Acute exposure to air pollutants increase the risk of acute glaucoma.

BACKGROUND: Ambient air pollution is related to the onset and progression of ocular disease. However, the effect of air pollutants on the acute glaucoma remains unclear. OBJECTIVE: To investigate the effect of air pollutants on the incidence of acute glaucoma (acute angle closure glaucoma and glaucomatocyclitic crisis) among adults. METHODS: We conducted a time-stratified case-crossover study based on the data of glaucoma outpatients from January, 2015 to Dec, 2021 in Shanghai, China. A conditional logistic regression model combined with a polynomial distributed lag model was applied for the statistical analysis. Each case serves as its own referent by comparing exposures on the day of the outpatient visit to the exposures on the other 3-4 control days on the same week, month and year. To fully capture the delayed effect of air pollution, we used a maximum lag of 7 days in main model. RESULTS: A total of 14,385 acute glaucoma outpatients were included in this study. We found exposure to PM2.5, PM10, nitrogen dioxide (NO2) and carbon monoxide (CO) significantly increased the odds of outpatient visit for acute glaucoma. Wherein the odds of acute glaucoma related to PM2.5 and NO2 were higher and more sustained, with OR of 1.07 (95%CI: 1.03-1.11) and 1.12 (95% CI: 1.08-1.17) for an IQR increase over lag 0-3 days, than PM10 and CO over lag 0-1 days (OR:1.03; 95% CI: 1.01-1.05; OR: 1.04; 95% CI: 1.01-1.07). CONCLUSIONS: This case-crossover study provided first-hand evidence that air pollutants, especially PM2.5 and NO2, significantly increased risk of acute glaucoma.

Nicotinamide ameliorates energy deficiency and improves retinal function in Cav-1-/- mice.

Caveolin-1(Cav-1) is involved in lipid metabolism and energy homeostasis, which is important for the energetically demanding retina. Although retinal function deficits were noted in Cav-1 knockout (Cav-1-/- ) mice, the underlying causes remain largely unknown. Here, we investigate if the disruption in energy homeostasis presents a potential mechanism for retinal function deficits in Cav-1-/- retina and if it can be ameliorated by nicotinamide (NAM). In this study, NAM was administrated orally for 2 weeks in Cav-1-/- mice before experiments. Oxidative lipidomics was conducted to detect the oxylipin changes, the retinal energy flux was measured by seahorse assay, and the retinal function was assessed by electroretinogram (ERG). Cav-1 deficiency induced the dysregulation of oxidative lipidomics and reduction in energy consumption/production in the retina by decreasing Na+ /K+ -ATPase, oxidative phosphorylation CII, cytochrome c, and oxygen consumption rate (OCR). A decrease in Sirt1 was also detected. Therapeutic administration of NAM significantly increased Sirt1 expression and improved energy deficiency by increasing Na+ /K+ -ATPase, cytochrome c, and OCR. The dysregulation of oxidative lipidomics was partially recovered, and the retinal function was improved as assessed by ERG compared to Cav-1-/- mice. Our study demonstrated the dysregulation of oxidative lipidomics in Cav-1-/- retina and established a link between energy deficiency and retinal function deficits in Cav-1-/- mice. Administration of NAM ameliorated energy deficiency, increased the expression of Sirt1, and improved retinal function, which presents a potential therapeutic strategy for Cav-1 deficiency-induced retinal function deficits.

The Application of Nitric Oxide for Ocular Hypertension Treatment.

Despite of various therapeutic methods for treating ocular hypertension and glaucoma, it still remains the leading cause of irreversible blindness. Intraocular pressure (IOP) lowering is the most effective way to slow disease progression and prevent blindness. Among the ocular hypotensive drugs currently in use, only a couple act on the conventional outflow system, which is the main pathway for aqueous humor outflow and the major lesion site resulting in ocular hypertension. Nitric oxide (NO) is a commendable new class of glaucoma drugs that acts on the conventional outflow pathway. An increasing number of nitric oxide donors have been developed for glaucoma and ocular hypertension treatment. Here, we will review how NO lowers IOP and the types of nitric oxide donors that have been developed. And a brief analysis of the advantages and challenges associated with the application will be made. The literature used in this review is based on Pubmed database search using 'nitric oxide' and 'glaucoma' as key words.

