Novel Corneal Protein Biomarker Candidates Reveal Iron Metabolic Disturbance in High Myopia Eyes.

Myopia is a major public health concern with increasing global prevalence and is the leading cause of vision loss and complications. The potential role of the cornea, a substantial component of refractive power and the protective fortress of the eye, has been underestimated in the development of myopia. Our study acquired corneal stroma tissues from myopic patients undergoing femtosecond laser-assisted small incision lenticule extraction (SMILE) surgery and investigated the differential expression of circulating proteins between subjects with low and high myopia by means of high-throughput proteomic approaches-the quantitative tandem mass tag (TMT) labeling method and parallel reaction monitoring (PRM) validation. Across all corneal stroma tissue samples, a total of 2,455 proteins were identified qualitatively and quantitatively, 103 of which were differentially expressed between those with low and high myopia. The differentially abundant proteins (DAPs) between the groups of stroma samples mostly demonstrated catalytic activity and molecular function regulator and transporter activity and participated in metabolic processes, biological regulation, response to stimulus, and so forth. Pathway enrichment showed that mineral absorption, ferroptosis, and HIF-1 signaling pathways were activated in the human myopic cornea. Furthermore, TMT analysis and PRM validation revealed that the expression of ferritin light chain (FTL, P02792) and ferritin heavy chain (FTH1, P02794) was negatively associated with myopia development, while the expression of serotransferrin (TF, P02787) was positively related to myopia status. Overall, our results indicated that subjects with low and high myopia could have different proteomic profiles or signatures in the cornea. These findings revealed disturbances in iron metabolism and corneal oxidative stress in the more myopic eyes. Iron metabolic proteins could serve as an essential modulator in the pathogenesis of myopia.

The susceptibility of SERPINE1 rs1799889 SNP in diabetic vascular complications: a meta-analysis of fifty-one case-control studies.

BACKGROUND: The serine protease inhibitor-1 (SERPINE1) rs1799889 single nucleotide polymorphism (SNP) has been constantly associated with diabetes mellitus (DM) and its vascular complications. The aim of this meta-analysis was to evaluate this association with combined evidences. METHODS: The systematic search was performed for studies published up to March 2021 which assess the associations between SERPINE1 rs1799889 SNP and the risks of DM, diabetic retinopathy (DR), diabetic cardiovascular disease (CVD) and diabetic nephropathy (DN). Only case-control studies were identified, and the linkage between SERPINE1 rs1799889 polymorphism and diabetic vascular risks were evaluated using genetic models. RESULTS: 51 comparisons were enrolled. The results revealed a significant association with diabetes risk in overall population (allelic: OR = 1.34, 95 % CI = 1.14-1.57, homozygous: OR = 1.66, 95 % CI = 1.23-2.14, heterozygous: OR = 1.35, 95 % CI = 1.08-1.69, dominant: OR = 1.49, 95 % CI = 1.18-1.88, recessive: OR = 1.30, 95 % CI = 1.06-1.59) as well as in Asian descents (allelic: OR = 1.45, 95 % CI = 1.16-1.82, homozygous: OR = 1.88, 95 % CI = 1.29-2.75, heterozygous: OR = 1.47, 95 % CI = 1.08-2.00, dominant: OR = 1.64, 95 % CI = 1.21-2.24, recessive: OR = 1.46, 95 % CI = 1.09-1.96). A significant association was observed with DR risk (homozygous: OR = 1.25, 95 % CI = 1.01-1.56, recessive: OR = 1.20, 95 % CI = 1.01-1.43) for overall population, as for the European subgroup (homozygous: OR = 1.32, 95 % CI = 1.02-1.72, recessive: OR = 1.38, 95 % CI = 1.11-1.71). A significant association were shown with DN risk for overall population (allelic: OR = 1.48, 95 % CI = 1.15-1.90, homozygous: OR = 1.92, 95 % CI = 1.26-2.95, dominant: OR = 1.41, 95 % CI = 1.01-1.97, recessive: OR = 1.78, 95 % CI = 1.27-2.51) and for Asian subgroup (allelic: OR = 1.70, 95 % CI = 1.17-2.47, homozygous: OR = 2.46, 95 % CI = 1.30-4.66, recessive: OR = 2.24, 95 % CI = 1.40-3.59) after ethnicity stratification. No obvious association was implied with overall diabetic CVD risk in any genetic models, or after ethnicity stratification. CONCLUSIONS: SERPINE1 rs1799889 4G polymorphism may outstand for serving as a genetic synergistic factor in overall DM and DN populations, positively for individuals with Asian descent. The association of SERPINE1 rs1799889 SNP and DR or diabetic CVD risks was not revealed.

Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin.

