Improved heart function and cardiac remodelling following sacubitril/valsartan in acute coronary syndrome with HF.

AIMS: This study sought to assess the effect of treatment of sacubitril/valsartan (S/V) on improving cardiac function and reversing cardiac remodelling in patients with acute coronary syndrome (ACS) complicated with heart failure with reduced ejection fraction after percutaneous coronary intervention (PCI). METHODS AND RESULTS: We enrolled 275 ACS patients with reduced left ventricular ejection fraction after PCI. The patients were divided into the routine and S/V groups according to the treatment drugs. The symptoms, N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations, echocardiographic parameters [left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI), left ventricular end-diastolic volume index (LVEDVI), and left ventricular end-systolic volume index (LVESVI)], major adverse cardiac events (MACEs), and adverse reactions were recorded at baseline and 6 months after treatment when a clinical follow-up was performed. The S/V group was further divided into prespecified subgroups including unstable angina (UA) group, non-ST-elevation myocardial infarction (NSTEMI) group, and ST-elevation myocardial infarction (STEMI) group according to the type of ACS. We analysed the changes in LVEF, LVMI, LVEDVI, LVESVI, and NT-proBNP in both groups and evaluated the correlation between the changes in the above variables (ΔLVEF, ΔLVMI, ΔLVEDVI, ΔLVESVI, and ΔNT-proBNP). Cox regression model was used to assess the independent risk factors of MACE. Prespecified subgroup analyses were also conducted. Compared with baseline, LVEF increased significantly (P < 0.05), NT-proBNP, LVMI, and LVESVI decreased significantly in both groups after 6 months (P < 0.05), and LVEDVI decreased significantly in the S/V group (P = 0.001). In the S/V group, ΔLVEF (t = -2.745, P = 0.006), ΔNT-proBNP (P = 0.009), ΔLVEDVI (t = 4.203, P = 0.001), and ΔLVESVI (t = 3.907, P = 0.001) were significantly improved than those in the routine group. In the S/V group, ΔLVEF was negatively correlated with ΔNT-proBNP (r = -0.244, P = 0.004), ΔLVMI (r = -0.190, P = 0.028), ΔLVEDVI (r = -0.173, P = 0.045), and ΔLVESVI (r = -0.261, P = 0.002). In Cox regression model analysis, ΔLVEF {hazard ratio [HR] = 0.87 [95% confidence interval (CI) 0.80-0.95], P = 0.003}, ΔLVEDVI [HR = 1.04 (95% CI 1.01-1.06), P = 0.013], and ΔLVESVI [HR = 1.04 (95% CI 1.01-1.08), P = 0.026] were independent risk factors for MACE. Subgroup analysis showed that ΔLVEF (t = 6.290, P = 0.001), ΔLVEDVI (t = 2.581, P = 0.011), and ΔNT-proBNP (P = 0.019) in the NSTEMI group were significantly improved than those in the UA group, ΔLVEDVI in the NSTEMI group was significantly better than that in the STEMI group (t = -3.365, P = 0.001), and ΔLVEF in the STEMI group was significantly better than that in the UA group (t = -3.928, P = 0.001). There was a significant difference in the survival probability without MACE among the three groups in the analysis of the Kaplan-Meier curve (P = 0.042). The incidence of MACE in the UA group was significantly higher than that in the NSTEMI group (32.4% vs. 6.3%, P = 0.004). CONCLUSIONS: The cardiac function is improved and cardiac remodelling is reversed significantly after treatment of S/V in ACS patients with reduced left ventricular ejection fraction after PCI, and the improvement is more obvious than the routine group. There is a significant negative correlation between the change in LVEF and the changes in NT-proBNP, LVMI, LVEDVI, and LVESVI. The increase of LVEF and the decrease of LVEDVI and LVESVI are protective factors to improve the prognosis. Patients with myocardial infarction and reduced left ventricular ejection fraction might benefit more from the initiation of S/V as first-line heart failure treatment after PCI.

Unveiling sub-bandgap energy-level structures on machined optical surfaces based on weak photo-luminescence.

