Hyperglycemia-regulated tRNA-derived fragment tRF-3001a propels neurovascular dysfunction in diabetic mice.

Neurovascular dysfunction is a preclinical manifestation of diabetic complications, including diabetic retinopathy (DR). Herein, we report that a transfer RNA-derived RNA fragment, tRF-3001a, is significantly upregulated under diabetic conditions. tRF-3001a downregulation inhibits Müller cell activation, suppresses endothelial angiogenic effects, and protects against high-glucose-induced retinal ganglion cell injury in vitro. Furthermore, tRF-3001a downregulation alleviates retinal vascular dysfunction, inhibits retinal reactive gliosis, facilitates retinal ganglion cell survival, and preserves visual function and visually guided behaviors in STZ-induced diabetic mice and db/db diabetic mice. Mechanistically, tRF-3001a regulates neurovascular dysfunction in a microRNA-like mechanism by targeting GSK3B. Clinically, tRF-3001a is upregulated in aqueous humor (AH) samples of DR patients. tRF-3001a downregulation inhibits DR-induced human retinal vascular endothelial cell and Müller cell dysfunction in vitro and DR-induced retinal neurovascular dysfunction in C57BL/6J mice. Thus, targeting tRF-3001a-mediated signaling is a promising strategy for the concurrent treatment of vasculopathy and neuropathy in diabetes mellitus.

Metabolomic profiling of a neurodegenerative retina following optic nerve transection.

The degeneration of retinal ganglion cells (RGCs) often causes irreversible vision impairment. Prevention of RGC degeneration can prevent or delay the deterioration of visual function. The present study aimed to investigate retinal metabolic profiles following optic nerve transection (ONT) injury and identify the potential metabolic targets for the prevention of RGC degeneration. Retinal samples were dissected from ONT group and non­ONT group. The untargeted metabolomics were carried out using liquid chromatography­tandem mass spectrometry. The involved pathways and biomarkers were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and MetaboAnalyst 5.0. In the ONT group, 689 disparate metabolites were detected, including lipids and lipid­like molecules. A total of 122 metabolites were successfully annotated and enriched in 50 KEGG pathways. Among them, 'sphingolipid metabolism' and 'primary bile acid biosynthesis' were identified involved in RGC degeneration. A total of five metabolites were selected as the candidate biomarkers for detecting RGC degeneration with an AUC value of 1. The present study revealed that lipid­related metabolism was involved in the pathogenesis of retinal neurodegeneration. Taurine, taurochenodesoxycholic acid, taurocholic acid (TCA), sphingosine, and galabiosylceramide are shown as the promising biomarkers for the diagnosis of RGC degeneration.

Regulatory effect of long-stranded non-coding RNA-CRNDE on neurodegeneration during retinal ischemia-reperfusion.

Ischemia/reperfusion (I/R) injury is a common pathological mechanism involved in many ocular diseases. I/R is characterized by microvascular dysfunction and neurodegeneration. However, the mechanisms of neurodegeneration induced by I/R remain largely unknown. This study showed that the expression of long non-coding RNA-CRNDE was significantly upregulated after retinal ischemia-reperfusion (RIR). LncRNA-CRNDE knockdown alleviated retinal neurodegeneration induced by RIR injury, as shown by decreased reactive gliosis and reduced retinal cells loss. Furthermore, lncRNA-CRNDE knockdown directly regulated Müller cell function and indirectly affected RGC function in vitro. In addition, lncRNA-CRNDE knockdown led to a significant reduction in the release of several cytokines after RIR. This study suggests that lncRNA-CRNDE is a promising therapeutic target for RIR.

Involvement of transient receptor potential channels in ocular diseases: a narrative review.

Background and Objective: Transient receptor potential (TRP) channels are a superfamily of functionally diverse and widely expressed cation channels which exhibit complex regulatory patterns and sensitivity to multiple environmental factors. The involvement of these ion channels is critical in various physiological functions and pathophysiological conditions. In recent decades, a growing number of studies have identified the essential role that TRP channels play in many ocular diseases. In this study, we performed a narrative review of research on the expression and function of TRP channels in various eye diseases. Methods: PubMed, Google Scholar, and Web of Science were searched for all relevant original papers and reviews published from database inception to January 31, 2022. Searches were conducted using the related keywords 'transient receptor potential channels', 'TRPs', 'Ca2+ signaling', 'iron channel', 'TRPV4', 'TRPM1', 'retina', 'optic nerve', 'cornea', 'retinal ganglion cells', 'ON-bipolar', 'TRPs and retina', 'TRP channel and retinal ganglion cells', 'TRPs and cornea', 'diabetes', 'glaucoma', 'dry eye disease', 'cataract', 'retinopathy of prematurity', 'retinoblastoma', and 'congenital stationary night blindness'. Key Content and Findings: In this narrative review, we summarize the history of TRP channels and introduce the TRP channel-related literature in eye disease. Next, we discuss the molecular mechanisms of TRP channels in various eye diseases and suggest future research directions. Conclusions: The relevant studies indicate that TRP channels play vital roles in various eye diseases. However, considerable work is needed to more fully understand the functional and mechanistic aspects of how TRP channels contribute to the pathophysiology of eye disease, especially in the context of animal models and patients. Further investigations will aid in the development of future drugs targeting TRP channels for eye diseases.

Identification of aberrantly expressed circular RNAs in hyperlipidemia-induced retinal vascular dysfunction in mice.

