SIRT4 Protects Müller Glial Cells Against Apoptosis by Mediating Mitochondrial Dynamics and Oxidative Stress.

SIRT4 is a member of the sirtuin family, which is related to mitochondrial function and possesses antioxidant and regulatory redox effects. Currently, the roles of SIRT4 in retinal Müller glial cells, oxidative stress, and mitochondrial function are still unclear. We confirmed, by immunofluorescence staining, that SIRT4 is located mainly in the mitochondria of retinal Müller glial cells. Using flow cytometry and Western blotting, we analyzed cell apoptosis, intracellular reactive oxygen species (ROS) levels, apoptotic and proapoptotic proteins, mitochondrial dynamics-related proteins, and mitochondrial morphology and number after the overexpression and downregulation of SIRT4 in rMC-1 cells. Neither the upregulation nor the downregulation of SIRT4 alone affected apoptosis. SIRT4 overexpression reduced intracellular ROS, reduced the BAX/BCL2 protein ratio, and increased the L-OPA/S-OPA1 ratio and the levels of the mitochondrial fusion protein MFN2 and the mitochondrial cleavage protein FIS1, increasing mitochondrial fusion. SIRT4 downregulation had the opposite effect. Mitochondria tend to divide after serum starvation for 24 h, and SIRT4 downregulation increases mitochondrial fragmentation and oxidative stress, leading to aggravated cell damage. The mitochondrial division inhibitor Mdivi-1 reduced oxidative stress levels and thus reduced cell damage caused by serum starvation. The overexpression of SIRT4 in rMC-1 cells reduced mitochondrial fragmentation caused by serum starvation, leading to mitochondrial fusion and reduced expression of cleaved caspase-3, thus alleviating the cellular damage caused by oxidative stress. Thus, we speculate that SIRT4 may protect retinal Müller glial cells against apoptosis by mediating mitochondrial dynamics and oxidative stress.

Independent Relationship of Lipoprotein(a) and Carotid Atherosclerosis With Long-Term Risk of Cardiovascular Disease.

BACKGROUND: Lipoprotein(a) (Lp(a)) is considered to be a causal risk factor of atherosclerotic cardiovascular disease (ASCVD), but whether there is an independent or joint association of Lp(a) and atherosclerotic plaque with ASCVD risk remains uncertain. This study aims to assess ASCVD risk independently or jointly conferred by Lp(a) and carotid atherosclerotic plaque. METHODS AND RESULTS: A total of 5471 participants with no history of cardiovascular disease at baseline were recruited and followed up for ASCVD events (all fatal and nonfatal acute coronary and ischemic stroke events) over a median of 11.5 years. Independent association of Lp(a), or the joint association of Lp(a) and carotid plaque with ASCVD risk, was explored using Cox proportional hazards models. Overall, 7.6% of the participants (60.0±7.9 years of age; 2649 [48.4%] men) had Lp(a) ≥50 mg/dL, and 539 (8.4/1000 person-years) incident ASCVD events occurred. Lp(a) concentrations were independently associated with long-term risk of total ASCVD events, as well as coronary events and ischemic stroke events. Participants with Lp(a) ≥50 mg/dL had a 62% higher risk of ASCVD incidence (95% CI, 1.19-2.21) than those with Lp(a) <10 mg/dL, and they exhibited a 10-year ASCVD incidence of 11.7%. This association exists even after adjusting for prevalent plaque. Moreover, participants with Lp(a) ≥30 mg/dL and prevalent plaque had a significant 4.18 times higher ASCVD risk than those with Lp(a) <30 mg/dL and no plaque. CONCLUSIONS: Higher Lp(a) concentrations are independently associated with long-term ASCVD risk and may exaggerate cardiovascular risk when concomitant with atherosclerotic plaque.

Nonoptimum Temperatures Are More Closely Associated With Fatal Myocardial Infarction Than With Nonfatal Events.