Sub-bandgap defect energy levels (SDELs) introduced by the point defects located in surface defect areas are considered the main factors in decreasing laser-induced damage thresholds (LIDTs). The suppression of SDELs could greatly increase LIDTs. However, no available method could detect SDELs, limiting the characterization and suppression of SDELs. Herein, a self-designed photo-luminescence detection system is developed to explore the weak transient-steady photo-luminescence properties of machined surfaces. Based on the excitation laser wavelength dependence of photo-luminescence properties, a sub-bandgap energy-level structure (SELS) containing SDELs is unveiled for the first time. Based on the developed mathematical model for predicting LIDTs, the feasibility of the detection method was verified. In summary, this work provides a novel approach to characterize SDELs on machined surfaces. This work could construct electronic structures and explore the transition behaviors of electrons, which is vital to laser-induced damage. Besides, this work could predict the LIDTs of the machined surfaces based on their PL properties, which provides convenience for evaluating the LIDTs of various optical elements in industrial production. Moreover, this work provides a convenient method for raising the LIDTs of various optical elements through monitoring and suppressing the SDELs on machined surfaces.

Evolution of the point defects involved under the action of mechanical forces on mechanically machined fused silica surfaces.

Point defects with different species are concentrated on most mechanically machined fused silica optical surfaces with surface defects, which would sharply decrease the laser damage resistance under intense laser irradiation. Various point defects have distinct roles in affecting the laser damage resistance. Especially, the proportions of various point defects have not been identified, posing the challenge in relating the intrinsic quantitative relationship among various point defects. To fully reveal the comprehensive effect of various point defects, it is necessary to systematically explore the origins, evolution laws and especially the quantitative relationship among point defects. Herein, seven types of point defects are determined. The unbonded electrons in point defects are found to tend to be ionized to induce laser damage and there is a definite quantitative relationship between the proportions of oxygen-deficient point defects and that of peroxide point defects. The conclusions are further verified based on the photoluminescence (PL) emission spectra and the properties (e.g., reaction rule and structural feature) of the point defects. On basis of the fitted Gaussian components and electronic-transition theory, the quantitative relationship between PL and the proportions of various point defects is constructed for the first time. E'-Center accounts for the highest proportion among them. This work is beneficial for fully revealing the comprehensive action mechanisms of various point defects and providing new insights in elucidating the defect-induced laser damage mechanisms of optical components under intense laser irradiation from the atomic scale.

Geriatric nutritional risk index predicts all-cause mortality in the oldest-old patients with acute coronary syndrome: A 10-year cohort study.

Background and objective: Nutritional status assessment in acute coronary syndrome (ACS) patients has been neglected for a long time. The geriatric nutritional risk index (GNRI) is a sensitive indicator for assessing the nutritional status of the elderly. This study aims to explore the association between GNRI and all-cause mortality in the oldest-old patients with ACS. Methods: The patients who met the inclusion criteria were consecutively enrolled from January 2006 to December 2012. Clinical data were collected on admission, and all subjects were followed after being discharged. The nutritional status was evaluated using GNRI. The relationship between GNRI and all-cause mortality was assessed by using different analyses. Results: A total of 662 patients with a mean age of 81.87 ± 2.14 years old were included in our study, and followed (median: 63 months, IQR 51-71). Patients whose GNRI ≤ 98 were reported as at risk of malnutrition (31.11%, n = 206). In multivariable analysis, we found that for each SD increase in GNRI, the risk of all-cause mortality lowered by 23%, and the HR for GNRI ≤ 98 was 1.39 (95% CI 1.04-1.86). After stratifying patients into three groups by tertiles of GNRI, we found that the HRs for tertile 2 and tertile 3 were 1.49 (95% CI 1.02-2.19) and 1.74 (95% CI 1.22-2.50), respectively. The trend test revealed a dose-response relationship between GNRI and all-cause mortality in the oldest-old with ACS. Lastly, in subgroup analyses, we found a reliable association between GNRI and all-cause mortality. Conclusion: Malnutrition is common in the oldest-old patients with ACS, and GNRI could predict their long-term all-cause mortality in a dose-dependent manner. GNRI may be a prospective index for risk-stratification and secondary-prevention in the oldest-old patients with ACS.

Evaluation of antioxidation, regulation of glycolipid metabolism and potential as food additives of exopolysaccharide from Sporidiobolus pararoseus PFY-Z1.

