Xiubin Liang

Type 2 diabetes mellitus (T2DM) increases the risk of biliary diseases (BD). This study aimed to evaluate the association between sodium-glucose cotransporter-2 inhibitors (SGLT2i) use andBD risk in T2DM patients, compared with sulfonylureas. We conducted a multi-center retrospective cohort study using electronic health records from Nanjing Medical University (January 2017-September 2022). Adults aged 18-75 years with T2DM newly prescribed SGLT2i or sulfonylureas were included. Propensity score with inverse probability of treatment weighting (IPTW) was applied to balance baseline covariates. Follow-up continued until BD onset, last visit, death, or study end. Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) complemented by sensitivity analyses, time-stratified analyses and subgroup analyses. Metabolic and biliary biomarkers were also compared. A total of 1,901 T2DM patients were included (453 SGLT2i users and 1,448 sulfonylurea users). BD occurred in 24 SGLT2i users and in 188 sulfonylurea users. After IPTW adjustment, SGLT2i use was associated with a lower BD risk (HR 0.595, 95% CI 0.410-0.863, p = 0.020), remaining significant beyond 24 months and was stronger in patients aged over 60 years, without diabetic complications, or with high comorbidity burdens, consistent regardless of prior biguanides use. Glycemic control and body weight remained comparable, whereas SGLT2i users showed higher high-density lipoprotein cholesterol and lower total bile acid, and bilirubin levels. SGLT2i use was associated with a lower BD risk in T2DM patients, particularly with long-term treatment and among high-risk subgroups. Improved biliary biomarkers paralleled this reduction, suggesting a potential link that warrants further study.

This study aimed to develop a data-driven prediction model for cardiac surgery-associated acute kidney injury (CSA-AKI) at the end of surgery using machine learning (ML) algorithms. We retrospectively collected clinical data from patients undergoing cardiac surgery at Nanjing First Hospital between June 2016 and January 2023. Feature selection was performed using Lasso regression to identify variables most strongly associated with CSA-AKI. Six ML algorithms-logistic regression (LR), random forest (RF), gradient boosting decision tree (GBDT), eXtreme Gradient Boosting Trees (XGBoost), support vector machine (SVM), and an ensemble model (ENS, integrating GBDT, XGBT, and RF)-were developed and evaluated. External validation was performed on 1,174 patients from the MIMIC-IV database. Model interpretability was assessed via SHAP analysis. In this study of 2,277 cardiac surgery patients, the incidence of CSA-AKI was 22.6%. Patients were divided into training (n = 1,593) and internal validation (n = 684) sets, with comparable AKI rates (22.6% vs. 22.5%). An external validation cohort (n = 1,174) showed a higher AKI incidence (86.9%) and differing baseline characteristics. Feature selection via Lasso regression identified 11 key predictors, with intraoperative red blood cell (RBC) transfusion and cardiopulmonary bypass (CPB) time consistently ranking among the top contributors. Six ML models were developed, with the ensemble model achieving the highest AUC (0.856). External validation confirmed model robustness, with SVM performing best (AUC = 0.847). Confusion matrix analysis demonstrated high accuracy across models, and SHAP analysis reinforced the importance of transfusion and CPB time in AKI prediction. ML models, particularly the ensemble approach, provide reliable prediction of CSA-AKI, with generalizability validated in an external cohort. These models facilitate early identification of high-risk patients, enabling timely perioperative interventions to improve clinical outcomes.

Background & aims Diabetes is known to increase the risk of gallstone disease. This study assesses the impact of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on the incidence of biliary diseases, relative to sulfonylureas, in patients with type 2 diabetes mellitus (T2DM) and lithogenic diet (LD)-fed mice. Methods A retrospective cohort analysis was performed on T2DM patient data who commenced SGLT2i or sulfonylurea therapy from January 1, 2017, to September 1, 2022-sourced from Nanjing Medical University’s database. They were matched using propensity scores (PS) and inverse probability of treatment weighting (IPTW). Follow-up for developing biliary diseases was conducted up to the earliest relevant end-point. Cox models, PS matching, and sensitivity analyses, including standard mortality ratio weighting (SMRW), were applied to determine hazard ratios (HRs) and confidence intervals (CIs). Parallelly, LD-fed C57BL/6J mice were administered SGLT2i or sulfonylureas to corroborate findings in animal models. Results From the 1,901 patients analyzed over an average of 2.83 years, SGLT2i therapy correlated with a substantially lower risk of developing biliary diseases (HR 0.595, 95% CI 0.410-0.863), particularly among defined subgroups. A downward trend in risk was observed with extended use beyond two years. Concordant data from the mouse model pointed towards SGLT2i mitigating gallstone formation, with putative mechanisms including reduced liver injury and dyslipidemia, as well as improved gallbladder motility and bile acid production. Conclusion SGLT2i potentially reduces the risk of biliary diseases compared to sulfonylureas, meriting further clinical investigation.

