The STAT1-SLC31A1 axis: Potential regulation of cuproptosis in diabetic retinopathy.

BACKGROUND: By identifying molecular biological markers linked to cuproptosis in diabetic retinopathy (DR), new pathobiological pathways and more accessible diagnostic markers can be developed. METHODS: The datasets related to DR were acquired from the Gene Expression Omnibus database, while genes associated with cuproptosis were sourced from previously published compilations. Consensus clustering was conducted to delineate distinct DR subclasses. Feature genes were identified utilizing weighted correlation network analysis (WGCNA). Additionally, two machine-learning algorithms were employed to refine the selection of feature genes. Finally, we conducted preliminary validation experiments to ascertain the involvement of cuproptosis in DR development and the transcriptional regulation of critical genes using both the streptozotocin-induced diabetic mouse model and the high glucose-induced BV2 model. RESULTS: In the STZ-induced diabetic mouse retinas, a decrease in the expression of cuproptosis signature proteins (FDX1, DLAT, and NDUFS8) suggested the occurrence of cuproptosis in DR. Subsequently, the expression of eight cuproptosis differential genes was validated through the STZ-induced diabetes and oxygen-induced retinopathy (OIR) models, with the key gene SLC31A1 showing upregulation in both models and dataset species. Further analyses, including weighted gene co-expression network analysis, GSVA, and immune infiltration analysis, indicated a close correlation between cuproptosis and microglia function. Additionally, validation in an in vitro model of microglia indicated the occurrence of cuproptosis in microglia under high glucose conditions, alongside abnormal expression of STAT1 with SLC31A1. CONCLUSION: Our findings suggest that STAT1/SLC31A1 may pave the way for a deeper comprehension of the mechanistic basis of DR and offer potential therapeutic avenues.

Therapeutic potential of flavopiridol in diabetic retinopathy: Targeting DDX58.

Diabetic retinopathy (DR), a common complication of diabetes, is characterized by inflammation and neovascularization, and is intricately regulated by the ubiquitin-proteasome system (UPS). Despite advancements, identifying ubiquitin-related genes and drugs specifically targeting DR remains a significant challenge. In this study, bioinformatics analyses and the Connectivity Map (CMAP) database were utilized to explore the therapeutic potential of genes and drugs for DR. Through these methodologies, flavopiridol was identified as a promising therapeutic candidate. To evaluate flavopiridol's therapeutic potential in DR, an in vitro model using Human Umbilical Vein Endothelial Cells (HUVECs) induced by high glucose (HG) conditions was established. Additionally, in vivo models using mice with streptozotocin (STZ)-induced DR and oxygen-induced retinopathy (OIR) were employed. The current study reveals that flavopiridol possesses robust anti-inflammatory and anti-neovascularization properties. To further elucidate the molecular mechanisms of flavopiridol, experimental validation and molecular docking techniques were employed. These efforts identified DDX58 as a predictive target for flavopiridol. Notably, our research demonstrated that flavopiridol modulates the DDX58/NLRP3 signaling pathway, thereby exerting its therapeutic effects in suppressing inflammation and neovascularization in DR. This study unveils groundbreaking therapeutic agents and innovative targets for DR, and establishes a progressive theoretical framework for the application of ubiquitin-related therapies in DR.

A New Modulator of Neuroinflammation in Diabetic Retinopathy: USP25.

Diabetic retinopathy (DR) is a diabetes-associated complication that poses a threat to vision, distinguished by persistent and mild inflammation of the retinal microvasculature. The activation of microglia plays a crucial role in driving this pathological progression. Previous investigations have demonstrated that ubiquitin-specific peptidase 25 (USP25), a deubiquitinating enzyme, is involved in the regulation of immune cell activity. Nevertheless, the precise mechanisms through which USP25 contributes to the development of DR remain incompletely elucidated. Firstly, we have demonstrated the potential mechanism by which ROCKs can facilitate microglial activation and augment the synthesis of inflammatory mediators through the modulation of NF-κB signaling pathways in a high-glucose milieu. Furthermore, our study has provided novel insights by demonstrating that the regulatory role of USP25 in the secretion of proinflammatory factors is mediated through the involvement of ROCK in modulating the expression of NF-κB and facilitating the nuclear translocation of the phosphatase NF-κB. This regulatory mechanism plays a crucial role in modulating the activation of microglial cells within a high-glycemic environment. Hence, USP25 emerges as a pivotal determinant for the inflammatory activation of microglial cells, and its inhibition exhibits a dual effect of promoting retinal neuron survival while suppressing the inflammatory response in the retina. In conclusion, the promotion of diabetic retinopathy (DR) progression by USP25 is attributed to its facilitation of microglial activation induced by high glucose levels, a process mediated by the ROCK pathway. These findings highlight the importance of considering USP25 as a potential therapeutic target for the management of diabetic neuroinflammation.

Do socio-economic factors matter? A comprehensive evaluation of tourism eco-efficiency determinants in China based on the Geographical Detector Model.

Constructed on the total-factor analysis framework, this paper develops a comprehensive evaluation system and adopts the Super-SBM model to both analyze and enunciate the characteristics of tourism eco-efficiency in China during 2000-2017. This paper also identifies the determinants associated with spatial differentiation of tourism eco-efficiency by employing a novel geographical technique, namely the Geographical Detector Model. The results indicate that the tourism eco-efficiency exhibits great potential for growth. Besides, pure technical efficiency drives the optimized development of eco-efficiency. Also, there is significant spatial variations in eco-efficiency across different provinces and regions in China. Urbanization contributes to tourism eco-efficiency remarkably, followed by openness, technical level, economic scale, industrial structure, capital effect, environmental regulation, and tourism growth. The relational interrelations of tourism eco-efficiency determinants are the bi-enhancement and the nonlinear-enhancement interactions. The implications of research findings are discussed and may be applied to a multitude of corporate environmental-economic management scenarios.