Long-term polystyrene nanoparticles exposure reduces electroretinal responses and exacerbates retinal degeneration induced by light exposure.

The impact of plastic pollution on living organisms have gained significant research attention. However, the effects of nanoplastics (NPs) on retina remain unclear. This study aimed to investigate the effect of long-term polystyrene nanoparticles (PS-NPs) exposure on mouse retina. Eight weeks old C57BL/6 J mice were exposed to PS-NPs at the diameter of 100 nm and concentration of 10 mg/L in drinking water for 3 months. PS-NPs were able to penetrate the blood-retina barrier, accumulated at retinal tissue, caused increased oxidative stress level and reduced scotopic electroretinal responses without remarkable structural damage. PS-NPs exposure caused cytotoxicity and reactive oxygen species accumulation in cultured photoreceptor cell. PS-NPs exposure increased oxidative stress level in retinal pigment epithelial (RPE) cells, leading to changes of gene and protein expression indicative of compromised phagocytic activity and cell junction formation. Long-term PS-NPs exposure also aggravated light-induced photoreceptor cell degeneration and retinal inflammation. The transcriptomic profile of PS-NPs-exposed, light-challenged retinal tissue shared similar features with those of age-related macular degeneration (AMD) patients in the activation of complement-mediated phagocytic and proinflammatory responses. Collectively, these findings demonstrated the oxidative stress- and inflammation-mediated detrimental effect of PS-NPs on retinal function, suggested that long-term PS-NPs exposure could be an environmental risk factor contributing to retinal degeneration.

Serum amyloid A aggravates endotoxin-induced ocular inflammation through the regulation of retinal microglial activation.

Serum amyloid A (SAA) are major acute-phase response proteins which actively participate in many inflammatory diseases. This study was designed to explore the function of SAA in acute ocular inflammation and the underlying mechanism. We found that SAA3 was upregulated in endotoxin-induced uveitis (EIU) mouse model, and it was primarily expressed in microglia. Recombinant SAA protein augmented intraocular inflammation in EIU, while the inhibition of Saa3 by siRNA effectively alleviated the inflammatory responses and rescued the retina from EIU-induced structural and functional damage. Further study showed that the recombinant SAA protein activated microglia, causing characteristic morphological changes and driving them further to pro-inflammatory status. The downregulation of Saa3 halted the amoeboid change of microglia, reduced the secretion of pro-inflammatory factors, and increased the expression of tissue-reparative genes. SAA3 also regulated the autophagic activity of microglial cells. Finally, we showed that the above effect of SAA on microglial cells was at least partially mediated through the expression and signaling of Toll-like receptor 4 (TLR4). Collectively, our study suggested that microglial cell-expressed SAA could be a potential target in treating acute ocular inflammation.

Gene Expression Profiling Reveals Potential Players of Sex Determination and Asymmetrical Development in Chicken Embryo Gonads.

Despite the notable progress made in recent years, the understanding of the genetic control of gonadal sex differentiation and asymmetrical ovariogenesis in chicken during embryonic development remains incomplete. This study aimed to identify potential key genes and speculate about the mechanisms associated with ovary and testis development via an analysis of the results of PacBio and Illumina transcriptome sequencing of embryonic chicken gonads at the initiation of sexual differentiation (E4.5, E5.5, and E6.5). PacBio sequencing detected 328 and 233 significantly up-regulated transcript isoforms in females and males at E4.5, respectively. Illumina sequencing detected 95, 296 and 445 DEGs at E4.5, E5.5, and E6.5, respectively. Moreover, both sexes showed asymmetrical expression in gonads, and more DEGs were detected on the left side. There were 12 DEGs involved in cell proliferation shared between males and females in the left gonads. GO analysis suggested that coagulation pathways may be involved in the degradation of the right gonad in females and that blood oxygen transport pathways may be involved in preventing the degradation of the right gonad in males. These results provide a comprehensive expression profile of chicken embryo gonads at the initiation of sexual differentiation, which can serve as a theoretical basis for further understanding the mechanism of bird sex determination and its evolutionary process.