The roles of macrophage autophagy in atherosclerosis.

Although various types of drugs and therapies are available to treat atherosclerosis, it remains a major cause of mortality throughout the world. Macrophages are the major source of foam cells, which are hallmarks of atherosclerotic lesions. Consequently, the roles of macrophages in the pathophysiology of atherosclerosis are increasingly investigated. Autophagy is a self-protecting cellular catabolic pathway. Since its discovery, autophagy has been found to be associated with a variety of diseases, including cardiovascular diseases, malignant tumors, neurodegenerative diseases, and immune system disorders. Accumulating evidence demonstrates that autophagy plays an important role in inhibiting inflammation and apoptosis, and in promoting efferocytosis and cholesterol efflux. These facts suggest the induction of autophagy may be exploited as a potential strategy for the treatment of atherosclerosis. In this review we mainly discuss the relationship between macrophage autophagy and atherosclerosis and the molecular mechanisms, as well as the recent advances in targeting the process of autophagy to treat atherosclerosis.

Three-Dimensional Feature Tracking Study of Healthy Chinese Ventricle by Cardiac Magnetic Resonance.

PURPOSE: Myocardial strain, as a crucial quantitative indicator of myocardial deformation, can detect the changes of cardiac function earlier than parameters such as ejection fraction (EF). It has reported that cardiac magnetic resonance(CMR) and post-processing software possess the ability to obtain the stability and repeatability strain values. Recently, the normal strain values range of people are debatable, especially in the Chinese population. Therefore, we aim to explore the ventricular characteristics and the myocardial strain values of the Chinese people by using the cardiac magnetic resonance feature tracking (CMR-FT). Additionally, we attempted to use the myocardial and chordae tendineae contours to calculate the ventricular volumes by the CMR-FT. This study may provide valuable insights into the application of CMR-FT in tracking the ventricular characteristics and myocardial strain for Chinese population, especially in suggesting an referable myocardial strain parameters of the Chinese. METHODS: A total of 109 healthy Chinese individuals (age range: 18 to 58 years; 52 males and 57 females) underwent 3.0T CMR to acquire the cardiac images. The commercial post-processing software was employed to analyse the image sequence by semi-automatic processing, then the biventricular morphology (End-Diastolic Volume, EDV; EDV/Body Surface Area, EDV/BSA), function(EF; Cardiac Output, CO; Cardiac Index, CI) and strain(Radial Strain, RS; Circumferential Strain, CS; Longitudinal Strain, LS) values were obtained.The biventricular myocardial strain values were stratified according to the age and gender. The Left Ventricular( LV base, mid, apex) and myocardial strain values of three coronary artery areas were calculated based on the the strain value of LV American Heart Association(AHA) 16 segments. RESULTS: It was shown that the females had larger LV globe strain values compared with the males (LVGPRS: 42.0 ± 8.5 versus 33.6 ± 6.2%, P < 0.001; LVGPCS: -21.2 ± 2.1 versus - 19.7 ± 2.3%, P < 0.001; LVGPLS: -16.4 ± 2.6 versus - 14.6 ± 2.2%, P < 0.001;). Moreover, the differences in RS, CS, and LS among the LV myocardium 16 segments were obvious. However, the right ventricle (RV) strain values showed non-normal distribution in the volunteers of this research. CONCLUSIONS: Here, we successfully tracked the characteristics of bilateral ventricles in healthy Chinese populations through using the 3.0T CMR. We confirmed that there was a gender difference in LV Globe Strain values. In addition, we obtained strain values for each myocardial segment of the LV and different coronary artery regions based on the AHA 16 segments method, Our results also showed that the RV strain values with a non-normal distribution, and RV global strain values were not related to the gender and age. Furthermore, LVGPRS, LVGPLS, and RVGPRS were significantly correlated with BMI, CO, CI, and EDV in the Chinese population.

Low ambient temperature and temperature drop as novel risk factors of acute glaucoma: a case-crossover study.