BACKGROUND: Doxorubicin, an anthracycline chemotherapeutic agent, is widely used in the treatment of many cancers. However, doxorubicin posts a great risk of adverse cardiovascular events, which are thought to be caused by oxidative stress. We recently reported that the ubiquitin E3 ligase TRIM21 interacts and ubiquitylates p62 and negatively regulates the p62-Keap1-Nrf2 antioxidant pathway. Therefore, we sought to determine the role TRIM21 in cardiotoxicity induced by oxidative damage. METHODS: Using TRIM21 knockout mice, we examined the effects of TRIM21 on cardiotoxicity induced by two oxidative damage models: the doxorubicin treatment model and the Left Anterior Descending (LAD) model. We also explored the underlying mechanism by RNA-sequencing of the heart tissues, and by treating the mouse embryonic fibroblasts (MEFs), immortalized rat cardiomyocyte line H9c2, and immortalized human cardiomyocyte line AC16 with doxorubicin. FINDINGS: TRIM21 knockout mice are protected from heart failure and fatality in both the doxorubicin and LAD models. Hearts of doxorubicin-treated wild-type mice exhibit deformed mitochondria and elevated level of lipid peroxidation reminiscent of ferroptosis, which is alleviated in TRIM21 knockout hearts. Mechanistically, TRIM21-deficient heart tissues and cultured MEFs and H9c2 cells display enhanced p62 sequestration of Keap1 and are protected from doxorubicin-induced ferroptosis. Reconstitution of wild-type but not the E3 ligase-dead and the p62 binding-deficient TRIM21 mutants impedes the protection from doxorubicin-induced cell death. INTERPRETATION: Our study demonstrates that TRIM21 ablation protects doxorubicin-induced cardiotoxicity and illustrates a new function of TRIM21 in ferroptosis, and suggests TRIM21 as a therapeutic target for reducing chemotherapy-related cardiotoxicity. FUNDING: NIH (CA129536; DK108989): data collection, analysis. Shanghai Pujiang Program (19PJ1401900): data collection. National Natural Science Foundation (31971161): data collection. Department of Veteran Affairs (BX004083): data collection. Tianjin Science and Technology Plan Project (17ZXMFSY00020): data collection.

Value of Blood-Based microRNAs in the Diagnosis of Acute Myocardial Infarction: A Systematic Review and Meta-Analysis.

Background: Recent studies have shown that blood-based miRNAs are dysregulated in patients with acute myocardial infarction (AMI) and are therefore a potential tool for the diagnosis of AMI. Therefore, this study summarized and evaluated studies focused on microRNAs as novel biomarkers for the diagnosis of AMI from the last ten years. Methods: MEDLINE, the Cochrane Central database, and EMBASE were searched between January 2010 and December 2019. Studies that assessed the diagnostic accuracy of circulating microRNAs in AMI were chosen. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the curve (AUC) were used to assess the test performance of miRNAs. Results: A total of 58 studies that included 8,206 participants assessed the diagnostic accuracy of circulating miRNAs in AMI. The main results of the meta-analyses are as follows: (1) Total miRNAs: the overall pooled sensitivity and specificity were 0.82 (95% CI: 0.79-0.85) and 0.87 (95% CI: 0.84-0.90), respectively. The AUC value was 0.91 (95% CI: 0.88-0.93) in the overall summary receiver operator characteristic (SROC) curve. (2) The panel of two miRNAs: sensitivity: 0.88 (95% CI: 0.77-0.94), specificity: 0.84 (95% CI: 0.72-0.91), AUC: 0.92 (95% CI: 0.90-0.94). (3) The panel of three miRNAs: sensitivity: 0.91 (95% CI: 0.85-0.94), specificity: 0.87 (95% CI: 0.77-0.92), AUC: 0.92 (95% CI: 0.89-0.94). (4) Results by types of miRNAs: miRNA-1: sensitivity: 0.78 (95% CI: 0.71-0.84), specificity: 0.86 (95% CI: 0.77-0.91), AUC: 0.88 (95% CI: 0.85-0.90); miRNA-133a: sensitivity: 0.85 (95% CI: 0.69-0.94), specificity: 0.92 (95% CI: 0.61-0.99), AUC: 0.93 (95% CI: 0.91-0.95); miRNA-208b: sensitivity: 0.80 (95% CI: 0.69-0.88), specificity: 0.96 (95% CI: 0.77-0.99), AUC: 0.91 (95% CI: 0.88-0.93); miRNA-499: sensitivity: 0.85 (95% CI: 0.77-0.91), specificity: 0.95 (95% CI: 0.89-0.98), AUC: 0.96 (95% CI: 0.94-0.97). Conclusion: miRNAs may be used as potential biomarkers for the detection of AMI. For single, stand-alone miRNAs, miRNA-499 may have better diagnostic accuracy compared to other miRNAs. We propose that a panel of multiple miRNAs with high sensitivity and specificity should be tested.