At present, there are relatively few studies on the production of exopolysaccharide (EPS) by yeasts. Therefore, exploring the properties of EPS produced by yeast can not only enrich the source of EPS, but also play an important role in its future application in the food field. The aim of this study was to explore the biological activities of EPS (named SPZ) from Sporidiobolus pararoseus PFY-Z1, as well as the dynamic changes in physical and chemical properties that occur during simulated gastrointestinal digestion, and the effects of SPZ on microbial metabolites during fecal fermentation in vitro. The results revealed that SPZ had good water solubility index, water-holding capacity, emulsifying ability, coagulated skim milk, antioxidant properties, hypoglycemic activities, and bile acid-binding abilities. Furthermore, the content of reducing sugars increased from 1.20 ± 0.03 to 3.34 ± 0.11 mg/mL after gastrointestinal digestion, and had little effect on antioxidant activities. Moreover, SPZ could promote the production of short-chain fatty acids during fermentation for 48 h, in particular, propionic acid and n-butyric acid increased to 1.89 ± 0.08 and 0.82 ± 0.04 mmol/L, respectively. Besides this, SPZ could inhibit LPS production. In general, this study can help us to better understand the potential bioactivities, and the changes in bio-activities of compounds after digestion of SPZ.

Triglyceride glucose index predicts all-cause mortality in oldest-old patients with acute coronary syndrome and diabetes mellitus.

BACKGROUND: Acute coronary syndrome (ACS) and diabetes mellitus (DM) are the leading health risks for the elderly. Triglyceride-glucose (TyG) index is a novel and reliable indicator of insulin resistance (IR). This study aims to explore the relationship between the TyG index and all-cause mortality in oldest-old patients with ACS and DM. METHODS: Seven hundred twenty hospitalized patients with ACS aged ≥ 80 years were enrolled, and 699 patients signed informed consent for the study. During the follow-up period, 37 were lost to follow-up, and the follow-up rate was 94.7%. 231 ACS patients with DM were selected for the study's analyses. Kaplan-Meier curve, Cox regression model and receiver operating characteristic (ROC) curve were used to analyze the association between the TyG index and all-cause mortality. RESULTS: The mean age of participants was 81.58 ± 1.93 years, and 32.47% were women. Compared to TyG tertile 1, the Hazard Ratio (HR) [95% confidence interval (CI)] of all-cause mortality was 2.04 (1.09, 3.81) for TyG tertile 3 in the fully adjusted model. For the TyG index per standard deviation (SD) increment, the HR (95% CI) of all-cause mortality was 1.44 (1.13, 1.83). Further, the association between the TyG index and all-cause mortality was dose-response (P for trend = 0.026). ROC curve analyses indicated that the TyG index outperformed FBG and TG in the prediction of mortality risk and improved the prognostic value of the Gensini score combined with LVEF. CONCLUSION: The TyG index predicts the risk of all-cause mortality in the oldest-old ACS patients with DM.

Tortuosity of branch retinal artery is more associated with the genesis and progress of diabetic retinopathy.

Objective: The purpose of this study is to investigate the potential of using the tortuosity of branch retinal artery as a more promising indicator for early detection and accurate assessment of diabetic retinopathy (DR). Design and method: The diagnoses, consisting of whether DR or not as well as DR severity, were given by ophthalmologists upon the assessment of those fundus images from 495 diabetic patients. Meanwhile, benefiting from those good contrast and high optical resolution fundus images taken by confocal scanning laser ophthalmoscope, the branch arteries, branch veins, main arteries and main veins in retina can be segmented independently, and the tortuosity values of them were further extracted to investigate their potential correlations with DR genesis and progress based on one-way ANOVA test. Results: For both two comparisons, i.e., between non-DR group and DR group as well as among groups with different DR severity levels, larger tortuosity increments were always observed in retinal arteries and the increments in branch retinal vessels were even larger. Furthermore, it was newly found that branch arterial tortuosity was significantly associated with both DR genesis (p=0.030) and DR progress (p<0.001). Conclusion: Based on this cohort study of 495 diabetic patients without DR and with different DR severity, the branch arterial tortuosity has been found to be more closely associated with DR genesis as well as DR progress. Therefore, the branch arterial tortuosity is expected to be a more direct and specific indicator for early detection of DR as well as accurate assessment of DR severity, which can further guide timely and rational management of DR to prevent from visual impairment or even blindness resulting from DR.