Association between Cerebrospinal Fluid Soluble TREM2, Alzheimer's Disease and Other Neurodegenerative Diseases.

BACKGROUND: Cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is a potential biomarker and therapy target for neurodegenerative diseases (NDDs). The purpose of this meta-analysis was to investigate the association between CSF sTREM2 level and NDDs, and to reveal the dynamic changes in CSF sTREM2 level in Alzheimer's disease (AD) continuum. METHODS: We systematically searched PubMed, Embase, Web of Science, and Cochrane Library databases for observational studies, which compared the levels of CSF sTREM2 between NDDs and controls. Sources of heterogeneity were analyzed using sensitivity analysis, subgroup analysis and meta-regression. We assessed pooled data using a random-effects model. RESULTS: Twenty-two observational studies which included 5716 participates were identified. Compared with the controls, the whole AD continuum group showed a significant increase in CSF sTREM2 level (standardized mean difference [SMD]: 0.41, 95% confidence intervals [CI]: 0.24, 0.58, p < 0.001). The mild cognitive impairment (MCI) group displayed the largest effect size (SMD, 0.49 [95% CI: 0.10, 0.88], p = 0.014), followed by the AD cohort (SMD, 0.40 [95% CI: 0.18, 0.63], p < 0.001). The increase in sTREM2 in the preclinical stage of AD (pre-AD) group was the lowest (SMD, 0.29 [95% CI: 0.03, 0.55], p = 0.031). Other NDDs also showed an increase in the CSF sTREM2 levels compared with control groups (SMD, 0.77 [95% CI: 0.37, 1.16], p < 0.001). CONCLUSIONS: The pooled data confirmed that NDDs are associated with increased CSF sTREM2 level, thereby suggesting the CSF sTREM2 as a potential dynamic biomarker and therapy target for NDDs.

TREM2 deficiency in microglia accelerates photoreceptor cell death and immune cell infiltration following retinal detachment.

Retinal detachment (RD) occurs in several major retinal conditions and often causes irreversible vision loss due to photoreceptor cell death. Retinal residential microglial cells are activated following RD and participate in photoreceptor cell death via direct phagocytosis and the regulation of inflammatory responses. Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor exclusively expressed on microglial cells in the retina, and has been reported to affect microglial cell homeostasis, phagocytosis and inflammatory responses in the brain. In this study, increased expression of multiple cytokines and chemokines in the neural retina was observed starting at 3 h following RD. Trem2 knockout (Trem2-/-) mice exhibited significantly more photoreceptor cell death than wild-type controls at 3 days after RD, and the number of TUNEL positive photoreceptor cells progressively decreased from day 3 to day 7 post-RD. A significant thinning of the outer nuclear layer (ONL), with multiple folds was observed in the Trem2-/- mice at 3 days post-RD. Trem2 deficiency reduced microglial cell infiltration and phagocytosis of stressed photoreceptors. There were more neutrophils in Trem2-/- retina following RD than in controls. Using purified microglial cells, we found Trem2 knockout is associated with increased CXCL12 expression. The aggravated photoreceptor cell death was largely reversed by blocking the CXCL12-CXCR4 mediated chemotaxis in Trem2-/- mice after RD. Our findings suggested that retinal microglia are protective in preventing further photoreceptor cell death following RD by phagocytosing presumably stressed photoreceptor cells and by regulating inflammatory responses. TREM2 is largely responsible for such protective effect and CXCL12 plays an important role in regulating neutrophil infiltration after RD. Collectively, our study pinpointed TREM2 as a potential target of microglial cells to ameliorate RD-induced photoreceptor cell death.

Integrated Analysis of Genes Associated With Immune Microenvironment and Distant Metastasis in Uveal Melanoma.

