ShengqingJiangzhuo capsule ameliorates diabetic nephropathy by improving Keap1/Nrf2 signaling pathway.

BACKGROUND: Diabetic nephropathy (DN) is a major contributor to end-stage renal failure, and lacking effective treatment options. Shengqing Jiangzhuo capsule (SQJZJN), a traditional Chinese medicine prescription with known efficacy in chronic kidney disease, has not been thoroughly investigated for its potential in DN protection. METHODS: Eight-week-old male C57BLKS/J db/db, C57BLKS/J db/m mice, and human glomerular mesangial cell (HMC) cells cultured with high glucose were used as experimental models in this study. RESULTS: The in vivo investigation showed that SQJZJN can significantly ameliorate renal pathological damage, reduce serum creatinine, and lower urinary microalbumin levels in db/db mice. In vitro, SQJZJN treatment mitigated advanced glycation end products (AGEs) and reactive oxygen species (ROS), leading to a reduction in renal cell apoptosis. Mechanistically, SQJZJN activated the Keap1/Nrf2/ARE pathway by promoting nuclear factor erythroid-derived 2-related factor 2 (Nrf2), γ-glutamylcysteine synthetase heavy subunit (γ-GCS), and Heme oxygenase-1 (HO-1) expressions, while decreasing Kelch-like ECH-associated protein 1 (KEAP1) expressions. CONCLUSION: These findings suggest that SQJZJN exerts a protective effect on DN, potentially through the activation of the Keap1/Nrf2/ARE pathway.

Dysregulated lipid metabolism is associated with kidney allograft fibrosis.

BACKGROUND: Interstitial fibrosis and tubular atrophy (IF/TA), a histologic feature of kidney allograft destruction, is linked to decreased allograft survival. The role of lipid metabolism is well-acknowledged in the area of chronic kidney diseases; however, its role in kidney allograft fibrosis is still unclarified. In this study, how lipid metabolism contributes to kidney allografts fibrosis was examined. METHODS: A comprehensive bioinformatic comparison between IF/TA and normal kidney allograft in the Gene Expression Omnibus (GEO) database was conducted. Further validations through transcriptome profiling or pathological staining of human recipient biopsy samples and in rat models of kidney transplantation were performed. Additionally, the effects of enhanced lipid metabolism on changes in the fibrotic phenotype induced by TGF-ß1 were examined in HK-2 cell. RESULTS: In-depth analysis of the GEO dataset revealed a notable downregulation of lipid metabolism pathways in human kidney allografts with IF/TA. This decrease was associated with increased level of allograft rejection, inflammatory responses, and epithelial mesenchymal transition (EMT). Pathway enrichment analysis showed the downregulation in mitochondrial LC-fatty acid beta-oxidation, fatty acid beta-oxidation (FAO), and fatty acid biosynthesis. Dysregulated fatty acid metabolism was also observed in biopsy samples from human kidney transplants and in fibrotic rat kidney allografts. Notably, the areas affected by IF/TA had increased immune cell infiltration, during which increased EMT biomarkers and reduced CPT1A expression, a key FAO enzyme, were shown by immunohistochemistry. Moreover, under TGF-ß1 induction, activating CPT1A with the compound C75 effectively inhibited migration and EMT process in HK-2 cells. CONCLUSIONS: This study reveal a critical correlation between dysregulated lipid metabolism and kidney allograft fibrosis. Enhancing lipid metabolism with CPT1A agonists could be a therapeutic approach to mitigate kidney allografts fibrosis.

Machine learning-based models for predicting mortality and acute kidney injury in critical pulmonary embolism.

