DRD4 alleviates acute kidney injury by suppressing ISG15/NOX4 axis-associated oxidative stress.

Acute kidney injury (AKI) is a life-threatening health condition associated with increasing morbidity and mortality. Despite extensive research on the mechanisms underlying AKI, effective clinical tools for prediction and treatment remain scarce. Oxidative stress and mitochondrial damage play a critical role in AKI and dopamine D4 receptor (DRD4) has been confirmed to be associated with oxidative stress. In this study, we hypothesized that DRD4 could attenuate AKI through its antioxidative and antiapoptotic effects. In vivo, DRD4 was remarkably decreased in the kidneys of mice subjected to ischemia/reperfusion injury (IRI) or cisplatin treatment. Notably, DRD4 significantly attenuated nephrotoxicity by suppressing oxidative stress and enhancing mitochondrial bioenergetics through the downregulation of reactive oxygen species (ROS) generation and NADPH oxidase 4 (NOX4) expression. In vitro, DRD4 demonstrated the ability to ameliorate oxidative stress-induced apoptosis in HK-2 cells subjected to hypoxia/reoxygenation- or cisplatin treatment. Transcriptome sequencing revealed that, mechanistically, DRD4 reduced the expression of its downstream target, interferon-stimulated gene 15 (ISG15), suppressing NOX4 ISGylation, enhancing the ubiquitination of NOX4, leading to its degradation, and ultimately counteracting oxidative stress-induced AKI. Altogether, these findings underscore the significance of DRD4 in AKI and elucidate DRD4 as a potential protectant against IRI or cisplatin-induced nephrotoxicity.

Development and validation of a prognostic nomogram for adult patients with renal sarcoma: A retrospective study based on the SEER database.

Background: Renal sarcoma (RS) is rarely seen in clinical practice. The purpose of this study was to develop a prognostic nomogram model, which could predict the probability of overall survival (OS) and cancer-specific survival (CSS) in adult patients with RS. Methods: Patients diagnosed with RS were recruited from the SEER database between 2004 and 2015, and randomized to two cohorts: the training cohort and the validation cohort. Uni- and multivariate Cox regression analyses in the training cohort were used to screen independent prognostic factors for OS and CSS. Prognostic nomograms for OS and CSS were created separately for adult RS patients based on independent risk factors. The area under the receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were used to validate the nomograms. Results: A total of 232 eligible patients were recruited, including 162 in the training cohort and 70 in the validation cohort. Sex, histological type, SEER stage, and surgery were independent prognostic factors for OS, while histological type, SEER stage, surgery, chemotherapy were independent prognostic factors for CSS. Based on the above independent prognostic factors, prognostic nomograms for OS and CSS were created respectively. In the training cohort, the AUCs of the nomograms for OS and CSS were 0.742 and 0.733, respectively. In the validation cohort, the AUCs of the nomograms for OS and CSS were 0.837 and 0.758, respectively. The calibration curves of the nomograms showed high consistencies between the predicted and actual survival rates. Finally, the DCA demonstrated that the nomograms in the wide high-risk threshold had a higher net benefit than the SEER stage. Conclusion: A prognostic nomogram for renal sarcoma was created and validated for reliability and usefulness in our study, which assisted urologists in accurately assessing the prognosis of adult RS patients.

Urine Exosomal AMACR Is a Novel Biomarker for Prostate Cancer Detection at Initial Biopsy.

Objectives: The aim of this study is to identify and validate urine exosomal AMACR (UE-A) as a novel biomarker to improve the detection of prostate cancer (PCa) and clinically significant PCa (Gleason score ≥ 7) at initial prostate biopsy. Methods: A total of 289 first-catch urine samples after the digital rectal exam (DRE) were collected from patients who underwent prostatic biopsy, and 17 patients were excluded due to incomplete clinical information. Urine exosomes were purified, and urinary exosomal AMACR (UE-A) was measured by enzyme-linked immunosorbent assay (ELISA). The diagnostic performance of UE-A was evaluated by receiver operating characteristic (ROC) analysis, decision curve analysis (DCA), and waterfall plots. Results: The expression of AMACR in PCa and csPCa was significantly higher than that in BPH and non-aggressive (p < 0.001). The UE-A presented good performance in distinguishing PCa from BPH or BPH plus non-significant PCa (nsPCa) from csPCa with an area under the ROC curve (AUC) of 0.832 and 0.78, respectively. The performance of UE-A was further validated in a multi-center cohort of patients with an AUC of 0.800 for detecting PCa and 0.749 for detecting csPCa. The clinical utility assessed by DCA showed that the benefit of patients using UE-A was superior to PSA, f/t PSA, and PSAD in both the training cohort and the validation cohort in terms of all threshold probabilities. Setting 95% sensitivity as the cutoff value, UE-A could avoid 27.57% of unnecessary biopsies, with only 4 (1.47%) csPCa patients missed. Conclusions: We demonstrated the great performance of UE-A for the early diagnosis of PCa and csPCa. UE-A could be a novel non-invasive diagnostic biomarker to improve the detection of PCa and csPCa.