BACKGROUND: Ambient temperatures trigger hospitalisation, mortality, and emergency department visits for myocardial infarction (MI). However, nonoptimum temperature-related risks of fatal and nonfatal MI have not yet been compared. METHODS: From 2007 to 2019, 416,894 MI events (233,071 fatal and 183,823 nonfatal) were identified in Beijing, China. A time-series analysis with a distributed-lag nonlinear model was used to compare the relative and population-attributable risks of fatal and nonfatal MI associated with nonoptimum temperatures. RESULTS: The reference was the optimum temperature of 24.3°C. For single-lag effects, cold (-5.2°C) and heat (29.6°C) effects had associations that persisted for more days for fatal MI than for nonfatal MI. For cumulative-lag effects over 0 to 21 days, cold effects were higher for fatal MI (relative risk [RR] 1.99, 95% confidence interval [CI] 1.68-2.35) than for nonfatal MI (RR 1.60, 95% CI 1.32-1.94) with a P value for difference in effect sizes of 0.048. In addition, heat effects were higher for fatal MI (RR 1.33, 95% CI 1.24-1.44) than for nonfatal MI (RR 0.99, 95% CI 0.91-1.08) with a P value for difference in effect sizes of 0.002. The attributable fraction of nonoptimum temperatures was higher for fatal MI (25.6%, 95% CI 19.7%-30.6%) than for nonfatal MI (19.1%, 95% CI 12.1%-25.0%). CONCLUSIONS: Fatal MI was more closely associated with nonoptimum temperatures than nonfatal MI, as evidenced by single-lag effects that have associations which persisted for more days, higher cumulative-lag effects, and higher attributable risks for fatal MI. Strategies are needed to mitigate the adverse effects of nonoptimum temperatures.

Associations between urban exposome and recurrence risk among survivors of acute myocardial infarction in Beijing, China.

Few previous studies have investigated the impacts of coexposure to multiple urban environmental factors on the prognosis of acute myocardial infarction (AMI) events. This study aimed to evaluate the associations between the urban exposome and AMI recurrence. We used data from 88,509 AMI patients from a large cohort obtained from the Beijing Cardiovascular Disease Surveillance System between 2013 and 2019. Twenty-six types of urban exposures were assessed within 300-m, 500-m, and 1000-m buffers of patients' home addresses in the baseline and cumulative average levels. We used the Cox proportional hazard model along with the Elastic Net (ENET) algorithm to estimate the hazard ratios (HRs) of recurrent AMI per interquartile range increase in each selected urban exposure. The increased risk of AMI recurrence was significantly associated with lower urban function diversity in the 500-m buffer, longer distance to subway stations and higher PM2.5 for both baseline and cumulative average exposure. The cumulative averages of two urban factors, including the distance to parks, and the density of fruit and vegetable shops in the 1000-m buffer, were also identified as significant factors affecting the risk of AMI recurrence. These findings can help improve the urban design for promoting human cardiovascular health.

Association of neighborhood physical activity facilities with incident cardiovascular disease.

BACKGROUND: The availability of physical activity (PA) facilities in neighborhoods is hypothesized to influence cardiovascular disease (CVD), but evidence from individual-level long-term cohort studies is limited. We aimed to assess the association between neighborhood exposure to PA facilities and CVD incidence. METHODS: A total of 4658 participants from the Chinese Multi-provincial Cohort Study without CVD at baseline (2007-2008) were followed for the incidence of CVD, coronary heart disease (CHD), and stroke. Availability of PA facilities was defined as both the presence and the density of PA facilities within a 500-m buffer zone around the participants' residential addresses. Time-dependent Cox regression models were performed to estimate the associations between the availability of PA facilities and risks of incident CVD, CHD, and stroke. RESULTS: During a median follow-up of 12.1 years, there were 518 CVD events, 188 CHD events, and 355 stroke events. Analyses with the presence indicator revealed significantly lower risks of CVD (hazard ratio [HR] 0.80, 95% confidence interval ([CI] 0.65-0.99) and stroke (HR 0.76, 95% CI 0.60-0.97) in participants with PA facilities in the 500-m buffer zone compared with participants with no nearby facilities in fully adjusted models. In analyses with the density indicator, exposure to 2 and ≥ 3 PA facilities was associated with 35% (HR 0.65, 95% CI 0.47-0.91) and 28% (HR 0.72, 95% CI 0.56-0.92) lower risks of CVD and 40% (HR 0.60, 95% CI 0.40-0.90) and 38% (HR 0.62, 95% CI 0.46-0.84) lower risks of stroke compared with those without any PA facilities in 500-m buffer, respectively. Effect modifications between presence of PA facilities and a history of hypertension for incident stroke (P = 0.049), and a history of diabetes for incident CVD (P = 0.013) and stroke (P = 0.009) were noted. CONCLUSIONS: Residing in neighborhoods with better availability of PA facilities was associated with a lower risk of incident CVD. Urban planning intervention policies that increase the availability of PA facilities could contribute to CVD prevention.

