Ying Xie

Background: Diabetic nephropathy (DN) is characterized by tubular injury and tubulointerstitial fibrosis, leading to progressive renal dysfunction. While dysregulation of autophagy has been linked to DN pathogenesis, the underlying regulatory mechanisms remain incompletely understood. This study aimed to test the hypothesis that transcription factor 3 (TCF3) serves as a critical upstream regulator of autophagy dysfunction in DN by suppressing Netrin-1 expression, thereby promoting epithelial-mesenchymal transition (EMT) through activation of the PI3K/Akt/mTOR pathway. Methods: We established a DN rat model using high-fat diet followed by low-dose streptozotocin injection (25 mg/kg). Thirty-five male Sprague-Dawley rats were divided into five groups ( n = 6–7/group, with specific numbers clearly defined for each experimental condition): control, DN, DN + vector, DN + TCF3-shRNA lentivirus, and DN + TCF3-shRNA + 3-methyladenine (3-MA). All key experiments were performed with at least three independent biological replicates. In vitro , HK-2 cells were categorized into four groups: normal glucose (NG, 5.5 mmol/L), high glucose (HG, 30 mmol/L), HG with negative control siRNA (HG + si-NC), and HG with TCF3-targeting siRNA (HG + TCF3-siRNA). Western blotting was utilized to determine the expression levels of autophagy-related proteins, EMT-associated proteins, and PI3K/Akt/mTOR signaling pathway-related proteins. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to assess the mRNA expression levels of TCF3 and Netrin-1. Additionally, a dual-luciferase reporter gene assay was performed to investigate the interaction between TCF3 and Netrin-1. Statistical analyses were performed using one-way ANOVA followed by Tukey’s post-hoc test, with p < 0.05 considered statistically significant. Results: We first confirmed that TCF3 expression was significantly elevated in both DN rat kidneys (2.8-fold increase at protein level, p < 0.001) and high glucose-treated HK-2 cells (2.5-fold at protein level, p < 0.001) compared to controls. Both the DN rat model and HG-stimulated HK-2 cells exhibited enhanced EMT markers, with significantly increased α-SMA and vimentin expression ( p < 0.001), and decreased E-cadherin levels ( p < 0.001). TCF3 knockdown significantly attenuated these EMT changes and increased autophagy markers, as evidenced by decreased P62 levels ( p < 0.01) and increased LC3-II/I ratio ( p < 0.001) and Beclin-1 expression ( p < 0.01). The dual luciferase assay confirmed direct binding of TCF3 to the Netrin-1 promoter, with a 57% ± 4.3% reduction ( p < 0.001) in luciferase activity. Mechanistically, TCF3 silencing mitigated HG-induced fibrosis and promoted autophagy by increasing Netrin-1 expression and suppressing the PI3K/Akt/mTOR signaling pathway. Conclusion: Our findings demonstrate that TCF3 functions as a critical negative regulator of autophagy in DN, establishing a novel TCF3-Netrin-1-autophagy regulatory axis. This study provides new mechanistic insights distinct from previous work by demonstrating the direct transcriptional repression of Netrin-1 by TCF3 in renal pathophysiology. The limitation of our study includes the lack of human DN tissue validation and TCF3-specific pharmacological inhibitors. These findings suggest TCF3 as a potential therapeutic target for preventing renal fibrosis in DN through restoration of autophagy function.

Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a critical health concern, with metabolic dysfunction-associated steatohepatitis (MASH) representing a severe subtype that poses significant risks. This study aims to develop a robust diagnostic model for high-risk MASH utilizing a multi-omics approach. Methods We initiated proteomic analysis to select differential proteins, followed by liver transcriptional profiling to localize these proteins. An intersection of differential proteins and liver-expressed genes facilitated the identification of candidate biomarkers. Subsequently, scRNA-seq data helped ascertain the subcellular localization of these biomarkers in kupffer cells. We then established two MASLD models to investigate the co-localization of F4/80 and the target proteins in Kupffer cells using immunofluorescence dual-labeling. Correlation analyses were performed using blood samples from a discovery cohort of 144 individuals with liver pathology to validate the relationships between candidate biomarkers and MASLD phenotypes. Using LASSO regression, we established the ABD-LTyG predictive model for high-risk MASH (NAS ≥ 4 + F ≥ 2) and validated its efficacy in an independent cohort of 171 individuals. Finally, we compared this model against three classic non-invasive liver fibrosis diagnostic methods. Results A proteo-transcriptomic comparison identified 58 consistent biomarkers in plasma and liver, with 25 closely associated with MASLD phenotype. Utilizing single-cell data and the HPA database, we delineated the localization of these biomarkers in liver cells, identifying TREM2, IL18BP, and LGALS3BP predominantly in the Kupffer cell subpopulation. Validation in animal models confirmed elevated expression and cellular localization of TREM2, IL18BP, and LGALS3BP in MASLD. To enhance diagnostic capability, we integrated clinical characteristics using LASSO regression to develop the ABD-LTyG model, comprising AST, BMI, total bilirubin (TB), vitamin D, TyG, and the biomarkers LGALS3BP and TREM2. This model demonstrated an AUC of 0.832 (95% CI 0.753–0.911) in the discovery cohort and 0.807 (95% CI 0.742–0.872) in the validation cohort for diagnosing high-risk MASH, outperforming traditional assessments such as FIB-4, NFS, and APRI. Conclusion The integration of circulating biomarkers and clinical parameters into the ABD-LTyG model offers a promising approach for diagnosing high-risk MASH. This study underscores the importance of multi-omics strategies in enhancing diagnostic accuracy and guiding clinical decision-making. Graphical abstract

Background Immune cells play a crucial role in the progression of thyroid cancer. However, previous research on the link between immune cells and thyroid cancer has produced conflicting results. Methods Based on the public available genome-wide association studies summary statistics, we performed a two-sample Mendelian randomization (MR) to evaluate the causal association between 731 immune phenotypes (including median fluorescence intensities, absolute cell counts, relative cell counts, and morphological parameters) and thyroid cancer. The inverse variance weighting method was employed to investigate the causal relationship between exposure and outcome. Moreover, multiple sensitivity analyses, such as MR-Egger, weighted median, and MR-PRESSO, were simultaneously applied to reinforce the final results. Results After false discovery rate correction, four immunophenotypes were found to be significantly associated with a decreased risk of thyroid cancer. And six immunophenotypes were significantly associated with an increased risk of thyroid cancer. Conclusions Our study has demonstrated the close connection between immune cells and thyroid cancer by genetic means, thus providing guidance for future clinical research.

High glucose (HG) induced endothelial senescence is related to endothelial dysfunction and cardiovascular complications in diabetic patients. Humanin, a member of mitochondrial derived peptides (MDPs), is thought to contribute to aging-related cardiovascular protection. The goal of the study is to explore the pathogenesis of HG-induced endothelial senescence and potential anti-senescent effects of Humanin. Human umbilical vein endothelial cells (HUVECs) were exposed to glucose to induce senescence, determined by β-galactosidase staining and the expressions of p21, p53, and p16. A clinically relevant dose of HG (15 mM, HG) induced endothelial senescence after 72 h incubation without elevated apoptosis. HG-induced senescence was attributed to the induction of reactive oxygen species (ROS) caused by SIRT6 downregulation, as ROS inhibitor N-acetyl cysteine blocked HG-induced senescence, while inactivation of SIRT6 increased ROS levels and promoted senescence. Strikingly. pretreatment with [Gly14]-Humanin (HNG) antagonized the downregulation of SIRT6 in response to HG and alleviated ROS production and cell senescence. HG-induced reduction of SIRT6 results in ROS overproduction and endothelial senescence. Humanin protects against HG-induced endothelial senescence via SIRT6. This study provides new directions for biological products related to Humanin to be a potential candidate for the prevention of vascular aging in diabetes.

The aim of the study was to explore the clinical features related to early hypothyroidism and the relationship between the changes of thyrotropin receptor antibodies (TRAb) and early hypothyroidism in the course of ¹³¹I treatment for Graves’ disease. This study was a retrospective observation, including 226 patients who received the first ¹³¹I treatment. The general information and laboratory tests were collected before and after ¹³¹I treatment, and the laboratory data affecting the difference in disease outcome were analyzed. According to the changes of antibodies in the third month, whether the changes of antibodies were involved in the occurrence of early-onset hypothyroidism was analyzed. Early onset hypothyroidism occurred in 165 of 226 patients, and the results showed that the incidence of early hypothyroidism was higher in patients with low baseline TRAb level (p=0.03) and increased TRAb after treatment (p=0.007). Both baseline TRAb levels (p131I treatment. Monitoring this index during RAI treatment is helpful in identifying early-onset hypothyroidism and mastering the clinical outcome and prognosis of Graves’ disease. Received: 29 November 2023 Accepted after revision: 15 February 2024 Article published online: 04 April 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany

Background. Cellular senescence is thought to play a significant role in the onset and development of diabetic nephropathy. The goal of this study was to explore potential biomarkers associated with diabetic glomerulopathy from the perspective of senescence. Methods. Datasets about human glomerular biopsy samples related to diabetic nephropathy were systematically obtained from the Gene Expression Omnibus database. Hub senescence‐associated genes were investigated by differential gene analysis and Least Absolute Shrinkage and Selection Operator analysis. Cluster analysis was employed to identify senescence molecular subtypes. A single‐cell dataset was used to validate the above findings and further evaluate the senescence environment. The relationship between these genes and the glomerular filtration rate was explored based on the Nephroseq database. These gene expressions have also been explored in various kidney diseases. Results. Twelve representative senescence‐associated genes (VEGFA, IQGAP2, JUN, PLAT, ETS2, ANG, MMP14, VEGFC, SERPINE2, CXCR2, PTGES, and EGF) were finally identified. Biological changes in immune inflammatory response, cell cycle regulation, metabolic regulation, and immune microenvironment have been observed across different molecular subtypes. The above results were also validated based on single‐cell analysis. Additionally, we also identified several significantly altered cell communication pathways, including COLLAGEN, PTN, LAMININ, SPP1, and VEGF. Finally, almost all these genes could well predict the occurrence of diabetic glomerulopathy based on receiver operating characteristic analysis and are associated with the glomerular filtration rate. These genes are differently expressed in various kidney diseases. Conclusion. The present study identified potential senescence‐associated biomarkers and further explored the heterogeneity of diabetic glomerulopathy that might provide new insights into the diagnosis, assessment, management, and personalized treatment of DN.

Ashitaba seems to improve glucose intolerance and decrease triglyceride (TG) and total cholesterol (TC), which contribute to the development of non-alcoholic fatty liver disease (NAFLD). However, it remains to be explored the mechanism of Ashitaba in managing NAFLD. We determined the impact of Ashitaba on NAFLD, particularly its underlying mechanisms at the bioinformatic level. The established NAFLD mouse model was treated with or without Ashitaba, and the underlying mechanism was explored using transcriptomics paired with metabolomics. Ashitaba reduced obesity and liver steatosis in NAFLD mice. It identified 429 differentially expressed genes (DEGs) and verified 45 differential metabolites, especially those that alleviate NAFLD via the FXR signaling pathway. Our data may provide insight into the therapeutic impact of Ashitaba in the management of NAFLD and may be useful in clinical interventions for NAFLD.

Introduction: non-alcoholic fatty liver disease (NAFLD) is a disease in which there is excessive fat deposition in hepatocytes due to hepatoprotective factors. Objectives: to assess the association of the triglyceride-glucose index with the occurrence of non-alcoholic fatty liver disease and mortality in elderly inpatients. To identify the TyG index as a predictive factor of NAFLD. Methods: this prospective observational study included elderly inpatients admitted to the Department of Endocrinology at the Linyi Geriatrics Hospital, Affiliated to Shandong Medical College, between August 2020 and April 2021. The TyG index was calculated according to an established Result: a total of 264 patients were enrolled, with 52 (19.7 %) cases occurred NAFLD. Multivariate logistic regression analysis showed that TyG (OR = 3.889; 95 % CI: 1.134-11.420; p = 0.014) and ALT (OR = 1.064; 95 % CI: 1.012-1.118; p = 0.015) were independently associated with the occurrence of NAFLD. Furthermore, receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) of TyG was 0.727, with sensitivity = 80.4 % and specificity = 57.8 % at cut off = 8.71. A Cox proportional hazards regression model showed that, after adjusting for age, sex, smoking, drinking, hypertension, and type 2 diabetes TyG > 8.71 (HR = 3.191; 95 % CI: 1.347 to 7.560; p < 0.001) was an independent risk factor for mortality in the elderly. Conclusions: the TyG index can predict non-alcoholic fatty liver disease and mortality in elderly Chinese inpatients.