Wnt 3a Protects Myocardial Injury in Elderly Acute Myocardial Infarction by Inhibiting Serum Cystatin C/ROS-Induced Mitochondrial Damage.

Aging represents an independent risk factor affecting the poor prognosis of patients with acute myocardial infarction (AMI). This present research aimed to explore the molecular mechanism of myocardial injury in elderly AMI by animals and cells experiment. Our previous clinical study found the serum Cystatin C (Cys-C) increased in the elderly AMI population, while the mechanism underlying high Cys-C induced myocardial injury of AMI remains unclear. In the in-vitro study, we confirmed that Wnt/ß-catenin could significantly reduce the expression of cytoplasmic Cys-C through transnuclear action, and highly attenuate the occurrence of mitochondrial oxidative stress injury induced via Cys-C/reactive oxygen species (ROS). Furthermore, the addition of exogenous Wnt3a and inhibition of Cys-C expression could effectively inhibit mitochondrial oxidative stress injury and relieve the acute myocardial hypoxia injury. These results indicate that Cys-C exerted damaging effects on the hypoxic aging cardiomyocyte through the ROS/mitochondrial signaling pathway. Inhibition of this pathway effectively reduced the apoptosis of aging cardiomyocytes. In the in-vivo study, we also explored the function of the Wnt/Cys-C pathway on the ischemic infarction heart. We confirmed that Wnt/ß-catenin served as the upstream protective protein of this pathway, and the promotion of this pathway improved the cardiac structure and function of the elderly AMI mice effectively.

An Overview of Laser Metal Deposition for Cladding: Defect Formation Mechanisms, Defect Suppression Methods and Performance Improvements of Laser-Cladded Layers.

With the development of society and the economy, there is an increasing demand for surface treatment techniques that can efficiently utilize metal materials to obtain good performances in the fields of mechanical engineering and the aerospace industry. The laser metal deposition (LMD) technique for cladding has become a research focus in recent years because of its lower dilution rate, small heat-effect zone and good metallurgical bonding between the coating and substrate. This paper reviews the simulation technology for the melt pool's grain growth mechanism, temperature and stress distribution that are directly related to defect formation in LMD technology. At the same time, the defect suppression method and the performance improvement method of the cladded layer in LMD technology are introduced. Finally, it is pointed out that the active selection of materials according to the required performance, combined with the controllable processing technology, to form the corresponding microstructure, and finally, to actively realize the expected function, is the future development direction of LMD technology.

Study on mechanism of improving efficiency of permanent-magnet small ball-end magnetorheological polishing by increasing magnetorheological fluid temperature.

Permanent-magnet small ball-end magnetorheological polishing method can be used to polish the small part with complex structure. However, the material removal rate of this method is low, which is difficult to improve the output and reduce the cost. In this research, the effect of magnetorheological fluid temperature on the material removal rate is theoretically analyzed by measuring the effect of temperature on the flow properties of magnetorheological fluid, establishing the hydrodynamic model of polishing zone and solving the material removal parameters. It is found that with the increase of the magnetorheological fluid temperature, the polishing relative velocity increases accordingly, which can promote the improvement of material removal rate. But the shear stress decreases accordingly, which inhibits the improvement of material removal rate. The verification experiment results show that the promoting effect can exceeds the inhibitory effect, so that the material removal rate increases with the increase of magnetorheological fluid temperature. When the magnetorheological fluid temperature increases to 60 °C, the material removal rate is improved by 108.4% and the polished surface roughness Sa can reach 14.9 nm. Therefore, increasing the magnetorheological fluid temperature can significantly improve the efficiency of permanent-magnet small ball-end magnetorheological polishing and obtain high quality polished surface.

Analysis of Knee Joint Injury Caused by Physical Training of Freshmen Students Based on 3T MRI and Automatic Cartilage Segmentation Technology: A Prospective Study.

