Identification of key genes modules linking diabetic retinopathy and circadian rhythm.

Background: Diabetic retinopathy (DR) is a leading cause of vision loss worldwide. Recent studies highlighted the crucial impact of circadian rhythms (CR) on normal retinopathy in response to the external light cues. However, the role of circadian rhythms in DR pathogenesis and potential investigational drugs remains unclear. Methods: To investigate the weather CR affects DR, differential expression analysis was employed to identify differentially expressed genes (DEGs) from the GEO database (GSE160306). Functional enrichment analysis was conducted to identify relevant signaling pathways. LASSO regression was utilized to screen pivotal genes. Weighted gene co-expression network anlaysis (WGCNA) was applied to identify different modules. Additionally, we use the Comparative Toxicogenomics Database (CTD) database to search key genes related to drugs or molecular compounds. The diabetic mouse model received three consecutive intraperitoneal injections of streptozotocin (STZ) during 3 successive days. Results: We initially identified six key genes associated with circadian rhythm in DR, including COL6A3, IGFBP2, IGHG4, KLHDC7A, RPL26P30, and MYL6P4. Compared to normal tissue, the expression levels of COL6A3 and IGFB2 were significantly increased in DR model. Furthermore, we identified several signaling pathways, including death domain binding, insulin-like growth factor I binding, and proteasome binding. We also observed that COL6A3 was positively correlated with macrophages (cor=0.628296895, p=9.96E-08) and Th17 cells (cor=0.665120835, p=9.14E-09), while IGFBP2 showed a negatively correlated with Tgd (cor=-0.459953045, p=0.000247284) and Th2 cells (cor=-0.442269719, p=0.000452875). Finally, we identified four drugs associated with key genes: Resveratrol, Vitamin E, Streptozocin, and Sulindac. Conclusion: Our findings revealed several key genes related to circadian rhythms and several relevant drugs in DR, providing a novel insight into the mechanism of DR and potential implications for future DR treatment. This study contributes to a better understanding of CR in DR and its implications for future therapeutic interventions.

Incidence, Prophylaxis and Prognosis of Acute Postoperative Endophthalmitis After Cataract Surgery: A Multicenter Retrospective Analysis in Northern China from 2013 to 2019.

Objective: To investigate the incidence of acute postoperative endophthalmitis (POE) after cataract surgery in Northern China from 2013 to 2019, evaluate the efficacy of prophylaxis and analyze the predictors of visual prognosis among POE patients. Methods: The study was conducted as a retrospective multi-center research, with seven hospitals in Northern China enrolled. The diagnosis of acute-onset POE was made on the basis of clinical manifestations within six weeks after initial surgery. By reviewing electronic medical system, the number of cataract surgeries and acute POE cases were recorded to estimate the overall incidence and incidences by different years and hospitals. Perioperative measures for preventing infection in different hospitals were collected. The correlations between unfavorable final vision and potential factors including basic information and clinical characteristics were examined to determine the predictive factors for final visual prognosis. Results: Of 72,255 cataract surgeries performed during seven years in the seven hospitals, 19 cases developed acute POE, yielding an overall incidence of 0.026%. The average incidence of acute POE among seven hospitals significantly declined annually during the past 7 years (p = 0.021). In Hospital-D, the incidence of acute POE significantly decreased after the application of 0.5% povidone-iodine (PVP-I) for conjunctival washing (p = 0.003). Two hospitals adopting tobramycin in the irrigation solution achieved a significant lower incidence of POE than the other hospitals (p = 0.044). The positive rate of pathogen culture was just 17.6% (3/19). Patients with presenting BCVA of CF or better were more likely to present with unfavorable final vision than those with worse presenting BCVA (p = 0.003). Conclusion: The overall incidence of acute POE after cataract surgery from 2013 to 2019 in Northern China was 0.026%, and the incidence declined annually over the period. Presenting BCVA could be a significant prognosis factor for predicting the final visual outcomes of acute POE patients.

Impact of Air Pollution on the Ocular Surface and Tear Cytokine Levels: A Multicenter Prospective Cohort Study.