Geographic Variation in Mortality of Acute Myocardial Infarction and Association With Health Care Accessibility in Beijing, 2007 to 2018.

Background Little is known about geographic variation in acute myocardial infarction (AMI) mortality within fast-developing megacities and whether changes in health care accessibility correspond to changes in AMI mortality at the small-area level. Methods and Results We included data of 94 106 AMI deaths during 2007 to 2018 from the Beijing Cardiovascular Disease Surveillance System in this ecological study. We estimated AMI mortality for 307 townships during consecutive 3-year periods with a Bayesian spatial model. Township-level health care accessibility was measured using an enhanced 2-step floating catchment area method. Linear regression models were used to examine the association between health care accessibility and AMI mortality. During 2007 to 2018, median AMI mortality in townships declined from 86.3 (95% CI, 34.2-173.8) to 49.4 (95% CI, 30.5-73.7) per 100 000 population. The decrease in AMI mortality was larger in townships where health care accessibility increased more rapidly. Geographic inequality, defined as the ratio of the 90th to 10th percentile of mortality in townships, increased from 3.4 to 3.8. In total, 86.3% (265/307) of townships had an increase in health care accessibility. Each 10% increase in health care accessibility was associated with a -0.71% (95% CI, -1.08% to -0.33%) change in AMI mortality. Conclusions Geographic disparities in AMI mortality among Beijing townships are large and increasing. A relative increase in township-level health care accessibility is associated with a relative decrease in AMI mortality. Targeted improvement of health care accessibility in areas with high AMI mortality may help reduce AMI burden and improve its geographic inequality in megacities.

Using street view imagery to examine the association between urban neighborhood disorder and the long-term recurrence risk of patients discharged with acute myocardial infarction in central Beijing, China.

Background: To examine the association between urban neighborhood disorder and the recurrence risk of patients with acute myocardial infarction (AMI) in central Beijing, China. Methods: Recurrent AMI was identified by the Beijing Monitoring System for Cardiovascular Diseases through the end of 2019 for patients discharged with AMI between 2007 and 2017. Cox proportional hazards models were performed to estimate associations between neighborhood disorder and AMI recurrence. Results: Of 66,238 AMI patients, 11,872 had a recurrent event, and 3117 died from AMI during a median followup of 5.92 years. After covariate adjustment, AMI patients living in the high tertile of neighborhood disorder had a higher recurrence risk (hazard ratio [HR] 1.08, 95 % confidence interval [CI], 1.03-1.14) compared with those in the low tertile. A stronger association was noted for fatal recurrent AMI (HR 1.21, 95 % CI 1.10-1.34). The association was mainly observed in females (HR 1.04, 95 % CI: 1.02 to 1.06). Conclusions: Serious neighborhood disorder may contribute to higher recurrence risk, particularly fatal recurrence, among AMI patients. Policies to eliminate neighborhood disorders may play an important role in the secondary prevention of cardiovascular disease.

Association between Intermediate-Density Lipoprotein Particles and the Progression of Carotid Atherosclerosis: A Community-Based Cohort Study.

AIM: Experimental studies report that intermediate-density lipoprotein (IDL), the precursor of low-density lipoprotein, promotes atherosclerotic plaque formation. However, whether IDL is involved in the development of atherosclerosis in humans is still unclear. The aim of this community-based study is to examine the association between IDL particle (IDL-P) concentrations and the 5-year progression of carotid atherosclerosis. METHODS: Baseline IDL-P concentrations were measured using nuclear magnetic resonance spectroscopy in 927 participants aged 45-74 years with no history of cardiovascular disease (CVD) at baseline. To estimate the association between baseline IDL-P concentrations and 5-year progression of carotid atherosclerosis, indicated by atherosclerotic plaque progression and changes in total plaque area (TPA), multivariable-adjusted regression was employed. RESULTS: During the 5-year follow-up period, 45.8% of participants developed new plaques. Baseline IDL-P concentrations were significantly associated with the progression of carotid atherosclerosis. Participants in the highest quartile of IDL-P concentrations exhibited 1.36-fold (95% confidence interval [CI]: 1.09-1.68) increased progression of carotid plaque and 1.67-fold (95% CI: 1.04-2.69) higher TPA than those in the lowest quartile. These relationships were independent of baseline concentrations of low-density lipoprotein particles and very-low-density lipoprotein particles and their subclasses. CONCLUSIONS: Elevated IDL-P concentrations were independently associated with the progression of carotid atherosclerosis, suggesting that IDL-P is a novel risk factor for the development of atherosclerosis.

