a potential reagent to overcome this issue for its anti-fibrosis effect on various human diseases, but it is unclear on the fibrosis of Tenon's fibroblasts. This study was conducted to investigate the effect of EGCG on TGF-ß1-induced myofibroblast transformation of human Tenon's fibroblasts. The human Tenon's fibroblasts were incubated in the medium containing 10 ng/mL TGF-ß1, and subsequently treated with EGCG or mitomycin C (MMC). The cell proliferation and migration were analyzed. The expression of alpha-smooth muscle actin (α-SMA), type I collagen (Col-I), and p-Smad2/3 were also evaluated. It showed that EGCG and MMC strongly inhibited the elevation in cell number in tissue explants compared to the tissues treated with TGF-ß1 alone. Scratch-Wound assay showed that 48 h after TGF-ß1 induction, only 10% of the wound width remained. But cells treated with EGCG still showed over 93% wound width. Further, EGCG effectively inhibited TGF-ß1-induced expression of α-SMA and Col-I as well as phosphorylation of Smad2/3 in Tenon's fibroblasts. Altogether, we concluded that EGCG suppressed the myofibroblast transformation in Tenon's fibroblasts through inactivating TGF-ß1/Smad signaling. These findings demonstrate that EGCG can be considered as one of the possible antifibrotic reagents for preventing postoperative scarring in glaucoma filtration surgery.

Increased Expression of Growth Hormone-Releasing Hormone in Fibrinous Inflammation of Proliferative Diabetic Retinopathy.

PURPOSE: To investigate the involvement of growth hormone-releasing hormone (GHRH) - growth hormone (GH) signaling in pathogenesis of proliferative diabetic retinopathy (PDR). DESIGN: Experimental laboratory study. METHODS: Vitreous humor, aqueous humor, and serum were obtained from 36 eyes of 36 patients with or without type 2 diabetes from 2017 to 2019. For histologic examination, 6 fibrovascular membranes were excised from eyes with active PDR. Three fibrovascular membranes were excised from nondiabetic patients with proliferative vitreoretinopathy (PVR) as controls. RESULTS: In PDR, the fibrovascular tissues consisted of a mature region containing fibrocytes, and an immature region populated by abundant polymorphonuclear leukocytes in a fibrinogen meshwork. Clusters of leukocytes were found adhering to the vascular walls. In PVR, no fibrinogen and polymorphonuclear leukocyte was observed in the fibrovascular membranes. The levels of GHRH and GH in PDR were significantly increased (P < .001), with 1.8-fold and 72.8-fold in vitreous humor, and 2-fold and 4.9-fold in aqueous humor, respectively, when compared with corresponding levels in controls. No significant difference was detected for insulin-like growth factor-1. Immunohistochemistry showed intense expression of GHRH and its receptor GHRH-R in polymorphonuclear leukocytes, vascular endothelial cells, and fibrocytes in fibrovascular membranes of PDR. GHRH staining was not detectable in infiltrating cells within the fibrovascular membrane of PVR. CONCLUSIONS: These findings reveal a possible involvement of GHRH/GHRH-R in fibrinous inflammation that might contribute to the formation of fibrovascular membrane in PDR through mediating activities of leukocytes, vascular endothelial cells, and fibrocytes. Targeting GHRH/GHRH-R may be considered as a potential therapeutic approach for the treatment of PDR.

Phase Instability amid Dimensional Crossover in Artificial Oxide Crystal.

Artificial crystals synthesized by atomic-scale epitaxy provide the ability to control the dimensions of the quantum phases and associated phase transitions via precise thickness modulation. In particular, the reduction in dimensionality via quantized control of atomic layers is a powerful approach to revealing hidden electronic and magnetic phases. Here, we demonstrate a dimensionality-controlled and induced metal-insulator transition (MIT) in atomically designed superlattices by synthesizing a genuine two-dimensional (2D) SrRuO_{3} crystal with highly suppressed charge transfer. The tendency to ferromagnetically align the spins in an SrRuO_{3} layer diminishes in 2D as the interlayer exchange interaction vanishes, accompanying the 2D localization of electrons. Furthermore, electronic and magnetic instabilities in the two SrRuO_{3} unit cell layers induce a thermally driven MIT along with a metamagnetic transition.