Purpose: To assess air pollution-induced changes on ocular surface and tear cytokine levels. Methods: As a prospective multicenter cohort study, 387 dry eye disease (DED) participants were recruited from five provinces in China and underwent measurements of ocular surface disease index (OSDI), Schirmer's I test (ST), tear meniscus height (TMH), tear film break-up time (TBUT), corneal fluorescein staining (CFS), meibomian gland (MG) function, and tear cytokines. The associations between ocular surface parameters and exposure to particulate matter (PM), ozone (O3), nitrogen dioxide (NO2), and sulfur dioxide (SO2) for 1 day, 1 week, and 1 month before the examination were analyzed in single- and multi-pollutant models adjusted for confounding factors. Results: In the multi-pollutant model, the OSDI score was positively correlated with PM with diameter ≤2.5 µm (PM2.5), O3, and SO2 exposure [PM2.5: ß (1 week/month) = 0.229 (95% confidence interval (CI): 0.035-0.424)/0.211 (95% CI: 0.160-0.583); O3: ß (1 day/week/month) = 0.403 (95% CI: 0.229-0.523)/0.471 (95% CI: 0.252-0.693)/0.468 (95% CI: 0.215-0.732); SO2: ß (1 day/week) = 0.437 (95% CI: 0.193-0.680)/0.470 (95% CI: 0.040-0.901)]. Tear secretion was negatively correlated with O3 and NO2 exposures but positively correlated with PM2.5 levels. Air pollutants were negatively correlated with TBUT and positively related with CFS score. Besides SO2, all other pollutants were associated with aggravated MG dysfunction (MG expression, secretion, and loss) and tear cytokines increasement, such as PM2.5 and interleukin-8 (IL-8) [ß (1 day) = 0.016 (95% CI: 0.003-0.029)], PM with diameter ≤10 µm (PM10) and IL-6 [ß (1 day) = 0.019 (95% CI: 0.006-0.033)], NO2 and IL-6 [ß (1 month) = 0.045 (95% CI: 0.018-0.072)], among others. The effects of air pollutants on DED symptoms/signs, MG functions and tear cytokines peaked within 1 week, 1 month, and 1 day, respectively. Conclusion: Increased PM2.5, O3, and SO2 exposures caused ocular discomfort and damage with tear film instability. PM10 exposure led to tear film instability and ocular injury. PM, O3, and NO2 exposures aggravated MG dysfunction and upregulated tear cytokine levels. Therefore, each air pollutant may influence DED via different mechanisms within different time windows.

The effects of short-term and long-term air pollution exposure on meibomian gland dysfunction.

We aim to assess the effects of different air pollutants on meibomian gland dysfunction (MGD). As a prospective multicenter study, 864 patients were recruited from four different regions (i.e., coal, oil, steel, and living). The oil region had a significantly lower temperature and higher O3 and SO2 concentrations than other regions. Notably, participants in oil region presented with more frequent and serious MGD signs and higher cytokine levels (median interleukin 6 [IL-6] in oil: 2.66, steel: 0.96, coal: 0.38, living: 0.56; IL-8 in oil: 117.52, steel: 46.94, coal: 26.89, living: 33; vascular endothelial growth factor [VEGF] in oil: 25.09, steel: 14.02, coal: 14.02, living: 28.47). The short-term fluctuations of cytokine levels were associated with the changes in gas levels (PM2.5 and IL-8: ß = 0.016 [0.004-0.029]; O3 and IL-6: ß = 0.576 [0.386-0.702]; O3 and IL-8: ß = 0.479 [0.369-0.890]; SO2 and VEGF: ß = 0.021 [0.001-0.047]). After long-term exposure, lid margin neovascularization (r = 0.402), meibomian gland (MG) expression (r = 0.377), MG secretion (r = 0.303), MG loss (r = 0.404), and tear meniscus height (r = - 0.345) were moderately correlated with air quality index (AQI). Individuals in oil region had more serious MGD signs and higher cytokine levels. MGD is susceptible to long-term exposure to high AQI.

(-)-4-O-(4-O-ß-D-glucopyranosylcaffeoyl) quinic acid exerts anti-tumour effects against uveal melanoma through PI3K/AKT pathway.

PURPOSE: Uveal melanoma is the most common primary intraocular tumour in adults. There is no standard adjuvant treatment to prevent metastasis and no effective therapy in the metastatic setting. (-)-4-O-(4-O-ß-D-glucopyranosylcaffeoyl) quinic acid (QA) is a new compound isolated from the endophytic fungus Penicillium sp.FJ-1 of Avicennia marina, with potent activities to inhibit the PI3K. Our work further investigated effects of QA against uveal melanoma and explored its underlying mechanisms. METHODS: MP65 cells were treated with QA at different concentrations. CCK-8 assay was used to detect effects of QA on cell viability. PI staining was used to detect cell cycle arrest. Tumour model was established by injecting MP65 cells into nude mice subcutaneously. Tumour-bearing mice were divided into three groups (5 mice per group). Mice were treated with QA (5 or 10 mg/kg) or saline by intraperitoneal injection five times per week. RT-qPCR and western blot were used to detect the expression of genes and proteins, respectively. RESULTS: QA significantly inhibited the proliferation of uveal melanoma cells and induced the cell cycle arrest as well as autophagy. Moreover, QA treatment significantly slowed tumour growth of uveal melanoma, shown by decreased tumour volume and weight. Furthermore, QA treatment markedly decreased the protein expression of p-PI3K and p-AKT in tumour tissues. CONCLUSIONS: Our data provided scientific rationale to develop QA as a promising anti-tumour agent against uveal melanoma.

