Bone marrow mesenchymal stem cells inhibit ferroptosis via regulating the Nrf2-keap1/p53 pathway to ameliorate chronic kidney disease injury in the rats.

PURPOSE: Although bone marrow mesenchymal stem cells (BMMSCs) have been reported to exhibit a protective effect on animal models of chronic kidney disease (CKD), the exact mechanisms involved require further investigation. This study aims to investigate the underlying molecular mechanisms of BMMSCs in inhibiting ferroptosis and preventing an Adriamycin (ADR)-induced CKD injury. METHODS: A rat model of long-term CKD induced through the injection of ADR administered twice weekly via the tail vein was used in this study. After BMMSCs were systemically administered through the renal artery, pathological staining, western blotting, ELISA, and transmission electron microscopy were used to analyze ferroptosis. RESULTS: Analyses of renal function and histopathological findings indicated that ADR-mediated renal dysfunction improved in response to the BMMSC treatment, which was also sufficient to mediate the partial reversal of renal injury and mitochondrial pathological changes. BMMSCs decreased the ferrous iron (Fe2+) and reactive oxygen species and elevated glutathione (GSH) and GSH peroxidase 4. Moreover, the BMMSC treatment activated the expression of ferroptosis-related regulator NF-E2-related factor 2 (Nrf2) and inhibited Keap1 and p53 in CKD rat kidney tissues. CONCLUSIONS: BMMSCs alleviate CKD, possibly resulting from the inhibition of kidney ferroptosis by regulating the Nrf2-Keap1/p53 pathway.

Identification of ferroptosis­associated genes in chronic kidney disease.

Ferroptosis serves a pivotal role in developing chronic kidney disease (CKD). The present study aimed to detect and confirm the relevance of potential ferroptosis-related genes in CKD using bioinformatics and experimentation strategies. The original GSE15072 mRNA expression dataset was retrieved from the Gene Expression Omnibus database. Subsequently, the potential differentially expressed genes associated with ferroptosis of CKD were screened using R software. Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses, correlation analysis and protein-protein interactions (PPI) were performed for differentially expressed ferroptosis-associated genes (DFGs). Lastly, the expression levels of the top nine DFGs were measured in the kidney tissue of Adriamycin-induced CKD rats and healthy controls via reverse transcription-quantitative (RT-q)PCR analysis. Overall, 49 DFGs among 21 patients with CKD and nine healthy controls were identified. GO and KEGG enrichment analyses demonstrated that these DFGs were primarily involved in 'ferroptosis' and 'mitophagy'. PPI findings indicated that these ferroptosis-associated genes interacted with one another. RT-qPCR of CKD tissue from the rat model revealed that STAT3, MAPK14, heat shock protein (HSP)A5, MTOR and solute carrier family 2 member 1 (SLC2A1) mRNA levels in CKD were upregulated. Overall, 49 potential ferroptosis-associated genes of CKD were identified via bioinformatics analyses. STAT3, MAPK14, HSPA5, MTOR and SLC2A1 may influence CKD onset by regulating ferroptosis. The present results add to the existing body of knowledge about CKD and may be useful in the treatment of CKD.

Construction of novel lncRNA-miRNA-mRNA ceRNA networks associated with prognosis of hepatitis C virus related hepatocellular carcinoma.

Background: Hepatitis C virus (HCV) infection contribute to liver fibrosis and cirrhosis, which significantly increases the risk of hepatocellular carcinoma (HCC) development. Previous studies have demonstrated the pivotal role of competitive endogenous RNA (ceRNA) networks in tumorigenesis and cancer progression. Consequently, we herein seek to identify and evaluate the prognostic relevance of a novel ceRNA network associated with HCV-related HCC. Methods: Differentially expressed genes (DEGs) in GSE140846 dataset from GEO were identified using Network Analyst, and GO, KEGG and Reactome analyses were performed. Furthermore, a protein-protein interaction network was generated, and hub genes were detected. Hub gene expression levels, as well as those of their upstream lncRNAs and miRNAs and associated survival analyses were conducted using appropriate bioinformatics databases. Predicted target relationships were used to establish putative ceRNA networks for HCV-related HCC. Results: A total of 372 and 360 up- and down-regulated DE-mRNA were identified, which were associated with nuclear division, cell cycle, and ATPase activity. A PPI network containing 704 DE-mRNAs was constructed, and the 6 hub gene with the highest degree of connectivity were selected for subsequent analysis. We discovered that 22 miRNAs and 4 lncRNAs upstream of 11 hub gene were significantly associated with poor prognosis of HCV-related HCC, and used them to constructe a prognostic ceRNA network. Further experiments confirmed the ceRNA-regulatory relationship of BUB1-hsa-miR-193a-3p-MALAT1. Conclusion: This study provides novel insights into the lncRNA-miRNA-mRNA ceRNA network, and reveals potential lncRNA biomarkers in HCV related HCC.