Inflammatory infiltration plays an essential role in the progression of tumor malignancy. The aim of this study was to identify genes associated with inflammatory microenvironment and clinical traits for survival prediction of uveal melanoma (UVM) patients. The datasets and clinical characteristics of UVM were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We divided the UVM patients into low and high immune cell infiltration groups, identified differentially expressed genes (DEGs), constructed weighted gene co-expression network, and established prognostic prediction model and nomogram for UVM. Our analysis showed that DEGs were enriched in cytokine signaling in immune system, positive regulation of immune response and adaptive immune system. A total of fifteen candidate genes were extracted from DEGs and genes that were positively associated with tumor metastasis. Subsequently, five prognostic genes were selected to construct the final prognostic prediction model, including two up-regulated genes LHFPL3 antisense RNA 1 (LHFPL3-AS1) and LYN proto-oncogene (LYN), and three down-regulated genes SLCO4A1 antisense RNA 1 (SLCO4A1-AS1), Zinc-α2-glycoprotein 1 (AZGP1) and Deleted in Liver Cancer-1 (DLC1) in the high risk group. The model showed an Area Under Curve (AUC) value of 0.877. Our analysis highlighted the importance of immune-related genes in the progression of UVM and also provided potential targets for the immunotherapy of UVM.

mTORC1 Activation in Chx10-Specific Tsc1 Knockout Mice Accelerates Retina Aging and Degeneration.

Age-associated decline in retina function is largely responsible for the irreversible vision deterioration in the elderly population. It is also an important risk factor for the development of degenerative and angiogenic diseases. However, the molecular mechanisms involved in the process of aging in the retina remain largely elusive. This study investigated the role of mTORC1 signaling in aging of the retina. We showed that mTORC1 was activated in old-aged retina, particularly in the ganglion cells. The role of mTORC1 activation was further investigated in Chx10-Cre;Tsc1fx/fx mouse (Tsc1-cKO). Activation of mTORC1 was found in bipolar and some of the ganglion and amacrine cells in the adult Tsc1-cKO retina. Bipolar cell hypertrophy and Müller gliosis were observed in Tsc1-cKO since 6 weeks of age. The abnormal endings of bipolar cell dendritic tips at the outer nuclear layer resembled that of the old-aged mice. Microglial cell activation became evident in 6-week-old Tsc1-cKO. At 5 months, the Tsc1-cKO mice exhibited advanced features of old-aged retina, including the expression of p16Ink4a and p21, expression of SA-ß-gal in ganglion cells, decreased photoreceptor cell numbers, decreased electroretinogram responses, increased oxidative stress, microglial cell activation, and increased expression of immune and inflammatory genes. Inhibition of microglial cells by minocycline partially prevented photoreceptor cell loss and restored the electroretinogram responses. Collectively, our study showed that the activation of mTORC1 signaling accelerated aging of the retina by both cell autonomous and nonautonomous mechanisms. Our study also highlighted the role of microglia cells in driving the decline in retina function.

Weighted genes associated with the progression of retinoblastoma: Evidence from bioinformatic analysis.

Mechanisms underlying the development of malignant retinoblastoma (RB) remain largely unknown. The purpose of this study was to identify weighted genes that are associated with the progression of RB and to assess the usefulness of bioinformatic analysis in RB research. Bioinformatic analysis was performed to construct weighted gene co-expression and protein-protein interaction (PPI) networks and to predict long non-coding RNA (lncRNA)-microRNA (miRNA)-mRNA regulatory networks. RNA extracted from RB and adjacent retinal tissue was used to validate the results obtained from bioinformatic analysis, using a semi-quantitative PCR (qPCR) assay. Twenty-one modules were generated from 5000 most variably expressed genes. Both the light-yellow and red modules were significantly associated with the cellular anaplastic grade of RB. The genes clustered in the light-yellow module included protocadherin beta (PCDHBs) family members. The red module included 5 hub genes involved in cell division. According to the hypothesis that lncRNA may serve as a competing endogenous RNA (ceRNA) for miRNAs and modulates mRNA expression, a network was constructed between lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and cell division-related mRNAs. PCR analysis using 23 tumor tissues and 5 adjacent retinal tissue showed increased expression of PCDHB5 in tumor samples, and supported the predicted upregulation of mitotic checkpoint serine/threonine kinase (BUB1) by MALAT1 via miR-495-3p. Our study highlights the importance of bioinformatic analysis in identifying potential markers and mechanisms associated with the malignant transformation of RB, and provides evidence to suggest that PCDHB5 and the ceRNA regulatory network of MALAT1/miR-495-3p/BUB1 are involved in the progression of RB.