Background: The differential effects of various exercises on knee joint injury have not been well documented. Improper physical training can cause irreversible damage to the knee joint. MRI is generally used to precisely analyze morphological and biochemical changes in the knee cartilage. We compared the effects of long-walking and regular daily physical training on acute and chronic knee joint injuries as well as cartilage structure in freshmen students. Methods: A total of 23 young male college freshmen were recruited to participate in an 8-day 240 km long distance walk and a one-year daily training. 3D-DESSwe, 2D T2 mapping, DIXON, and T1WI of the right knee joint were performed using the MAGNETOM Spectra 3T MR scanner. The injury of meniscus, bone marrow edema, ligaments and joint effusion is graded. Cartilage volume, thickness and T2 values of 21 sub-regions of the knee cartilage were estimated using automatic cartilage segmentation prototype software. Friedman's test and Wilcoxon paired rank-sum test were used to compare quantitative indices of knee cartilage in three groups. Results: The injury to the medial meniscus and anterior cruciate ligament of the knee joint, joint effusion, and bone marrow edema was significantly higher in the long-walking group compared to the baseline and daily groups. Furthermore, injury to the lateral meniscus was significantly worse in the long-walking group compared to the baseline group but was significantly better in the daily group compared to the baseline group. No significant changes to the posterior cruciate ligament were observed among the three groups. Knee cartilage volume was significantly increased, mainly in the stress surface of the femur, patella, and the lateral area of the tibial plateau. Regular daily training did not significantly change the thickness of the knee cartilage. Conversely, knee cartilage thickness decreased in the long-walking group, especially in the medial and lateral areas of the femur and tibial plateau. Moreover, no significant changes were observed in the knee cartilage volume of the long-walking group. Both long-walking and daily groups showed reduced T2 values of the knee joint compared to the baseline. Conclusion: Among freshmen students and the training of this experimental intensity, our results show that regular daily training does not cause high-level injury to the knee joint, but improve the knee joint function adaptability by increasing cartilage volume. Moreover, knee injury caused by short-term long walking can be reversible.

Pathogenic Tconvs promote inflammatory macrophage polarization through GM-CSF and exacerbate abdominal aortic aneurysm formation.

Abdominal aortic aneurysms (AAAs) elicit massive inflammatory leukocyte recruitment to the aorta. CD4+ T cells, which include regulatory T cells (Tregs) and conventional T cells (Tconvs), are involved in the progression of AAA. Tregs have been reported to limit AAA formation. However, the function and phenotype of the Tconvs found in AAAs remain poorly understood. We characterized aortic Tconvs by bulk RNA sequencing and discovered that Tconvs in aortic aneurysm highly expressed Cxcr6 and Csf2. Herein, we determined that the CXCR6/CXCL16 signaling axis controlled the recruitment of Tconvs to aortic aneurysms. Deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF), encoded by Csf2, markedly inhibited AAA formation and led to a decrease of inflammatory monocytes, due to a reduction of CCL2 expression. Conversely, the exogenous administration of GM-CSF exacerbated inflammatory monocyte infiltration by upregulating CCL2 expression, resulting in worsened AAA formation. Mechanistically, GM-CSF upregulated the expression of interferon regulatory factor 5 to promote M1-like macrophage differentiation in aortic aneurysms. Importantly, we also demonstrated that the GM-CSF produced by Tconvs enhanced the polarization of M1-like macrophages and exacerbated AAA formation. Our findings revealed that GM-CSF, which was predominantly derived from Tconvs in aortic aneurysms, played a pathogenic role in the progression of AAAs and may represent a potential target for AAA treatment.

The effect of lactoferrin in aging: role and potential.

Aging is frequently accompanied by various types of physiological deterioration, which increases the risk of human pathologies. Global public health efforts to increase human lifespan have increasingly focused on lowering the risk of aging-related diseases, such as diabetes, neurodegenerative diseases, cardiovascular disease, and cancers. Dietary intervention is a promising approach to maintaining human health during aging. Lactoferrin (LF) is known for its physiologically pleiotropic properties. Anti-aging interventions of LF have proven to be safe and effective for various pharmacological activities, such as anti-oxidation, anti-cellular senescence, anti-inflammation, and anti-carcinogenic. Moreover, LF has a pivotal role in modulating the major signaling pathways that influence the longevity of organisms. Thus, LF is expected to be able to attenuate the process of aging and greatly ameliorate its effects.

Outcomes of Eyes Lost to Follow-Up in Patients with Central Retinal Vein Occlusion Who are Receiving Anti-Vascular Endothelial Growth Factor Treatment.