Novel Gerota-edge-sling technique facilitates retroperitoneal robot-assisted partial nephrectomy: a comparative study.

BACKGROUND: Retroperitoneal robotic partial nephrectomy is markedly restricted by limited space and visual field. We introduced a novel Gerota-edge-sling (GES) technique with self-designed traction devices to overcome these defects by attaching Gerota fascia to abdominal wall, and comparatively evaluated its utilization with routine technique. METHODS: A retrospective analysis was performed for consecutive patients who underwent routine (control group) or GES assisted (GES group) retroperitoneal robotic partial nephrectomy for localized renal tumors in our hospital between March 2018 and June 2020. Clinical data of perioperative outcomes and complications were collected and compared. Comparison of outcomes between anterior versus posterior tumor subgroups was also conducted. Linear regression analysis was used to define the relationship between dissection time and perinephric fat status in each group. RESULTS: Totally 103 patients were included, 48 in control and 55 in GES group respectively. All the procedures were completed successfully without conversion or positive surgical margin. GES group had significantly decreased console time (91 ± 36 min vs. 117 ± 41 min, p < 0.01) and dissection time (67 ± 35 min vs. 93 ± 38 min, p < 0.01) than control, while ischemia time, blood loss, and nephrometry score comparable between them. No major postoperative complications occurred. Dissection time of GES group was notably shorter than that of control in both anterior/posterior subgroups. Only in control group, dissection time was positively associated with perinephric fat status. CONCLUSIONS: The GES technique acting as an adjunct to robotic arms with space-sparing feature, notably improves surgical exposure and facilitates dissection in retroperitoneal partial nephrectomy, while having great feasibility, efficacy and safety.

The Adhesive Perinephric Fat Score is Correlated with Outcomes of Retroperitoneal Laparoscopic Adrenalectomy for Benign Diseases.

BACKGROUND: Retroperitoneal laparoscopic adrenalectomy (RLA) possessing unique superiority with minimal abdominal interference is complicated by the status of periadrenal fat, including its quantity and texture. We hypothesized that an adherent perinephric fat predictor, the Mayo Adhesive Probability score (Mayo score), is associated with the perioperative outcomes of RLA. METHODS: This retrospective study included consecutive patients who underwent RLA for the diagnosis of benign adrenal tumors at our institution between 2017 and 2020. Medical records were reviewed to evaluate the association between Mayo scores obtained from preoperative computed tomography imaging and surgical outcomes as well as complications. Factors independently related to perioperative results were analyzed using multivariable regression models. RESULTS: In total, 186 RLA were included. According to their Mayo scores, the patients were divided as follows: 0 (n = 51, 27.4%), 1 (n = 34, 18.3%), 2 (n = 45, 24.2%), 3 (n = 29, 15.6%), 4 (n = 16, 8.6%) and 5 (n = 11, 5.9%). Longer operative time (92.0 ± 25.0 vs. 114.7 ± 30.6 vs. 137.4 ± 27.1 min, P < 0.001), higher estimated blood loss (42.2 ± 28.1 vs. 70.5 ± 44.9 vs. 132.6 ± 63.4 mL, P < 0.001) and greater decline of hemoglobin (0.7 ± 0.4 vs. 1.0 ± 0.4 vs. 1.3 ± 0.6 g/dL, P < 0.001) were significantly associated with elevated Mayo score risks. No difference in complication rates was found. The score was identified as a unique, independent risk factor for perioperative outcomes on multivariable analysis. CONCLUSIONS: The Mayo score is a vital outcome predictor of RLA. It may be utilized in the preoperative planning for patients undergoing RLA.

ß-ionone Inhibits Epithelial-Mesenchymal Transition (EMT) in Prostate Cancer Cells by Negatively Regulating the Wnt/ß-Catenin Pathway.