Effects of miR-124-3p regulation of the p38MAPK signaling pathway via MEKK3 on apoptosis and proliferation of macrophages in mice with coronary atherosclerosis.

BACKGROUND: Atherosclerosis (AS) is the main cause of myocardial infarction and stroke. Macrophage apoptosis in the early stages can attenuate lesions, while in the late stage it is associated with AS plaque rupture. OBJECTIVES: To explore the effects of miR-124-3p regulation of the p38MAPK signaling pathway via the MEKK3 gene on the apoptosis and proliferation of macrophages in mice with coronary AS. MATERIAL AND METHODS: Fifty male apolipoprotein E (ApoE) -/- mice were equally assigned to a normal group and a coronary AS group. In the AS group, the mice were given a high-fat diet to establish a coronary AS model. The macrophages of the mice were isolated for culture and divided into 7 groups: normal, negative control (NC), control, miR-124-3p mimic, miR-124-3p inhibitor, si-MEKK3, and miR-124-3p inhibitor+si-MEKK3. RESULTS: Compared with the normal group, the AS group had lower expression levels of miR-124-3p and higher expression levels of MEKK3 and p-p38MAPK in the coronary artery tissue and peritoneal macrophages (all p < 0.050). We found that miR-124-3p could negatively regulate MEKK3 expression. Compared with the control group, the miR-124-3p mimic group and si-MEKK3 group had greater cell apoptosis rates and Bax levels, weaker cell proliferation and invasion abilities, slower cell cycle progression, and lower PCNA and Bcl-2 levels (all p < 0.050). This trend was also displayed in the miR-124-3p inhibitor+si-MEKK3 group when compared with the miR-124-3p inhibitor group, and in the si-MEKK3 group when compared with the miR-124-3p inhibitor+si-MEKK3 group (all p < 0.050). CONCLUSIONS: miR-124-3p overexpression can downregulate MEKK3 expression and inhibit the expression of the p38MAPK signaling pathway, thereby inhibiting macrophage proliferation and promoting macrophage apoptosis in mice with coronary AS.

Efficacy of statin treatment based on cardiovascular outcomes in elderly patients: a standard meta-analysis and Bayesian network analysis.

OBJECTIVE: Statins have been shown to be beneficial for the prevention of cardiovascular events. In elderly individuals, the efficacy of statins remains controversial and the comparative effect of statins has not been assessed. METHODS: MEDLINE, Embase, and the Cochrane Central database were searched for randomized controlled trials that assessed statins in older patients. RESULTS: Seventeen trials were analyzed. When used for secondary prevention, statins were associated with reduced risk of cardiovascular events, all-cause mortality, cardiovascular mortality, revascularization, and stroke. When used for primary prevention, statins reduced the risk of myocardial infarction and revascularization, but did not significantly affect other outcomes. A modest difference between pharmaceutical statin products was found, and high-quality evidence indicated that intensive atorvastatin had the greatest benefits for secondary prevention. CONCLUSIONS: In secondary prevention, evidence strongly suggests that statins are associated with a reduction in the risk of all-cause mortality, cardiovascular events, cardiovascular mortality, and revascularization. However, differences in the effects of various statins do not appear to have significant effects on therapy in secondary prevention for the elderly.

Clinical outcome comparison of percutaneous coronary intervention and bypass surgery in diabetic patients with coronary artery disease: a meta-analysis of randomized controlled trials and observational studies.

BACKGROUND: The optimal revascularization technique in diabetic patients with complex coronary artery disease (CAD), including left main CAD and multivessel coronary disease (MVD), remains controversial. The current study aimed to compare adverse clinical endpoints of coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) in patients with diabetes mellitus (DM). METHODS: Relevant studies were found from MEDLINE, OVID, Science Direct, Embase and the Cochrane Central database from January 2010 to April 2019. Risk ratio (RR) with 95% confidence interval (CI) was used to express the pooled effect on discontinuous variables. Outcomes evaluated were all-cause mortality, major adverse cardiac/cerebrovascular events (MACCE), cardiac death, myocardial infarction, stroke, and repeat revascularization. RESULTS: Sixteen studies were included (18,224 patients). PCI was associated with the increase risk for MACCE (RR 1.59, 95% CI 1.38-1.85), cardiac death (RR 1.76, 95% CI 1.11-2.80), MI (RR 1.98, 95% CI 1.53-2.57), repeat revascularization (RR 2.61, 95% CI 2.08-3.29). The risks for all-cause mortality (RR 1.23, 95% CI 1.00-1.52) and stroke (RR 0.71, 95% CI 0.48-1.03) were similar between two strategies. Stratified analysis based on studies design and duration of follow-up showed largely similar findings with the overall analyses, except for a significant increased risk of all-cause mortality (RR 1.32, 95% CI 1.04-1.67) in long-term group, and CABG was associated with a higher stroke rate compared to PCI, which are results that were found in RCTs (RR 0.47, 95% CI 0.28-0.79) and mid-term groups (RR 0.39, 95% CI 0.23-0.66). CONCLUSIONS: CABG was superior to PCI for diabetic patients with complex CAD (including left main CAD and/or MVD), but might be associated with a higher risk of stroke mid-term follow-up.Number of Protocol registration PROSPERO CRD 42019138505.