S100 calcium-binding protein 16 (S100A16) is implicated in both chronic kidney disease (CKD) and acute kidney injury (AKI). Previous research has shown that S100A16 contributes to AKI by facilitating the ubiquitylation and degradation of glycogen synthase kinase 3β (GSK3β) and casein kinase 1α (CK1α) through the activation of HMG-CoA reductase degradation protein 1 (HRD1). However, the mechanisms governing S100A16-induced HRD1 activation and the upregulation of S100A16 expression in renal injury are not fully understood. In this study, we observed elevated expression of Hypoxia-inducible Factor 1-alpha (HIF-1α) in the kidneys of mice subjected to ischemia-reperfusion injury (IRI). S100A16 deletion attenuated the increased HIF-1α expression induced by IRI. Using a S100A16 knockout rat renal tubular epithelial cell line (NRK-52E cells), we found that S100A16 knockout effectively mitigated apoptosis during hypoxic reoxygenation (H/R) and cell injury induced by TGF-β1. Our results revealed that H/R injuries increased both protein and mRNA levels of HIF-1α and HRD1 in renal tubular cells. S100A16 knockout reversed the expressions of HIF-1α and HRD1 under H/R conditions. Conversely, S100A16 overexpression in NRK-52E cells elevated HIF-1α and HRD1 levels. HIF-1α overexpression increased HRD1 and β-catenin while decreasing GSK-3β. HIF-1α inhibition restored HRD1 and β-catenin upregulation and GSK-3β downregulation by cellular H/R injury. Notably, Chromatin immunoprecipitation (ChIP) and luciferase reporter assays demonstrated HIF-1α binding signals on the HRD1 promoter, and luciferase reporter gene assays confirmed HIF-1α‘s transcriptional regulation of HRD1. Additionally, we identified Transcription Factor AP-2 Beta (TFAP2B) as the upregulator of S100A16. ChIP and luciferase reporter assays confirmed TFAP2B as a transcription factor for S100A16. In summary, this study identifies TFAP2B as the transcription factor for S100A16 and demonstrates HIF-1α regulation of HRD1 transcription within the S100A16-HRD1-GSK3β/CK1α pathway during renal hypoxia injury. These findings provide crucial insights into the molecular mechanisms of kidney injury, offering potential avenues for therapeutic intervention.

The scarcity of donor kidneys greatly impacts the survival of patients with end-stage renal failure. Pigs are increasingly becoming potential organ donors but are limited by immunological rejection. Based on the human kidney organoid already established with the CHIR99021 and FGF9 induction strategy, we generated porcine kidney organoids from porcine naïve-like ESCs (nESCs). The derived porcine organoids had a tubule-like constructure and matrix components. The porcine organoids expressed renal markers including AQP1 (proximal tubule), WT1 and PODO (podocyte), and CD31 (vascular endothelial cells). These results imply that the organoids had developed the majority of the renal cell types and structures, including glomeruli and proximal tubules. The porcine organoids were also identified to have a dextran absorptive function. Importantly, porcine organoids have a certain abundance of vascular endothelial cells, which are the basis for investigating immune rejection. The derived porcine organoids might serve as materials for immunosuppressor screening for xenotransplantation.

Islet beta cells (β-cells) produce insulin in response to high blood glucose levels, which is essential for preserving glucose homeostasis. Voltage-gated ion channels in β-cells, including Na ⁺, K ⁺, and Ca ²⁺ channels, aid in the release of insulin. The epithelial sodium channel alpha subunit (α-ENaC), a voltage-independent sodium ion channel, is also expressed in human pancreatic endocrine cells. However, there is no reported study on the function of ENaC in the β-cells. In the current study, we found that α-ENaC was expressed in human pancreatic glandule and pancreatic islet β-cells. In the pancreas of db/db mice, a high-fat diet-induced mice, and in mouse islet β-cells (MIN6 cells) treated with palmitate, α-ENaC expression was increased. When α-ENaC was overexpressed in MIN6 cells, insulin content and glucose-induced insulin secretion were significantly reduced. On the other hand, palmitate injured islet β-cells and suppressed insulin synthesis and secretion, but increased α-ENaC expression in MIN6 cells. However, α-ENaC knockout ( Scnn1a ^-/-) in MIN6 cells attenuated β-cell disorder induced by palmitate. Furthermore, α-ENaC regulated the ubiquitylation and degradation of sirtuin 2 in β-cells. α-ENaC also modulated β-cell function in correlation with the inositol-requiring enzyme 1 alpha/X-box binding protein 1 (IRE1α/XBP1) and protein kinase RNA-like endoplasmic reticulum kinase/C/EBP homologous protein (PERK/CHOP) endoplasmic reticulum stress pathways. These results suggest that α-ENaC may play a novel role in insulin synthesis and secretion in the β-cells, and the upregulation of α-ENaC promotes islet β-cell dysfunction. In conclusion, α-ENaC may be a key regulator involved in islet β-cell damage and a potential therapeutic target for type 2 diabetes mellitus.