Driving Time to the Nearest Percutaneous Coronary Intervention-Capable Hospital and the Risk of Case Fatality in Patients with Acute Myocardial Infarction in Beijing.

Timely arrival at a hospital capable of percutaneous coronary intervention (PCI) is critical in treating acute myocardial infarction (AMI). We examined the association between driving time to the nearest PCI-capable hospital and case fatality among AMI patients. A total of 142,474 AMI events during 2013-2019 from the Beijing Cardiovascular Disease Surveillance System were included in this cross-sectional study. The driving time from the residential address to the nearest PCI-capable hospital was calculated. Logistic regression was used to estimate the risk of AMI death associated with driving time. In 2019, 54.5% of patients lived within a 15-min drive to a PCI-capable hospital, with a higher proportion in urban than peri-urban areas (71.2% vs. 31.8%, p < 0.001). Compared with patients who had driving times ≤15 min, the adjusted odds ratios (95% CI, p value) for AMI fatality risk associated with driving times 16-30, 31-45, and >45 min were 1.068 (95% CI 1.033-1.104, p < 0.001), 1.189 (95% CI 1.127-1.255, p < 0.001), and 1.436 (95% CI 1.334-1.544, p < 0.001), respectively. Despite the high accessibility to PCI-capable hospitals for AMI patients in Beijing, inequality between urban and peri-urban areas exists. A longer driving time is associated with an elevated AMI fatality risk. These findings may help guide the allocation of health resources.

Overall and gender-specific associations between marital status and out-of-hospital coronary death during acute coronary events: a cross-sectional study based on data linkage in Beijing, China.

OBJECTIVES: To assess overall and gender-specific associations between marital status and out-of-hospital coronary death (OHCD) compared with patients surviving to hospital admission. DESIGN: A cross-sectional study based on linkage of administrative health databases. SETTING: Beijing, China. PARTICIPANTS: From 2007 to 2019, 378 883 patients with acute coronary event were identified in the Beijing Monitoring System for Cardiovascular Diseases, a validated city-wide registration system based on individual linkage of vital registration and hospital discharge data. OUTCOME MEASURES: OHCD was defined as coronary death occurring before admission. Multilevel modified Poisson regression models were used to calculate the prevalence ratios (PR) and 95% CIs. RESULTS: Among 378 883 acute coronary events, OHCD accounted for 33.8%, with a higher proportion in women compared with men (41.5% vs 28.7%, p<0.001). Not being married was associated with a higher proportion of OHCD in both genders, with a stronger association in women (PR 2.18, 95% CI 2.10 to 2.26) than in men (PR 1.97, 95% CI 1.91 to 2.02; p for interaction <0.001). The associations of OHCD with never being married (PR 1.98, 95% CI 1.88 to 2.08) and being divorced (PR 2.54, 95% CI 2.42 to 2.67) were stronger in men than in women (never married: PR 0.98, 95% CI 0.82 to 1.16; divorced: PR 1.47, 95% CI 1.34 to 1.61) (p for interaction <0.001 for both). Being widowed was associated with a higher proportion of OHCD in both genders, with a stronger association in women (PR 2.26, 95% CI 2.17 to 2.35) compared with men (PR 1.89, 95% CI 1.84 to 1.95) (p for interaction <0.001). CONCLUSIONS: Not being married was independently associated with a higher proportion of OHCD and the associations differed by gender. Our study may aid the development of gender-specific public health interventions in high-risk populations characterised by marital status to reduce OHCD burden.

SIRT4 Is Highly Expressed in Retinal Müller Glial Cells.