Identification of Prognostic alternative splicing signatures and their clinical significance in uveal melanoma.

As a posttranscriptional regulatory mechanism, alternative splicing (AS) has the potential to generate a large amount of protein diversity from limited genes. The purpose of our study was to assess the usefulness of prognostic splicing events as novel diagnostic and therapeutic signatures for uveal melanoma (UM). The datasets, clinical traits and AS data of UM were obtained from The Cancer Genome Atlas (TCGA) database and TCGA SpliceSeq database. Using bioinformatics analysis, we identified 1047 AS events as candidate AS events closely related to prognosis from 920 parent genes. The gene enrichment analysis indicated that these genes were mainly enriched in cellular components (CC) including cytosol, nucleoplasm, cytoplasm and ribosome, and in molecular functions (MF), including protein binding and poly(A) RNA binding. Furthermore, we selected all survival-associated splicing events to generate prognostic signatures, which included 4 exon skip (ES) events (DNASE1L1-90581-ES, NUDT1-78611-ES, BIN1-55198-ES, SEPN1-1195-ES) and 1 alternate promoter (AP) event (DPYSL2-83132-AP). The AS prognostic model was confirmed as independent overall survival (OS)-related factors (p = 0.014). A total of 17 splicing factors (SFs) involved in the regulation of AS were identified as related to the OS of UM patients. Our pooled data highlighted the usefulness and importance of AS biomarkers, which provided a potential strategy for the diagnosis and treatment of UM.

Targeting hypoxic tumor microenvironment in pancreatic cancer.

Attributable to its late diagnosis, early metastasis, and poor prognosis, pancreatic cancer remains one of the most lethal diseases worldwide. Unlike other solid tumors, pancreatic cancer harbors ample stromal cells and abundant extracellular matrix but lacks vascularization, resulting in persistent and severe hypoxia within the tumor. Hypoxic microenvironment has extensive effects on biological behaviors or malignant phenotypes of pancreatic cancer, including metabolic reprogramming, cancer stemness, invasion and metastasis, and pathological angiogenesis, which synergistically contribute to development and therapeutic resistance of pancreatic cancer. Through various mechanisms including but not confined to maintenance of redox homeostasis, activation of autophagy, epigenetic regulation, and those induced by hypoxia-inducible factors, intratumoral hypoxia drives the above biological processes in pancreatic cancer. Recognizing the pivotal roles of hypoxia in pancreatic cancer progression and therapies, hypoxia-based antitumoral strategies have been continuously developed over the recent years, some of which have been applied in clinical trials to evaluate their efficacy and safety in combinatory therapies for patients with pancreatic cancer. In this review, we discuss the molecular mechanisms underlying hypoxia-induced aggressive and therapeutically resistant phenotypes in both pancreatic cancerous and stromal cells. Additionally, we focus more on innovative therapies targeting the tumor hypoxic microenvironment itself, which hold great potential to overcome the resistance to chemotherapy and radiotherapy and to enhance antitumor efficacy and reduce toxicity to normal tissues.