BACKGROUND: To evaluate the anatomic and functional outcomes in eyes of patients with macular edema (ME) caused by central retinal vein occlusion (CRVO) who were lost to follow-up (LTFU) for more than 6 months following treatment with anti-vascular endothelial growth factor (VEGF) therapy and to determine the predictive factors of visual prognosis in these patients. METHODS: This study was conducted as a retrospective, case series investigation. Patients whose eyes were receiving intravitreal anti-VEGF treatment for CRVO-ME, with the next follow-up visit occurring more than 6 months following treatment were identified. Baseline disease characteristics (at the last visit before being LTFU), cause and duration of treatment interruption, and the resulting disease progression, complications, and outcomes were assessed. Baseline characteristics predictive of visual outcome were also analyzed. RESULTS: This study included a total of 17 eyes of 17 patients. The mean duration of being LTFU was 7.8 ± 2.1 months. On the return visit after being LTFU, 7 of 17 eyes (41.2%) developed neovascular complications. Despite treatment, 12 eyes (70.1%) lost ≥3 best-corrected visual acuity (BCVA) lines, with 2 eyes (11.8%) developing a final BCVA of hand motion or more severe. At the final visit, the mean logarithm of minimal angle of resolution (logMAR) BCVA deteriorated significantly compared to before being LTFU (P < 0.001). The increasing duration of being LTFU is associated with a deterioration of visual acuity prognosis. CONCLUSION: In CRVO-ME patients who are receiving anti-VEGF therapy, unintentional treatment interruptions can cause visually disastrous consequences, including irreversible blindness. Patients who were LTFU for a long period should be strongly warned about their poor visual prognosis.

Significance of RNA N6-Methyladenosine Regulators in the Diagnosis and Subtype Classification of Childhood Asthma Using the Gene Expression Omnibus Database.

RNA N6-methyladenosine (m6A) regulators play important roles in a variety of biological functions. Nonetheless, the roles of m6A regulators in childhood asthma remain unknown. In this study, 11 significant m6A regulators were selected using difference analysis between non-asthmatic and asthmatic patients from the Gene Expression Omnibus GSE40888 dataset. The random forest model was used to screen five candidate m6A regulators (fragile X mental retardation 1, KIAA1429, Wilm's tumor 1-associated protein, YTH domain-containing 2, and zinc finger CCCH domain-containing protein 13) to predict the risk of childhood asthma. A nomogram model was established based on the five candidate m6A regulators. Decision curve analysis indicated that patients could benefit from the nomogram model. The consensus clustering method was performed to differentiate children with asthma into two m6A patterns (clusterA and clusterB) based on the selected significant m6A regulators. Principal component analysis algorithms were constructed to calculate the m6A score for each sample to quantify the m6A patterns. The patients in clusterB had higher m6A scores than those in clusterA. Furthermore, we found that the patients in clusterA were linked to helper T cell type 1 (Th1)-dominant immunity while those in clusterB were linked to Th2-dominant immunity. In summary, m6A regulators play nonnegligible roles in the occurrence of childhood asthma. Our investigation of m6A patterns may be able to guide future immunotherapy strategies for childhood asthma.

Integrative analysis of competitive endogenous RNA network reveals the regulatory role of non-coding RNAs in high-glucose-induced human retinal endothelial cells.