The prevalence of glaucoma has seasonal variation in population, but the role of ambient temperature and its variation remains unclear in this seasonal trend. So, we conducted a time-stratified case-crossover study to examine the association of ambient temperature and temperature change between neighboring days (TCN) with the risk of acute glaucoma. Data on meteorological parameters and glaucoma outpatient visit between 2015 and 2021 covered all districts of Shanghai. Conditional logistic regression with distributed lag nonlinear model was applied to estimate the association of temperature or TCN with the risk of acute glaucoma. A total of 7,746 patients diagnosed with acute primary angle-closure glaucoma (APACG) were included in this analysis. We observed a significant increase in the risk of acute glaucoma with cold temperature and temperature drop. Compared with the referent temperature (32℃), moderate low (12 °C) and extreme low (4 °C) temperature exposures were associated with higher risk of acute glaucoma outpatient visit, with the highest cumulative OR of 1.46 (95% CI: 1.11, 1.91) and 1.50 (95% CI: 1.09, 2.06) over lag 0-2 days. Temperature drop (TCN = - 4 °C) also increases the risk of acute glaucoma (OR = 1.34, 95% CI: 1.07, 1.67) over lag 0-7 days, comparing with no temperature change. Patients of female and above age 65 were more vulnerable to cold exposure and temperature drop. This case-crossover study provided novel and robust individual-level evidence that low ambient temperature and temperature drop significantly increase the acute glaucoma risk. The findings provide protective strategies for glaucoma patient, especially for female and the old, under cold exposure and sudden temperature decline.

Reduction-responsive polymeric micelles for trans-corneal targeted delivery of microRNA-21-5p and glaucoma-specific gene therapy.

The therapeutic value of microRNA (miRNA) for the treatment of glaucoma has become a focus of attention. However, naked miRNA cannot cross the corneal barrier and reach the target tissue by itself. Thus, the precise transport of miRNA to the target sites is key to the success of gene therapy. Herein, we selected a miRNA, namely miR-21-5p, based on its unique intraocular pressure (IOP) mechano-sensing property. Moreover, a biocompatible polymeric poly(L-lysine) (PLL) micelle conjugated with collagenase and ABCA1 antibody was judiciously constructed to achieve the trans-corneal and target delivery of miR-21-5p to the trabecular meshwork (TM) and Schlemm's canal (SC) tissues inside the eye. The topically administrated PLL micelles as an eye drop successfully crossed the cornea with the help of collagenase and then preferentially accumulated in the target TM/SC tissues under the guidance of the ABCA1 antibody. When endocytosed by TM/SC cells, the PLL micelles could be decomposed in the reductive lysosomal environment to release miR-21-5p for successfully lowering the IOP by activating the miR-21-5p/eNOS/MMP9 signaling axis, which will open new prospects for glaucoma-specific gene therapy.

Endogenous dual stimuli-activated NO generation in the conventional outflow pathway for precision glaucoma therapy.

High intraocular pressure (IOP) has been regarded as a predominant risk factor for glaucoma. Nitric oxide (NO) is shown to lower IOP, but the magnitude and duration of IOP reduction are not satisfying due to the poor cornea penetration of NO drugs and limited NO generation in the trabecular meshwork (TM)/Schlemm's canal (SC) area. Herein, we introduce deep cornea penetrating biodegradable hollow mesoporous organosilica (HOS) nanocapsules for the efficient co-delivery of hydrophobic JS-K (JR) and hydrophilic l-Arginine (LO). The resulting HOS-JRLO can be reduced and oxidized by the ascorbic acid (AA) and catalysis of endothelial nitric oxide synthase (eNOS) in the TM/SC microenvironment to release NO for inducing appreciable IOP reduction in various glaucoma mouse models. In addition to developing an endogenous stimuli-responsive NO nanotherapeutic, this study is also expected to establish a versatile, non-invasive, and efficacious treatment paradigm for precision glaucoma therapy.

Autophagy Plays an Important Role in Anti-inflammatory Mechanisms Stimulated by Alpha7 Nicotinic Acetylcholine Receptor.