OBJECTIVES: We aimed to use machine learning (ML) algorithms to risk stratify the prognosis of critical pulmonary embolism (PE). MATERIAL AND METHODS: In total, 1229 patients were obtained from MIMIC-IV database. Main outcomes were set as all-cause mortality within 30 days. Logistic regression (LR) and simplified eXtreme gradient boosting (XGBoost) were applied for model constructions. We chose the final models based on their matching degree with data. To simplify the model and increase its usefulness, finally simplified models were built based on the most important 8 variables. Discrimination and calibration were exploited to evaluate the prediction ability. We stratified the risk groups based on risk estimate deciles. RESULTS: The simplified XGB model performed better in model discrimination, which AUC were 0.82 (95% CI: 0.78-0.87) in the validation cohort, compared with the AUC of simplified LR model (0.75 [95% CI: 0.69-0.80]). And XGB performed better than sPESI in the validation cohort. A new risk-classification based on XGB could accurately predict low-risk of mortality, and had high consistency with acknowledged risk scores. CONCLUSIONS: ML models can accurately predict the 30-day mortality of critical PE patients, which could further be used to reduce the burden of ICU stay, decrease the mortality and improve the quality of life for critical PE patients.

Genetic associations of leisure sedentary behaviors and the risk of 15 site-specific cancers: A Mendelian randomization study.

BACKGROUND AND AIMS: Leisure sedentary behavior (LSB) is associated with the risk of cancer, but the causal relationship between them has not been clarified. The aim of this study was to assess the potential causal association between LSB and risk of 15 site-specific cancers. METHODS: The causal association between LSB and cancer were assessed with univariate Mendelian randomization (UVMR) and multivariate Mendelian randomization (MVMR). 194 SNPs associated with LSB (from the UK Biobank 408,815 individuals) were adopted as the instrument variables. Sensitivity analyses were performed to ensure the robustness of the results. RESULTS: UVMR analysis revealed that television watching significantly increased the risk of endometrial cancer (OR = 1.29, 95% CI = 1.02-1.64, p = 0.04) (mainly the endometrioid histology [OR = 1.28, 95% CI = 1.02-1.60, p = 0.031])，breast cancer (OR = 1.16, 95% CI = 1.04-1.30, p = 0.007) (both ER+ breast cancer [OR = 1.17, 95% CI = 1.03-1.33, p = 0.015], and ER- breast cancer [OR = 1.55, 95% CI = 1.26-1.89, p = 2.23 × 10-5 ]). Although causal association was not found between television watching and ovarian cancer, it was seen in low grade and low malignant potential serous ovarian cancer (OR = 1.49, 95% CI = 1.07-2.08, p = 0.018). However, significant results were not obtained in the UVMR analysis between driving, computer use and the 15 types of cancer. Further MVMR analysis indicated that the above results are independent from most metabolic factors and dietary habits, but mediated by educational attainment. CONCLUSION: LSB in form of television watching has independent causal association with the risk of endometrial cancer, breast cancer, and ovarian cancer.

A novel oncolytic adenovirus targeting Wnt signaling effectively inhibits cancer-stem like cell growth via metastasis, apoptosis and autophagy in HCC models.

Cancer stem cells (CSCs), which are highly differentiated and self-renewing, play an important role in the occurrence, therapeutic resistant and metastasis of hepatacellular carcinoma (HCC). Oncolytic adenoviruses have targeted killing effect on tumor cells, and are invoked as candidate drugs for cancer treatment. We designed a dual-regulated oncolytic adenovirus Ad.wnt-E1A(△24bp)-TSLC1 that targets Wnt and Rb signaling pathways respectively, and carries the tumor suppressor gene, TSLC1. Previous studies have demonstrated that oncolytic adenovirus mediated TSLC1can target liver cancer and exhibit significant cytotoxicity. However, whether Ad.wnt-E1A(△24bp)-TSLC1 can effectively eliminate liver CSCs remains to be explored. We first used the spheroid culture to enrich the liver CSCs-like cells, and detected the self-renewal capacity, differentiation, drug resistance and tumorigenicity. The results showed that Ad-wnt-E1A(△24bp)-TSLC1 could effectively lead to autophagic death. In addition, recombinant adenovirus effectively induced the apoptosis, inhibit metastasis of hepatic CSCs-like cells in vivo. Further animal experiments indicated that Ad-wnt-E1A(△24bp)-TSLC1could effectively inhibit the growth of transplanted tumor of hepatic CSCs and prolong the survival time of mice. Therefore, the novel oncolytic adenovirus Ad.wnt-E1A(△24bp)-TSLC1 has potential application as a therapeutic target for HCC stem cells.