BACKGROUND: Increasing evidence has suggested that non-coding RNAs (ncRNAs) play critical roles in the pathogenesis of diabetic retinopathy (DR), but their underlying mechanisms remain unclear. The purpose of this study was to determine latent key genes and to structure a competing endogenous RNA (ceRNA) regulatory network to discover the potential molecular mechanisms governing the effects of high glucose on human retinal endothelial cells (HRECs). METHODS: We obtained microarray data for long non-coding RNA (lncRNA) and mRNA of high-glucose-induced HREC samples from NCBI GEO datasets. The ceRNA network was screened using intersecting prediction results from miRcode, TargetScan, miRTarBase and miRDB. The protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes and hub genes were obtained using the cytoHubba app. The ClusterProfiler package was applied for performing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The expression of key RNAs was verified using the qRT-PCR method. A key ceRNA subnetwork was constructed based on the criticality of the genes and its binding sites were verified by luciferase reporter assay. The viability and apoptosis of HRECs were tested using the transfection of the miR-449c inhibitor. RESULTS: A total of 3,328 lncRNAs and 2,017 mRNAs were screened for differentially expressed (DE) profiles. The newly constructed ceRNA network was composed of 410 lncRNAs, 35 miRNAs and 122 mRNAs. The 10 hub genes were identified through the PPI network. GO and KEGG analysis revealed that DE mRNAs were mainly related to the positive regulation of the mRNA catabolic process, cell polarity, and the G1/S transition of mitotic and cell cycle signaling pathways. QRT-PCR was used to verify RNAs and the most important genes were screened out. A key ceRNA subnetwork OIP5-AS1/miR-449c/MYC was established. The binding site was verified by luciferase reporter assay. The expression levels of OIP5-AS1 and MYC increased after miR-449c inhibitor transfection, miR-449c decreased, HRECs activity increased, and apoptosis decreased, compared with the control group. CONCLUSION: We successfully built the key ceRNA subnetwork, OIP5-AS1/miR-449c/MYC, by applying the GEO database for data analysis and mining. The results from the ceRNA network allow us to better understand the effect of ncRNAs on HRECs under hyperglycemic conditions and the pathogenesis of DR.

HMGB1 upregulates NF-kB by inhibiting IKB-α and associates with diabetic retinopathy.

AIMS: Diabetic retinopathy (DR) is the main cause of blindness in adults and investigating new therapeutic targets for DR is necessary. This study aimed to investigate the effect of high-mobility group box 1 (HMGB1) protein and its mechanism in diabetic retinopathy (DR) were investigated. MAIN METHODS: Human retinal endothelial cells (HREC) were uesd for chip-seq. Sprague Dawley (SD) rats were randomly divided into control group, HMGB1 group, diabetes mellitus (DM) combined with HMGB1 siRNA group, and DM group. Next, eyeballs were removed and retinas were detached for western blot. The DM model of cell was built by increasing the glucose concentration in cell culture medium. The regulation of HMGB1 was achieved by short hairpin (sh)-HMGB1 transfection, then, the transfected cells were harvested for luciferase assay, western blot and qRT-PCR analyses as well as proliferation and apoptosis detection. KEY FINDINGS: Chip-seq and luciferase assay showed the possible transcription factor functions of HMGB1 and IKB-α was one of the HMGB1 binding sites. In vivo and in vitro results indicated high expression of HMGB1 and NF-kB and low expression of IKB-α in DR and the expression of IKB-α and NF-kB was regulated by HMGB1. Moreover, cell assays showed that HMGB1 inhibited cell proliferation and promoted apoptosis. SIGNIFICANCE: The results from the present study showed that HMGB1 may be involved in the pathogenesis of DR as a transcription factor through NF-kB pathway. Therefore, blockade of HMGB1 may be a new method for the treatment of DR.

Serum microRNA-221 as a biomarker for diabetic retinopathy in patients associated with type 2 diabetes.

AIM: To investigate the candidate microRNA (miRNA), miR-221 as a novel biomarker for diabetic retinopathy (DR) in patients associated with type 2 diabetes (T2D). METHODS: The subjects involved were divided into four groups: healthy control (HC), no diabetic retinopathy (NDR), non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) group. Serum miR-221 was validated by real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Also, serum angiotensin II (Ang II) and vascular endothelial growth factor (VEGF) were examined by enzyme-linked immunosorbent assay. In addition, receiver operating characteristic (ROC) curve was performed to explore the diagnostic accuracy of miR-221, Ang II and VEGF for DR in patients with T2D. Spearman's rank correlation coefficient was executed to estimate the correlations of serum miR-221 with metabolic parameters and serum markers in patients with T2D. RESULTS: Primarily, serum miR-221, Ang II and VEGF were increased significantly in T2D patients compared to HC participant respectively, and progressive up-regulated in NDR, NPDR and PDR groups (P<0.001). Additionally, miR-221 in serum was remarkably positively correlated with metabolic parameters such as glycated hemoglobin (r=0.310, P=0.002) and homeostasis model assessment for insulin resistance (r=0.413, P<0.001), as well as serum markers for instance Ang II (r=0.667, P<0.001) and VEGF (r=0.499, P<0.001). Furthermore, serum miR-221 (AUC, 0.894; 95%CI, 0.833-0.955; P<0.001), Ang II (AUC, 0.888; 95%CI, 0.828-0.949; P<0.001) and VEGF (AUC, 0.785; 95%CI, 0.695-0.875; P<0.001) had evidently diagnostic efficiency in DR, and miR-221 is the most effective among them. CONCLUSION: Serum miR-221 as a potential biomarker could be related to not only occurrence but also progression for DR in patients with T2D. However, a prospective clinical trial is warranted.