Alpha7 nicotinic acetylcholine receptor (α7nAChR) has been reported to alleviate neuroinflammation. Here, we aimed to determine the role of autophagy in α7nAChR-mediated inhibition of neuroinflammation and its underlying mechanism. Experimental autoimmune encephalomyelitis (EAE) mice and lipopolysaccharide-stimulated BV2 microglia were used as in vivo and in vitro models of neuroinflammation, respectively. The severity of EAE was evaluated with neurological scoring. Autophagy-related proteins (Beclin 1, LC3-II/I, p62/SQSTM1) were detected by immunoblot. Autophagosomes were observed using transmission electron microscopy and tandem fluorescent mRFP-GFP-LC3 plasmid was applied to test autophagy flux. The mRNA levels of interleukin-6 (IL-6), IL-1ß, IL-18, and tumor necrosis factor-α (TNF-α) were detected by real-time PCR. We used 3-methyladenine (3-MA) and autophagy-related gene 5 small interfering RNA (Atg5 siRNA) to block autophagy in vivo and in vitro, respectively. Activating α7nAChR with PNU282987 ameliorates EAE severity and spinal inflammatory infiltration in EAE mice. PNU282987 treatment also enhanced monocyte/microglia autophagy (Beclin 1, LC3-II/I ratio, p62/SQSTM1, colocalization of CD45- or CD68-positive cells with LC3) both in spinal cord and spleen from EAE mice. The beneficial effects of PNU282987 on EAE mice were partly abolished by 3-MA, an autophagy inhibitor. In vitro, PNU282987 treatment increased autophagy and promoted autophagy flux. Blockade of autophagy by Atg5 siRNA or bafilomycin A1 attenuated the inhibitory effect of PNU282987 on IL-6, IL-1ß, IL-18, and TNF-α mRNA. Our results demonstrate for the first time that activating α7nAChR enhances monocyte/microglia autophagy, which suppresses neuroinflammation and thus plays an alleviative role in EAE.

Activation of Cannabinoid Receptor 2 Ameliorates DSS-Induced Colitis through Inhibiting NLRP3 Inflammasome in Macrophages.

Activation of cannabinoid receptor 2 (CB2R) ameliorates inflammation, but the underlying mechanism remains unclear. In the present study, we examined whether activation of CB2R could suppress the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome. In peritoneal macrophages isolated from C57BL/6 mice, LPS/DSS challenge for 24 h increased the expression of the components of NLRP3 inflammasome NLRP3, Casp-1 p20/Casp-1 p45 ratio, proIL-1ß and IL-1ß and also enhanced autophagy (LC3-II/LC3-I ratio, Beclin-1 and SQSTM1). Pretreatment of peritoneal macrophages with HU 308, a selective CB2R agonist, attenuated LPS/DSS-induced NLRP3 inflammasome activation, but further enhanced autophagy. In comparison with wild-type (WT) control, peritoneal macrophages from CB2R knockout (KO) mice had more robust NLRP3 inflammasome activation and attenuated autophagy upon LPS/DSS challenge. Knockdown autophagy-related gene 5 (Atg5) with a siRNA in peritoneal macrophages attenuated the inhibitory effects of HU 308 on LPS/DSS-induced NLRP3 inflammasome activation in vitro. In vivo, HU308 treatment attenuated DSS-induced colitis mice associated with reduced colon inflammation and inhibited NLRP3 inflammasome activation in wild-type mice. In CB2R KO mice, DSS-induced inflammation and NLRP3 inflammasome activation were more pronounced than those in WT control. Finally, we demonstrated that AMPK-mTOR-P70S6K signaling pathway was involved in this CB2R-mediated process. We conclude that activation of CB2R ameliorates DSS-induced colitis through enhancing autophagy that may inhibit NLRP3 inflammasome activation in macrophages.

NLRP3 inflammasome and its inhibitors: a review.

Inflammasomes are newly recognized, vital players in innate immunity. The best characterized is the NLRP3 inflammasome, so-called because the NLRP3 protein in the complex belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs) and is also known as "pyrin domain-containing protein 3". The NLRP3 inflammasome is associated with onset and progression of various diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, cryopyrin-associated periodic fever syndrome, as well as other auto-immune and auto-inflammatory diseases. Several NLRP3 inflammasome inhibitors have been described, some of which show promise in the clinic. The present review will describe the structure and mechanisms of activation of the NLRP3 inflammasome, its association with various auto-immune and auto-inflammatory diseases, and the state of research into NLRP3 inflammasome inhibitors.