Hyperlipidemia-induced retinal vascular dysfunction is a complex pathological process. circRNAs are important regulators of biological processes and disease progression. However, the expression pattern of circRNAs in hyperlipidemia-induced retinal vascular dysfunction remains unclear. Herein, we used a murine model of hyperlipidemia and identified 317 differentially expressed circRNAs between hyperlipidemic retinas and normolipidemic retinas by circRNA microarrays. GO analysis indicated that the host genes of dysregulated circRNAs were targeted to cell differentiation (ontology: biological process), cytoplasm (ontology: cellular component), and protein binding (ontology: molecular function). Pathway analysis revealed that circRNAs-mediated network was mostly enriched in focal adhesion signaling. Notably, circLDB1 was significantly up-regulated in the serum of coronary artery disease patients and aqueous humor of age-related macular degeneration patients. circLDB1 regulated endothelial cell viability, proliferation, and apoptosis in vitro. Thus, circRNAs are the promising targets for the prediction and diagnosis of hyperlipidemia-induced vascular diseases.

Correlates of pericardial adipose tissue volume using multidetector CT scanning in cardiac patients in China.

BACKGROUND: Pericardial adipose tissue (PAT) is an emerging cardiovascular risk factor, yet much less is understood about PAT volume in Chinese adults, especially in relation to physical activity. The study explores associations between demographic and clinical variables and PAT volume, using multidetector computed tomography (MDCT) scanning in China. We also examined the relationship between PAT volume and coronary artery disease (CAD). METHODS: An observational, correlational study design was used. Chinese (n=163) attended a study visit and underwent MDCT scanning between September 2014 and December 2015. RESULTS: Participants were 48.5% male and had a mean age of 60.6 (SD 9.4) years. PAT volume was higher (p=0.001) in males than in females. PAT volume was correlated with age (r=0.388, p=0.001), systolic blood pressure (r=0.205, p=0.009), body mass index (r=0.466, p=0.001), high-density cholesterol (r=-0.282, p=0.001), low-density cholesterol (r=0.177, p=0.024), and triglycerides (r=0.248, p=0.001). Both moderate intensity physical activity energy consumption (r=-0.363, p=0.001) and total physical activity (r=-0.290, p=0.001) had inverse relationships with PAT volume. Total sedentary energy consumption was positively related to PAT volume (r=0.266, p=0.001). Multiple regression revealed that age, male gender, BMI, LDL-C and total physical activity energy consumption were significant predictors of PAT volume (R2=0.465). The relationship between PAT volume and CAD was found to be significant in the adjusted models. CONCLUSIONS: Age, male gender, BMI, LDL-C and total physical activity energy consumption were significant predictors of PAT volume, and PAT volume itself is a predictor of CAD.

Far upstream element-binding protein 1 (FUBP1) is a potential c-Myc regulator in esophageal squamous cell carcinoma (ESCC) and its expression promotes ESCC progression.

The human far upstream element (FUSE) binding protein 1 (FUBP1) belongs to an ancient family which is required for proper regulation of the c-Myc proto-oncogene. Although c-Myc plays an important role in development of various carcinomas, the relevance of FUBP1 and their contribution to esophageal squamous cell carcinoma (ESCC) development remain unclear. In this study, we aimed to investigate the relationship between FUBP1 and c-Myc as well as their contribution to ESCC development. Western blot and immunohistochemical analyses were performed to evaluate FUBP1 expression. Coimmunoprecipitation analysis was performed to explore the correlation between FUBP1 and c-Myc in ESCC. In addition, the role of FUBP1 in ESCC proliferation was studied in ESCC cells through knocking FUBP1 down. The regulation of FUBP1 on proliferation was confirmed by Cell Counting Kit-8 (CCK-8) assay, flow cytometric assays, and clone formation assays. The expressions of FUBP1 and c-Myc were both upregulated in ESCC tissues. In addition to correlation between expression of FUBP1 and tumor grade, we also confirmed the correlation of FUBP1, c-Myc, and Ki-67 expression by twos. Moreover, upregulation of FUBP1 and c-Myc in ESCC was associated with poor survival. FUBP1 was confirmed to activate c-Myc in ESCC tissues and cells. FUBP1 was demonstrated to promote proliferation of ESCC cells. Moreover, downregulation of both FUBP1 and c-Myc was confirmed to inhibit proliferation of ESCC cells. Our results indicated that FUBP1 may potentially stimulate c-Myc expression in ESCC and its expression may promote ESCC progression.

Oxidative stress-mediated antiproliferative effects of furan-containing sulfur flavors in human leukemia Jurkat cells.

Antiproliferative effects of 15 sulfides were investigated in human leukemia Jurkat cells. Treatment with 5-50 µM of nine monosulfides and two linear disulfides did not induce DNA fragmentation. Whereas, furan-containing sulfur flavors including methyl 2-methyl-3-furyl disulfide (MMFDS), bis (2-methyl-3-furyl) disulfide (BMFDS), methyl furfuryl disulfide (MFDS) and difurfuryl disulfide (DFDS) induced DNA fragmentation to a varying extent in Jurkat cells. The cell viability-reduction effect of these sulfur flavors was in the following order: DFDS>BMFDS>MMFDS>>MFDS based on the IC50 values. MMFDS and BMFDS, but not DFDS, significantly increased the intracellular ROS level by 1.90- and 3.02-fold, respectively. Addition of N-acetylcysteine (NAC) or glutathione (GSH) partially suppressed induction of DNA fragmentation, apoptosis and caspase-3 activation by MMFDS and BMFDS. These results suggest that the furan-containing disulfides have a strong antiproliferative effect, and the oxidative stress and subsequent caspase-3 activation are involved in antiproliferative effect induced by MMFDS and BMFDS in Jurkat cells.