Optical coherence tomography measurements as potential imaging biomarkers for Parkinson's disease: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Retinal pathological changes may precede or accompany the deterioration of brain tissue in Parkinson's disease (PD). The purpose of this meta-analysis was to assess the usefulness of optical coherence tomography (OCT) measurements as potential imaging biomarkers for PD. METHODS: PubMed, Embase, Web of Science and Cochrane Library databases were systematically searched for observational studies (published prior to 30 May 2020) comparing the OCT measurements between PD patients and healthy controls (HCs). Our main end-points were peripapillary retinal nerve fiber layer (pRNFL) thickness, macular ganglion cell complex thickness, macular thickness and macular volume. Pooled data were assessed by use of a random-effects model. RESULTS: A total of 36 observational studies were identified that included 1712 patients with PD (2548 eyes) and 1778 HCs (2646 eyes). Compared with the HC group, the PD group showed a significant reduction in mean pRNFL thickness (weighted mean difference [WMD] -3.51 µm, 95% confidence interval [CI] -4.84, -2.18; p = 0.000), all quadrants at the pRNFL (WMD range -7.65 to -2.44 µm, all p < 0.05), macular fovea thickness (WMD -5.62 µm, 95% CI -7.37, -3.87; p = 0.000), all outer sector thicknesses at the macula (WMD range -4.68 to -4.10 µm, all p < 0.05), macular volume (WMD -0.21 mm3 , 95% CI -0.36, -0.06; p < 0.05) and macular ganglion cell complex thickness (WMD -4.18 µm, 95% CI -6.07, -2.29; p < 0.05). CONCLUSIONS: Our pooled data confirmed robust associations between retinal OCT measurements and PD, highlighting the usefulness of OCT measurements as potential imaging biomarkers for PD.

Volatile organic compounds analysis as a potential novel screening tool for colorectal cancer: A systematic review and meta-analysis.

The purpose of this meta-analysis was to assess the usefulness of volatile organic compounds (VOC) as a potential novel biomarker for colorectal cancer (CRC).We systematically searched PubMed, Embase, Web of Science, and Cochrane Library databases for observational studies (published before November 25th, 2019; no language restrictions) comparing the VOC analysis between patients with CRC and healthy controls. We evaluated the pooled sensitivity, specificity, diagnostic odds ratio, positive and negative likelihood ratio, as well as summary receiver operating characteristic curve and area under the curve.We identified a total of 10 observational studies that included 381 patients with CRC and 436 healthy controls. Bivariate analysis yielded a pooled sensitivity of 0.82 (95% confidence interval [CI] = 0.77-0.86), specificity of 0.79 (95% CI = 0.71-0.85), positive likelihood ratio of 3.8 (95% CI = 2.8-5.3), and negative likelihood ratio of 0.23 (95% CI = 0.17-0.30). The area under the curve was 0.87 (95% CI = 0.84-0.90). The pooled diagnostic odds ratio was 17 (95% CI = 10-28). Sensitivity analysis indicated that the pooled results were stabilized. The Deeks' funnel plot asymmetry test (P = .41) suggested no potential publication bias.Our pooled data confirmed the associations between VOC analysis and CRC, highlighting the usefulness of VOC analysis as a potential novel screening tool for CRC. However, standardization of VOC collection and analysis methods for CRC screening is required in future research.

Mitochondria as Potential Targets and Initiators of the Blue Light Hazard to the Retina.

Commercially available white light-emitting diodes (LEDs) have an intense emission in the range of blue light, which has raised a range of public concerns about their potential risks as retinal hazards. Distinct from other visible light components, blue light is characterized by short wavelength, high energy, and strong penetration that can reach the retina with relatively little loss in damage potential. Mitochondria are abundant in retinal tissues, giving them relatively high access to blue light, and chromophores, which are enriched in the retina, have many mitochondria able to absorb blue light and induce photochemical effects. Therefore, excessive exposure of the retina to blue light tends to cause ROS accumulation and oxidative stress, which affect the structure and function of the retinal mitochondria and trigger mitochondria-involved death signaling pathways. In this review, we highlight the essential roles of mitochondria in blue light-induced photochemical damage and programmed cell death in the retina, indicate directions for future research and preventive targets in terms of the blue light hazard to the retina, and suggest applying LED devices in a rational way to prevent the blue light hazard.

Insulin Degludec, a Novel Ultra-Long-Acting Basal Insulin versus Insulin Glargine for the Management of Type 2 Diabetes: A Systematic Review and Meta-Analysis.