Sirtuin 4 (SIRT4) is one of seven mammalian sirtuins that possesses ADP-ribosyltransferase, lipoamidase and deacylase activities and plays indispensable role in metabolic regulation. However, the role of SIRT4 in the retina is not clearly understood. The purpose of this study was to explore the location and function of SIRT4 in the retina. Therefore, immunofluorescence was used to analyze the localization of SIRT4 in rat, mouse and human retinas. Western blotting was used to assess SIRT4 and glutamine synthetase (GS) protein expression at different developmental stages in C57BL/6 mice retinas. We further analyzed the retinal structure, electrophysiological function and the expression of GS protein in SIRT4-deficient mice. Excitotoxicity was caused by intravitreal injection of glutamate (50 nmol) in mice with long-term intraperitoneal injection of resveratrol (20 mg/Kg), and then retinas were subjected to Western blotting and paraffin section staining to analyze the effect of SIRT4 on excitotoxicity. We show that SIRT4 co-locates with Müller glial cell markers (GS and vimentin). The protein expression pattern of SIRT4 was similar to that of GS, and both increased with development. There were no significant retinal structure or electrophysiological function changes in 2-month SIRT4-deficient mice, while the expression of GS protein was decreased. Moreover, long-term administration of resveratrol can upregulate the expression of SIRT4 and GS while reducing the retinal injury caused by excessive glutamate. These results suggest that SIRT4 is highly expressed in retinal Müller glial cells and is relevant to the expression of GS. SIRT4 does not appear to be essential in retinal development, but resveratrol, as an activator of SIRT4, can upregulate GS protein expression and protect the retina from excitotoxicity.

Trends and Inequalities in the Incidence of Acute Myocardial Infarction among Beijing Townships, 2007-2018.

Acute myocardial infarction (AMI) poses a serious disease burden in China, but studies on small-area characteristics of AMI incidence are lacking. We therefore examined temporal trends and geographic variations in AMI incidence at the township level in Beijing. In this cross-sectional analysis, 259,830 AMI events during 2007-2018 from the Beijing Cardiovascular Disease Surveillance System were included. We estimated AMI incidence for 307 consistent townships during consecutive 3-year periods with a Bayesian spatial model. From 2007 to 2018, the median AMI incidence in townships increased from 216.3 to 231.6 per 100,000, with a greater relative increase in young and middle-aged males (35-49 years: 54.2%; 50-64 years: 33.2%). The most pronounced increases in the relative inequalities was observed among young residents (2.1 to 2.8 for males and 2.8 to 3.4 for females). Townships with high rates and larger relative increases were primarily located in Beijing's northeastern and southwestern peri-urban areas. However, large increases among young and middle-aged males were observed throughout peri-urban areas. AMI incidence and their changes over time varied substantially at the township level in Beijing, especially among young adults. Targeted mitigation strategies are required for high-risk populations and areas to reduce health disparities across Beijing.

Resveratrol protects retinal ganglion cell axons through regulation of the SIRT1-JNK pathway.

It is reported that Ischemia and reperfusion damage (I/R damage) can lead to retinal ganglion cell (RGC) death and neurodegeneration, which in turn can lead to irreversible vision loss. In this study, we sought to understand the neuroprotective effect of resveratrol, the important activator of sirtuin1 (SIRT1), on RGC survival in I/R damage model and the molecular mechanism that mediate this effect. Our results show that resveratrol could reverse axonal swelling, holes, and the chaos of the nucleus in axons of RGCs caused by I/R. At the same time, resveratrol could also reverse the activation of retinal astrocytes and the loss of RGCs caused by I/R. Resveratrol increased the expression of SIRT1 while decreasing the phosphorylation of N-terminal kinase (JNK). SP600125(JNK inhibitor) decreased the phosphorylation of JNK while increasing the expression of SIRT1, indicating that SIRT1 and JNK can interact with each other. Simultaneous administration of resveratrol and sirtinol (SIRT1 inhibitor) neither increased the expression of SIRT1 nor decreased the phosphorylation of JNK, indicating that resveratrol affects the phosphorylation of JNK by SIRT1. In total, our research shows that resveratrol treatment significantly reduces apoptosis and axonal degeneration of RGCs, and this protection is partly mediated through the SIRT1-JNK pathway.

Resveratrol protects retinal ganglion cells against ischemia induced damage by increasing Opa1 expression.