Long non-coding RNA MALAT1 aggravates human retinoblastoma by sponging miR-20b-5p to upregulate STAT3.

OBJECTIVE: Retinoblastoma (RB) is an uncommon childhood carcinoma of the developing retina. Long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1), microRNA-20b-5p (miR-20b-5p) and signal transducer and activator of transcription 3 (STAT3) was revealed to partake in RB. But their relationship was still to be investigated, so we intended to discuss the specific interaction of MALAT1, miR-20b-5p and STAT3 in RB. METHODS: By RNA isolation and quantitation, we measured the MALAT1 expression in RB tissues and cell lines. Then, to determine the influence of MALAT1 on RB cells, RB cells were transfected with siRNA-MALAT1 or pcDNA-MALAT1. The interplay among MALAT1, miR-20b-5p and STAT3 were evaluated through dual luciferase reporter gene assay and RNA pull-down after RB cells treated with siRNA/pcDNA-MALAT1 or/and miR-20b-5p mimic/inhibitor. The influence of their interaction on cells was evaluated by cell counting kit-8, EdU assay and flow cytometry. Finally, the involvement of MALAT1 in tumorigenesis was elucidated in vivo. RESULTS: Both RB tissues and cells showed highly expressed MALAT1. When MALAT1 was downregulated, RB cell proliferation was hindered and apoptosis was accelerated. MALAT1 sponged miR-20b-5p and upregulated STAT3. Silencing MALAT1 or overexpressing miR-20b-5p inhibited proliferation and promoted apoptosis in RB cells. The tumor growth of nude mice treated with siRNA-MALAT1 was inhibited. CONCLUSION: MALAT1 could increase proliferation and reduce apoptosis by sponging miR-20b-5p to upregulate STAT3 in RB cells. Therefore, MALAT1 might be a latent target in the RB treatment.

Knockdown of STIL suppresses the progression of gastric cancer by down-regulating the IGF-1/PI3K/AKT pathway.

SCL/TAL1 interrupting locus (STIL) regulates the mitotic centrosome to promote the centriolar replication and cell cycling, and is associated with malignancies. However, the role and mechanism of STIL in gastric cancer (GC) remain elusive. STIL expression in GC tissue microarray was detected by immunohistochemistry (IHC). GC cells were transduced with control lentivirus or lentivirus for expression STIL-specific shRNA and the effect of STIL silencing on the malignant behaviors of GC cells was measured in vitro and in vivo. The potential mechanisms underlying the action of STIL were analyzed by transcriptome microarray and bioinformatics. STIL expression was up-regulated in GC tissues both in our cohort and the data from the cancer genome atlas, and positively associated with T stage and poor overall survival of GC patients. Knockdown of STIL significantly inhibited the proliferation and clonogenicity of human GC cells and attenuated the growth of implanted GC in vivo. Furthermore, STIL silencing induced cell cycle arrest in G2/M phase and apoptosis of GC cells. Transcriptome analysis indicated that STIL silencing modulated many gene expression, particularly for down-regulating the IGF-1/PI3K/AKT pathway. In addition, treatment with SC79, an AKT activator, significantly mitigated the effect of STIL-silencing in GC cells. In conclusion, STIL promotes gastric carcinogenesis and progression by enhancing the IGF-1/PI3K/AKT signaling, and STIL may be a novel target for intervention of GC.

Identification of a nine-miRNA signature for the prognosis of Uveal Melanoma.