INTRODUCTION: The purpose of this study was to compare insulin degludec with insulin glargine in terms of efficacy and safety in patients with type 2 diabetes. METHODS: We systematically searched PubMed, Embase, Web of Science, and Cochrane Library databases for randomized controlled trials published prior to 13 August 2018 (no language restrictions) which compared insulin degludec with insulin glargine. Our main endpoints were glycemic control, hypoglycemic event, weight gain, and serious adverse events (SAEs). We assessed pooled data using random-effects models. RESULTS: A total of 15 studies that included 9619 patients in the insulin degludec arm of the studies and 7075 patients in the insulin glargine arm were identified and subsequently assessed. Our analysis showed that compared with insulin glargine, insulin degludec yielded an improved mean reduction in fasting plasma glucose (FPG) (weighted mean difference [WMD] - 5.20 mg/dL, 95% confidence interval [CI] - 7.34, - 3.07, P < 0.00001) and a lower ratio of participants experiencing ≥ 1 severe   hypoglycemic event (relative risk [RR] 0.68, 95% CI 0.50, 0.93, P = 0.01) and nocturnal hypoglycemia (RR 0.81, 95% CI 0.75, 0.88, P < 0.0001); however, in the insulin degludec group there was a lower ratio of participants with glycated hemoglobin (HbA1c) of ≤ 7.0%    (RR 0.92, 95% CI 0.86, 0.98, P = 0.01). There was no statistically significant difference between the two treatment groups for HbA1c reduction (WMD 0.03, 95% CI - 0.00, 0.07, P = 0.08), body weight gain (WMD 0.12, 95% CI - 0.19, 0.43, P = 0.46), and proportion of participants with SAEs (RR 0.97, 95% CI 0.92, 1.02, P = 0.20). CONCLUSIONS: Insulin degludec and insulin glargine provide similar glycemic control, but insulin degludec also lowers the risk of hypoglycemia. Consequently, insulin degludec may be an alternative treatment for the management of patients with type 2 diabetes who are prone to hypoglycemia with insulin glargine.

Mitochondrial Fission Is Required for Blue Light-Induced Apoptosis and Mitophagy in Retinal Neuronal R28 Cells.

Light emitting diodes (LEDs) are widely used to provide illumination due to their low energy requirements and high brightness. However, the LED spectrum contains an intense blue light component which is phototoxic to the retina. Recently, it has been reported that blue light may directly impinge on mitochondrial function in retinal ganglion cells (RGCs). Mitochondria are high dynamic organelles that undergo frequent fission and fusion events. The aim of our study was to elucidate the role of mitochondrial dynamics in blue light-induced damage in retinal neuronal R28 cells. We found that exposure to blue light (450 nm, 1000 lx) for up to 12 h significantly up-regulated the expression of mitochondrial fission protein Drp1, while down-regulating the expression of mitochondrial fusion protein Mfn2 in cells. Mitochondrial fission was simultaneously stimulated by blue light irradiation. In addition, exposure to blue light increased the production of reactive oxygen species (ROS), disrupted mitochondrial membrane potential (MMP), and induced apoptosis in R28 cells. Notably, Drp1 inhibitor Mdivi-1 and Drp1 RNAi not only attenuated blue light-induced mitochondrial fission, but also alleviated blue light-induced ROS production, MMP disruption and apoptosis in cells. Compared with Mdivi-1 and Drp1 RNAi, the antioxidant N-acetyl-L-cysteine (NAC) only slightly inhibited mitochondrial fission, while significantly alleviating apoptosis after blue light exposure. Moreover, we examined markers for mitophagy, which is responsible for the clearance of dysfunctional mitochondria. It was found that blue light stimulated the conversion of LC3B-I to LC3B-II as well as the expression of PINK1 in R28 cells. Mdivi-1 or Drp1 RNAi efficiently inhibited the blue light-induced expression of PINK1 and co-localization of LC3 with mitochondria. Thus, our data suggest that mitochondrial fission is required for blue light-induced mitochondrial dysfunction and apoptosis in RGCs.