Serum microRNA-211 as a biomarker for diabetic retinopathy via modulating Sirtuin 1.

Diabetic retinopathy (DR) is a progressive microvascular complication associated with diabetes, and remains the leading cause of preventable blindness worldwide. Recent studies have revealed that microRNAs (miRNAs) were involving in the physiological and pathophysiological processes of diabetes and its microvascular and macrovascular complications. The purpose of the current investigation is to identify the candidate miR-211 as a novel biomarker for occurrence and progression of DR in clinical study and experimental research. Firstly, miR-211 was considered as a candidate miRNA identifying by miRNA microarray analysis, Venn diagram analysis, real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and receiver operating characteristic curve in clinical study. Then, the predicted Sirtuin 1 (SIRT1) may be the target gene of miR-211 searching by TargetScan 7.2. Moreover, miR-211 was significantly up-regulated, while SIRT1 mRNA significantly down-regulated measuring by qRT-PCR, meanwhile, SIRT1 protein was significantly down-regulated in coincidence with SIRT1 mRNA detecting by western blot, and even aggravated associated with diabetes duration in diabetic retinal tissues of vivo experiment. Additionally, miR-211 was directly targeted SIRT1 confirming by dual-luciferase reporter assay. Furthermore, with transfection of antagomiR-211, the apoptosis of HUVECs was significantly suppressed employing by flow cytometry analysis, nevertheless the viability of HUVECs was significantly promoted exploiting by Cell Counting Kit-8 assay. Finally, SIRT1 mRNA and SIRT1 protein were significantly up-regulated testing by qRT-PCR and western blot respectively in hyperglycemic HUVECs transfected with antagomiR-211 of vitro experiment. Consequently, the current clinical study and experimental research imply that serum miR-211 as a novel biomarker with high sensitivity and specificity could be associated with occurrence and progression of DR via targeting SIRT1.

Expression and significance of the Hedgehog signal transduction pathway in oxygen-induced retinal neovascularization in mice.

AIM: The aim of the study was to investigate the signal transduction mechanism of Hedgehog-vascular endothelial growth factor in oxygen-induced retinopathy (OIR) and the effects of cyclopamine on OIR. METHODS: An OIR model was established in C57BL/6J mice exposed to hyperoxia. Two hundred mice were randomly divided into a control group, an OIR group, an OIR-control group (treated with isometric phosphate-buffered saline by intravitreal injection), and a cyclopamine group (treated with cyclopamine by intravitreal injection), with 50 mice in each group. The retinal vascular morphology was observed using adenosine diphosphatase and number counting using hematoxylin and eosin-stained image. Quantitative real-time quantitative polymerase chain reaction was used to detect mRNA expression. Protein location and expression were evaluated using immunohistochemistry and Western blot. RESULTS: The OIR group and OIR-control group demonstrated large-area pathological neovascularization and nonperfused area when compared with the control group (both P<0.05). The area of nonperfusion and neovascularization in the cyclopamine group was significantly reduced compared with the OIR and OIR-control groups (both P<0.05). Compared with the control group, the OIR and OIR-control groups had more vascular endothelial cells breaking through the inner limiting membrane. The number of new blood vessel endothelial cell nuclei in the cyclopamine group was significantly reduced (both P<0.05) when compared with the OIR and OIR-control groups. The mRNA and protein expressions of Smoothened, Gli1, and vascular endothelial growth factor in the signal pathway of the OIR and OIR-control groups were significantly higher than those of the control group; however, in the cyclopamine group, these factors were reduced when compared with the OIR and OIR-control groups (all P<0.05). CONCLUSION: Our data suggest that abnormal expression of the Hedgehog signaling pathway may be closely associated with the formation of OIR. Inhibiting the Smoothened receptor using cyclopamine could control retinal neovascularization, providing new ideas and measures for the prevention of oxygen-induced retinal neovascularization.