Low triglyceride to high-density lipoprotein cholesterol ratio predicts hemorrhagic transformation in large atherosclerotic infarction of acute ischemic stroke.

The ratio of triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) is an objective approach to predicting poor outcomes in acute ischemic stroke (AIS). The impact of TG/HDL-C on hemorrhagic transformation (HT) after AIS remains unknown. The aim of this study was to explore the accurate effect of TG/HDL-C on HT after AIS. We enrolled a total of 1423 patients with AIS in the training cohort from a prospective, consecutive hospital-based stroke registry. Of the 1423 patients, HT occurred in 155 (10.89%) patients. The incidence of HT after AIS was significantly increased when there were low levels of TG (P=0.016) and TG/HDL-C (P=0.006) in patients with AIS attributable to large artery atherosclerosis (LAA), but not in those who suffered from cardioembolic stroke. After adjustment for covariates, a lower TG/HDL-C (OR=0.53, 95%CI=0.20-0.93) that was more than TG alone (OR=0.61, 95%CI=0.27-0.98) independently increased the risk of HT in LAA. Furthermore, our established nomogram indicated that lower TG/HDL-C was an indicator of HT. These findings were further validated in the test cohort of 558 patients with AIS attributable to LAA. In summary, a low level of TG/HDL-C is correlated with greater risk of HT after AIS attributable to LAA.

The Pharmacokinetics of Morphine and Codeine in Human Plasma and Urine after Oral Administration of Qiangli Pipa Syrup.

Papaveris pericarpium, a natural source of morphine and codeine, is the principal active component in many antitussive traditional Chinese medicines. We herein report the first PK study of papaveris pericarpium in human plasma and urine following oral administration of single (15, 30, 60 mL) and multiple dose (15 mL) of Qiangli Pipa Syrup (MOR 0.1 mg/mL, COD 0.028 mg/mL) by monitoring morphine and codeine using a HPLC-MS/MS method. Their Tmax and t1/2 values are independent of dosages, while the AUC0-t linearly increased with higher dosages, indicating linear PK characteristics. AUC0-t increased obviously after multiple doses, indicating possible risk of accumulative toxicity. Urine studies suggested risks of positive opiate drug tests with a cutoff of 300 ng/mL, which lasted 6-14 h at different doses. These results provide important information for clinical safety, efficacy and rational drug use of Qiangli Pipa Syrup and also guide the related judicial expertise of its administration.

Profile and 1-Year Outcome of Ischemic Stroke in East China: Nanjing First Hospital Stroke Registry.

BACKGROUND: The profile and 1-year outcome after acute ischemic stroke (AIS) in Nanjing, China, is uncertain. This study aimed to investigate the profile and outcome after 1-year follow-up of AIS in East China. METHODS: In a prospective cohort study, 2168 patients with AIS were recruited consecutively. The primary outcome was death or dependency defined as a modified Rankin Scale score of 3-6 at 12 months. Plausible risk factors of death or dependency, such as demographics, risk factors of cardiovascular diseases, clinical features, laboratory results, and complications after a stroke, were selected from available variables to perform multivariable logistic regression analyses. RESULTS: Eight hundred thirty-seven (38.6%) patients died or suffered from dependency. Multivariate logistic regression analysis showed that age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.03-1.05), history of diabetes mellitus (OR, 1.50; 95% CI, 1.10-2.04), prior stroke (OR, 2.08; 95% CI, 1.51-2.87), National Institutes of Health Stroke Scale (NIHSS) score (OR, 23.06; 95% CI, 14.24-37.34), estimated glomerular filtration rate (OR, 1.65; 95% CI, 1.02-2.66), pulmonary infection (OR, 2.98; 95% CI, 2.17-4.09), and gastrointestinal bleeding (OR, 7.81; 95% CI, 2.76-22.09) were significantly and independently associated with higher rates of mortality or disability (all P values < .05). Male gender (P values < .001) was the only factor associated with lower mortality or disability. CONCLUSIONS: The main dominating predictors for death or dependency were older age, female gender, diabetes mellitus, prior stroke, NIHSS score, estimated glomerular filtration rate, pulmonary infection, and gastrointestinal bleeding.