The present study aims to construct a miRNA-based predictive signature of Uveal melanoma (UM) based on the database of the cancer genome atlas (TCGA). We obtained miRNA expression profiles and clinical information of 80 UM patients from TCGA, and randomly divided them into a training and a testing set. After data processing and forward screening, a total of 204 miRNAs with prognostic value were then examined by the Cox proportional hazard regression model in the training set. Receiver operating curve (ROC) analysis was applied to validate the accuracy of the signature. The biological relevance of putative miRNA target genes was also analyzed using the bioinformatics method. As a result, a linear prognostic model consisting of 9 miRNAs (miR-195, miR-224, miR-365a, miR-365b, miR-452, miR-4709, miR-7702, miR-513c, miR-873) was developed to divide UM patients into a high- and a low-risk group. Patients assigned to the high-risk group had significantly shorter overall survival than those in the low-risk group, which was further confirmed by the Area under curve (AUC) value of 0.858 at 5 year obtained from ROC. Gene Ontology (GO) analysis indicated that predicted target genes of these miRNAs are primarily associated with the modulation of protein expression and function, such as the activity of ubiquitin protein ligase and protein kinase. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that these genes were involved in multiple signaling pathways linked to carcinogenesis. The tumor specific 9-miRNA signature was also verified in the testing and entire set. In summary, based on UM data of TCGA, we identified and validated a 9-miRNA-based prognostic signature.

Laparoscopic sleeve gastrectomy versus laparoscopic Roux-en-Y gastric bypass for morbid obesity and related comorbidities: a meta-analysis of 21 studies.

Laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG) are two most common weight loss procedures; our meta-analysis aims to compare these two in the treatment of morbid obesity and its related comorbidities. An electronic literature research of published studies concerning LRYGB and LSG was performed from inception to October 2013. Percentage of excess weight loss (%EWL), resolution or improvement rate of comorbidities, and adverse events were all pooled and compared by the software Review Manager 5.1. As a result, a total of 21 studies involving 18,766 morbidly obese patients were eventually selected according to the inclusion criteria. No significant difference was found in %EWL during 0.5- to 1.5-year follow-up (P > 0.05), but after that, LRYGB achieved higher %EWL than LSG (P < 0.05). Except for type 2 diabetes mellitus (T2DM) (P < 0.001), the difference between these two procedures in the resolution or improvement rate of other comorbidities did not reach a statistical significance (P > 0.05). There were more adverse events in LRYGB compared with LSG (P < 0.01). In conclusion, LRYGB is superior to LSG in efficacy but inferior to LSG in safety.

Roles of tumor necrosis factor alpha gene polymorphisms, tumor necrosis factor alpha level in aqueous humor, and the risks of open angle glaucoma: a meta-analysis.

PURPOSE: This meta-analysis was performed to clarify the association between tumor necrosis factor alpha (TNF-α) gene polymorphisms and open angle glaucoma (OAG) risks, and the association between the TNF-α level in aqueous humor (AH) and the risks of glaucoma. METHODS: A computerized literature search was performed for the relevant available studies from three databases including PubMed, ISI Web of Science, and Embase. The fixed or random effect model was selected based on the heterogeneity test using the Q test and the I(2) statistic. The associations between TNF-α gene polymorphisms and OAG risks were estimated by calculating pooled odds ratios (ORs) and the 95% confidence interval (CI), while a pooled standardized mean difference with 95% CI was used for the comparison of TNF-α levels in AH between patients with OAG and controls. Publication bias was estimated using Begg's funnel plots and Egger's regression test. RESULTS: A total of 14 (1,182 cases and 3,003 controls), five (808 cases and 1,039 controls), three (645 cases and 666 controls), and three studies (404 cases and 625 controls) were finally included in the analyses for the associations between TNF-α -308G/A, -857C/T, -863C/A, and -238G/A polymorphisms and the risks of OAG, respectively. The combined results showed that the TNF-α -308G/A gene polymorphism was significantly associated with risks of high-tension glaucoma (A versus G: OR=1.660, 95% CI=1.033-2.667; AA/AG versus GG: OR=1.713, 95% CI=1.10-2.651), but not with normal tension glaucoma or exfoliation glaucoma. Ethnicity-stratified analysis revealed that a significant association also existed in Asians (A versus G: OR=1.947, 95% CI=1.097-3.456; AA/AG versus GG: OR=1.949, 95% CI=1.140-3.332). None of the other polymorphisms was significantly associated with OAG risks. Furthermore, the pooled results of six studies showed that the TNF-α levels in the AH of patients with OAG was higher than that of the control subjects (standardized mean difference=0.517, 95% CI=0.207-0.826, p=0.001). Probability of publication bias was low across all comparisons illustrated by the funnel plots and Egger's test. CONCLUSIONS: This meta-analysis suggests that patients with OAG may have higher TNF-α levels compared with the control subjects, and the TNF-α -308G/A polymorphism is significantly associated with the risks of high-tension glaucoma. Since potential confounders could not be ruled out completely, further studies are needed to confirm these results.