Loss of idiopathic retinal ganglion cells (RGCs) leads to irreversible vision defects and is considered the primary characteristic of glaucoma. However, effective treatment strategies in terms of RGC neuroprotection remain elusive. In the present study, the protective effects of resveratrol on RGC apoptosis, and the mechanisms underlying its effects were investigated, with a particular emphasis on the function of optic atrophy 1 (Opa1). In an ischemia/reperfusion (I/R) injury model, the notable thinning of the retina, significant apoptosis of RGCs, reduction in Opa1 expression and long Opa1 isoform to short Opa1 isoform ratios (L­Opa1/S­Opa1 ratio) were observed, all of which were reversed by resveratrol administration. Serum deprivation resulted in reductions in R28 cell viability, superoxide dismutase (SOD) activity, Opa1 expression and induced apoptosis, which were also partially reversed by resveratrol treatment. To conclude, results from the present study suggest that resveratrol treatment significantly reduced retinal damage and RGC apoptosis in I/R injury and serum deprivation models. In addition, resveratrol reversed the downregulated expression of Opa1 and reduced SOD activity. Mechanistically, resveratrol influenced mitochondrial dynamics by regulating the L­Opa1/S­Opa1 ratio. Therefore, these observations suggest that resveratrol may exhibit potential as a therapeutic agent for RGC damage in the future.

Topical administration of rapamycin promotes retinal ganglion cell survival and reduces intraocular pressure in a rat glaucoma model.

Glaucoma is a progressive optic neuropathy that has become the most common cause of irreversible blindness worldwide. Studies have shown that the protein mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays a central role in regulating numerous functions, such as growth, proliferation, cytoskeletal organization, metabolism, and autophagy. Clinical trials have shown that Rho-associated protein kinase (ROCK) inhibitors reduced intraocular pressure (IOP) in patients with glaucoma and ocular hypertension (OHT). In this study, we explored whether rapamycin (RAPA) eye drops can reduce IOP and protect retinal ganglion cells (RGCs). Our results indicated that in rats treated with RAPA, the drug was detected in the aqueous humor (AH), and the IOP was reduced. This may be related to the inhibition of RhoA protein activation by RAPA and regulation of the actin cytoskeleton in trabecular meshwork (TM) cells. In addition, the retinal thickness and the survival rate of RGCs were significantly reduced in the OHT group compared with the control group. These changes in the OHT group were significantly improved after treatment with RAPA. This may be because RAPA inhibited the activation of glial cells and the release of proinflammatory factors, thereby attenuating further damage to the retina and RGCs. Taken together, the results of this study demonstrated that RAPA not only reduced IOP but also protected RGCs, suggesting that RAPA is likely to be an effective strategy for the treatment of glaucoma.

Role of the PGE2 receptor in ischemia-reperfusion injury of the rat retina.

Purpose: To investigate the function and expression of the PGE2 receptors EP1-4 in rat retinal ischemia-reperfusion (I/R) injury and to determine the regulatory role of resveratrol (RES) in this process. Methods: In vitro, we stimulated primary astrocytes extracted from the optic disc of rats with epidermal growth factor (EGF) and RES, and detected the location of EP1-4 expression with immunofluorescence. The expression of antiglial fibrillary acidic protein (GFAP), EGF receptor (EGFR), inducible NOS (iNOS), and EP1-4 in astrocytes was detected with western blotting. In vivo, we established an I/R injury model and RES treatment model with Sprague-Dawley rats. Changes in the thickness of the inner retina were observed with hematoxylin and eosin (H&E) staining. EP1-4 localization in the retina was observed with immunohistochemistry. The expression of COX-2, iNOS, and EP1-4 in the control and model groups was detected with western blotting. Results: In this study, immunofluorescence and immunohistochemistry showed that EP1-4 are expressed in astrocytes and the rat retina. EGF stimulation increased the expression of EGFR, iNOS, EP1, EP2, and EP4 in astrocytes. The expression of EP1-4 was statistically significantly increased on the third day after model induction, and EP1-4 expression decreased to normal levels on day 7. EGF and RES mediated the decrease in the expression of EP2. RES treatment significantly reduced retinal damage and RGC loss, as demonstrated by the relatively intact tissue structure on day 7 observed with H&E staining. Moreover, inflammation was associated with this I/R injury model, as demonstrated by the early induction of proinflammatory mediators, and this inflammation was significantly attenuated after RES treatment. Conclusions: These results indicate that the COX-2/PGE2/EPs pathway is involved in retinal damage and astrocyte inflammation. In addition, the results suggest that the neuroprotective effects of RES may be associated with decreased production of inflammatory mediators. These results suggest that the PGE2 receptor may be a key factor in the treatment of neurodegenerative diseases, and that RES may be used as a possible therapeutic strategy for glaucoma.