BACKGROUND: ß-ionone is a terminal cyclic analog of beta-carotenoids widely found in plants. In recent years, accumulating evidence has shown that ß-ionone exerts antitumor effects on various malignant tumors. However, limited studies have revealed the role of ß-ionone in regulating the epithelial-mesenchymal transition (EMT) of prostate cancer (PCa) cells. This study aimed to investigate the effect of ß-ionone on the EMT process of PCa, focusing on Wnt/ß-catenin signaling pathway. METHODS: After exposure to ß-ionone, cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the Brdu proliferation assay. The Transwell and wounding healing were used to investigate the migration and invasion abilities of PCa cells. Expression of proteins involved in the EMT process (E-cadherin, N-cadherin, vimentin) and proteins in the Wnt/ß-catenin pathway (ß-catenin, GSK3-ß, and p-GSK3-ß) were explored by western blotting. The effects of ß-ionone on ß-catenin degradation were explored by cycloheximide tracking assay and in vitro ubiquitination assay. Nude mouse xenograft model was served as the model system in vivo. RESULTS: The migration, invasion, and EMT process of PCa Human PC-3 prostate adenocarcinoma cells (PC3) and Human 22RV1 prostate adenocarcinoma cells (22RV1) cells were significantly inhibited after ß-ionone treatment. In addition, ß-ionone also inhibited the growth and EMT process of subcutaneous xenograft tumors in nude mice. The study also found that ß-catenin, which promotes EMT, was downregulated after ß-ionone treatment. Further mechanistic studies revealed that ß-ionone inhibited the Wnt/ß-catenin pathway by accelerating the ubiquitination and degradation of ß-catenin in PCa, thus inhibiting the downstream migration, invasion, and EMT processes. CONCLUSIONS: These findings demonstrate that ß-ionone may be a potential natural compound targeting the Wnt/ß-catenin pathway for the treatment of PCa.

Role of protein phosphatase 2A in kidney disease (Review).

Kidney disease affects millions of people worldwide and is a financial burden on the healthcare system. Protein phosphatase 2A (PP2A), which is involved in renal development and the function of ion-transport proteins, aquaporin-2 and podocytes, is likely to serve an important role in renal processes. PP2A is associated with the pathogenesis of a variety of different kidney diseases including podocyte injury, inflammation, tumors and chronic kidney disease. The current review aimed to discuss the structure and function of PP2A subunits in the context of kidney diseases. How dysregulation of PP2A in the kidneys causes podocyte death and the inactivation of PP2A in renal carcinoma tissues is discussed. Inhibition of PP2A activity prevents epithelial-mesenchymal transition and attenuates renal fibrosis, creating a favorable inflammatory microenvironment and promoting the initiation and progression of tumor pathogenesis. The current review also indicates that PP2A serves an important role in protection against renal inflammation. Understanding the detailed mechanisms of PP2A provides information that can be utilized in the design and application of novel therapeutics for the treatment and prevention of renal diseases.

Approximate Measurement Invariance of Willingness to Sacrifice for the Environment Across 30 Countries: The Importance of Prior Distributions and Their Visualization.

Nationwide opinions and international attitudes toward climate and environmental change are receiving increasing attention in both scientific and political communities. An often used way to measure these attitudes is by large-scale social surveys. However, the assumption for a valid country comparison, measurement invariance, is often not met, especially when a large number of countries are being compared. This makes a ranking of countries by the mean of a latent variable potentially unstable, and may lead to untrustworthy conclusions. Recently, more liberal approaches to assessing measurement invariance have been proposed, such as the alignment method in combination with Bayesian approximate measurement invariance. However, the effect of prior variances on the assessment procedure and substantive conclusions is often not well understood. In this article, we tested for measurement invariance of the latent variable "willingness to sacrifice for the environment" using Maximum Likelihood Multigroup Confirmatory Factor Analysis and Bayesian approximate measurement invariance, both with and without alignment optimization. For the Bayesian models, we used multiple priors to assess the impact on the rank order stability of countries. The results are visualized in such a way that the effect of different prior variances and models on group means and rankings becomes clear. We show that even when models appear to be a good fit to the data, there might still be an unwanted impact on the rank ordering of countries. From the results, we can conclude that people in Switzerland and South Korea are most motivated to sacrifice for the environment, while people in Latvia are less motivated to sacrifice for the environment.