Effect of High-Dose Statin Pretreatment on the Incidence of Periprocedural Myocardial Infarction in Patients Undergoing Percutaneous Coronary Intervention: Grading the Evidence Through a Cumulative Meta-analysis.

BACKGROUND: Previous studies have showed that high-dose statin pretreatment could reduce the incidence of periprocedural myocardial infarction (PMI) in patients undergoing percutaneous coronary intervention (PCI). However, previous analyses have not performed reliable grading of evidence. HYPOTHESIS: In previous analyses, it supposed that the high-dose statin pretreatment was effective in reduction of the rate of PMI. In this analysis, we evaluated the effect of high-dose statin pretreatment on the reduction of rate of PMI based on a cumulative meta-analysis and grading of evidence. METHODS: We assembled the relevant published randomized controlled trials that compared the efficacy of high-dose statin pretreatment prior to PCI. We evaluated the risk of PMI by a cumulative meta-analysis, with subgroups stratified by clinical classifications and different statin histories, and we conducted explicit grading of evidence. RESULTS: High-dose statin pretreatment caused a 55% reduction in PMI through this cumulative meta-analysis of 23 RCTs (odds ratio [OR]: 0.45, 95% confidence interval [CI]: 0.37-0.54). The effect of high-dose statin pretreatment was significant for the stable angina subgroup (OR: 0.42, 95% CI: 0.32-0.56), ACS subgroup (OR: 0.43, 95% CI: 0.29-0.64), and the mixed presentation subgroup (OR: 0.50, 95% CI: 0.36-0.70). In different statin therapy histories, high-dose statin pretreatment reduced incidence of PMI 55% in the statin-naive subgroup (OR: 0.45, 95% CI: 0.36-0.56) and 54% in the low-dose statin subgroup (OR: 0.46, 95% CI: 0.32-0.66). The GRADE system indicated that the overall evidence quality was moderate. This finding may strengthen the confidence in any recommendations. CONCLUSIONS: High-dose statin pretreatment can reduce the rate of PMI, irrespective of either the clinical presentation or previous statin-treatment history. Importantly, the overall GRADE evidence quality was moderate.

Rs7193343 polymorphism in zinc finger homeobox 3 (ZFHX3) gene and atrial fibrillation: an updated meta-analysis of 10 case-control comparisons.

BACKGROUND: The previous genome-wide studies have shown that rs7193343 single-nucleotide polymorphism (SNP) in zinc finger homeobox 3 (ZFHX3) gene correlate with risk of atrial fibrillation (AF). However, the distribution of this SNP differs significantly among various populations. The present study was to investigate whether combined evidence shows the association between ZFHX3 rs7193343 SNP and the risk of AF in various populations. METHODS: A systematic search of all studies published through Dec 2014 was conducted using the Medline, Embase, WanFang, ScienceDirect, CNKI, and OVID databases. The case-control studies that evaluated an association between rs7193343 SNP and risk of AF were identified. The association between the ZFHX3 rs7193343 SNP and AF susceptibility was assessed using genetic models. RESULTS: We collected 10 comparisons from six studies for rs7193343 SNP, including 1037 cases and 4310 controls in Asian, 5583 cases and 38215 controls in Caucasian, and then performed an updated meta-analysis and subgroup analysis based on ethnicity. In overall population, the occurrence of AF was found to be associated with T-allelic of rs7193343 SNP in ZFHX3 (OR =1.17, 95% CI 1.10-1.26). In subgroup analysis, we observed there was significant association between T-allele of rs7193343 and risk of AF in Caucasian subgroups (OR =1.20, 95% CI 1.12-1.30), but no statistically significance (OR = 1.07, 95% CI 0.92-1.24) in Asian population. CONCLUSION: In Caucasian population, genetic variant rs7193343 SNP is associated with risk of AF in Caucasian population. However, no association is found in Asian population based on the current evidence. Further studies with larger sample size involving case-control populations with multiple ethnics are still required in the future.