Exploration of age-related mitochondrial dysfunction and the anti-aging effects of resveratrol in zebrafish retina.

It is currently believed that aging is closely linked with mitochondrial dysfunction, and that resveratrol exhibits anti-aging and neuroprotective effects by improving mitochondrial function, even though the mechanisms are not well defined. This study explored mitochondrial quality (mitochondrial DNA integrity and copy number), mitochondrial function (fusion/fission, mitophagy/autophagy), antioxidant system and activity of the Akt/mTOR and Ampk/Sirt1/Pgc1α pathways, and inflammation in aging zebrafish retinas to identify the probable mechanisms of resveratrol's anti-aging and neuroprotective effects. mtDNA integrity, mtDNA copy number, mitochondrial fusion regulators, mitophagy, and antioxidant-related genes were all decreased whereas Akt/mTOR activity and inflammation was increased upon aging in zebrafish retinas. Resveratrol was shown to not only increase mitochondrial quality and function, but also to suppress Akt/mTOR activity in zebrafish retinas. These results support the notion that mitochondrial dysfunction and increased Akt/mTOR activity are major players in age-related retinal neuropathy in zebrafish, and demonstrate a trend towards mitochondrial fragmentation in the aging retina. Importantly, resveratrol promoted mitochondrial function, up-regulating Ampk/Sirt1/Pgc1α, and down-regulated Akt/mTOR pathway activity in zebrafish retinas, suggesting that it may be able to prevent age-related oculopathy.

Resveratrol Delays Retinal Ganglion Cell Loss and Attenuates Gliosis-Related Inflammation From Ischemia-Reperfusion Injury.

Purpose: Resveratrol has been shown to enhance the survival of retinal ganglion cells (RGCs) following ischemia-reperfusion (I/R) injury for glaucoma. However, the precise mechanisms for resveratrol's protective effects are still unclear. The aim of this study is to determine whether resveratrol can inhibit RGC apoptosis, retinal gliosis, and inflammation, all of which are critical events in retinal degeneration following I/R injury. Methods: Right retinal ischemia was induced in adult male Sprague Dawley rats by increasing intraocular pressure to 110 mm Hg for 60 minutes, and the left eyes maintained at normal pressure serve as the control. Intraperitoneal injection of resveratrol or control buffer was performed continuously for 3 days from pre- to post-I/R injury and the protective effects were evaluated and compared. RGCs were retrogradely labeled with Fluoro-Gold by injection into superior colliculi. Apoptosis was detected by TUNEL staining. Western blotting and immunostaining for Bax, Bcl-2, and Caspase-3 were used to explore the Bax-associated apoptotic pathway. Gliosis was assessed by western blotting and immunostaining of retinal cross sections with anti-glial fibrillary acidic protein (GFAP) antibodies. Results: In this study, resveratrol treatment significantly reduced retinal damage and RGC loss as demonstrated by the relatively intact tissue structure in hematoxylin and eosin staining at day 7 and increased Fluoro-Gold labeling of RGCs at day 14, respectively. We found that resveratrol exhibited an anti-apoptotic effect as assessed by reduced TUNEL staining, inhibition of the early upregulated expression of the apoptosis-related protein Bax, and decreased subsequently cleaved caspase-3. However, it did not affect Bcl-2 levels. Moreover, in our I/R injury model, the combined response of reactive gliosis and related inflammation, which were demonstrated by an early induction of pro-inflammatory mediators and subsequently increased GFAP level, were significantly attenuated after resveratrol treatment. Conclusions: These results demonstrate that resveratrol can prevent RGC death by blocking the Bax-caspase-3-dependent apoptotic pathway and suppressed gliosis-related inflammation in the retina after I/R injury. Together these results support the use of resveratrol as a possible therapeutic strategy for glaucoma.