S100 calcium-binding protein 16 (S100A16) is implicated in both chronic kidney disease (CKD) and acute kidney injury (AKI). Previous research has shown that S100A16 contributes to AKI by facilitating the ubiquitylation and degradation of glycogen synthase kinase 3β (GSK3β) and casein kinase 1α (CK1α) through the activation of HMG-CoA reductase degradation protein 1 (HRD1). However, the mechanisms governing S100A16-induced HRD1 activation and the upregulation of S100A16 expression in renal injury are not fully understood. In this study, we observed elevated expression of Hypoxia-inducible Factor 1-alpha (HIF-1α) in the kidneys of mice subjected to ischemia-reperfusion injury (IRI). S100A16 deletion attenuated the increased HIF-1α expression induced by IRI. Using a S100A16 knockout rat renal tubular epithelial cell line (NRK-52E cells), we found that S100A16 knockout effectively mitigated apoptosis during hypoxic reoxygenation (H/R) and cell injury induced by TGF-β1. Our results revealed that H/R injuries increased both protein and mRNA levels of HIF-1α and HRD1 in renal tubular cells. S100A16 knockout reversed the expressions of HIF-1α and HRD1 under H/R conditions. Conversely, S100A16 overexpression in NRK-52E cells elevated HIF-1α and HRD1 levels. HIF-1α overexpression increased HRD1 and β-catenin while decreasing GSK-3β. HIF-1α inhibition restored HRD1 and β-catenin upregulation and GSK-3β downregulation by cellular H/R injury. Notably, Chromatin immunoprecipitation (ChIP) and luciferase reporter assays demonstrated HIF-1α binding signals on the HRD1 promoter, and luciferase reporter gene assays confirmed HIF-1α's transcriptional regulation of HRD1. Additionally, we identified Transcription Factor AP-2 Beta (TFAP2B) as the upregulator of S100A16. ChIP and luciferase reporter assays confirmed TFAP2B as a transcription factor for S100A16. In summary, this study identifies TFAP2B as the transcription factor for S100A16 and demonstrates HIF-1α regulation of HRD1 transcription within the S100A16-HRD1-GSK3β/CK1α pathway during renal hypoxia injury. These findings provide crucial insights into the molecular mechanisms of kidney injury, offering potential avenues for therapeutic intervention.

Hepatic glucose and lipid metabolism disorders promote the development and progression of type 2 diabetes mellitus (T2DM), yet the underlying mechanisms are not fully understood. Here, we identify tripartite motif-containing protein 21 (TRIM21), a class IV TRIM family member, as a pivotal regulator of hepatic metabolism in T2DM for the first time. Bioinformatic analysis suggests that TRIM21 expression is significantly reduced in T2DM patients. Intriguingly, in a mouse model of obese diabetes, TRIM21 expression is predominantly reduced in the liver rather than in other metabolic organs. It is further demonstrated that hepatic overexpression of TRIM21 significantly ameliorates glucose intolerance, insulin resistance, hepatic steatosis, and dyslipidemia in obese diabetic mice. In contrast, the knockdown of TRIM21 promotes glucose intolerance, insulin resistance, and triglyceride accumulation. Mechanistically, both phosphoenolpyruvate carboxykinase 1 (PEPCK1) and fatty acid synthase (FASN) are the hepatic targets of TRIM21. We revealed that TRIM21 promotes the degradation of PEPCK1 and FASN through a direct protein–protein interaction mediated K48-linked ubiquitination. Notably, overexpression of PEPCK1 and FASN essentially abolished the beneficial effects achieved by TRIM21 overexpression in obese diabetic mice. Overall, our data demonstrate that TRIM21 is a novel regulator of hepatic metabolic disorder, and suggest TRIM21 as a promising therapeutic target for T2DM.