[Hsa_circ_0005221 promotes prostate cancer progression through the miR-339-5p/STAT5a pathway].

OBJECTIVE: To investigate the molecular mechanism of hsa_circ_0005221 regulating the progression of PCa through the miR-339-5p/STAT5a pathway. METHODS: Localizations of hsa_circ_0005221 and miR-339-5p in cells were detected by nuclear-cytoplasmic isolation. MiRNA-339-5p was selected as the target miRNA bound to hsa_circ_0005221 by RNA pull-down assay. The binding site of the luciferase reporter gene was predicted by software and the binding capability of miR-339-5p validated by luciferase assay. The expression of hsa_circ_0005221 in the prostatic epithelial and PCa cells was determined by qPCR. The hsa_circ_0005221-overexpressed plasmid and siRNA were transfected into the PCa cells for measurement of their proliferation, invasion and migration abilities and the levels of epithelial-mesenchymal transformation (EMT) and apoptosis. After knockdown of hsa_circ_0005221 and transfection of miR-339-5p mimics and miR-339-5p inhibitor, the proliferation, invasion and migration abilities of the DU145 and LNCaP cells were detected, and so were the levels of the EMT signature protein, STAT5a and cell apoptosis. RESULTS: The expression of hsa_circ_0005221 was significantly higher in the PCa than in the prostatic epithelial cells. Nuclear-cytoplasmic isolation experiments showed that hsa_circ_0005221 and miR-339-5p were mainly located in the cytoplasm. The proliferation, invasion and migration abilities and EMT were decreased and the apoptosis increased in the DU145 and LNCaP cells with knockdown of hsa_circ_0005221, which was just the reverse in those with overexpressed hsa_circ_0005221. Among the top 5 miRNAs predicted by software, miR-339-5p, miR-17 and miR-520h were shown by pull-down assay to be bound to hsa_circ_0005221, with most obvious changes in miR-339-5p when hsa_circ_0005221 knocked down or overexpressed. Luciferase reporter gene assay showed the binding of hsa_circ_0005221 to miR-339-5p. Knockdown of hsa_circ_0005221 and transfection of miR-339-5p mimics into the DU145 and LNCaP cells significantly reduced the proliferation, invasion and migration abilities of the cells and the N-cad level, increased their apoptosis and E-cad level, and up-regulated the expression of STAT5a, while overexpression of hsa_circ_0005221 and transfection of miR-339-5p mimics induced just the opposite effects. CONCLUSIONS: Hsa_circ_0005221 enhances the progression of prostate cancer through the miR-339-5p/STAT5a pathway.

Polycyclic Aromatic Hydrocarbons and the Risk of Kidney Stones in US Adults: An Exposure-Response Analysis of NHANES 2007-2012.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) exposure may cause various diseases. However, the association between PAHs exposure and kidney stones remains unclear. The purpose of this study was to examine the relationship between PAHs and the risk of kidney stones in the US population. METHODS: The study included a total of 30,442 individuals (≥20 years) from the 2007-2012 National Health and Nutrition Examination Survey (NHANES). Nine urinary PAHs were included in this study. Logistic regression and dose-response curves were used to evaluate the association between PAHs and the risk of kidney stones. RESULTS: We selected 4385 participants. The dose-response curves showed a significant positive association between total PAHs, 2-hydroxynaphthalene, 1-hydroxyphenanthrene, 2-hydroxyphenanthrene, 9-hydroxyfluorene and the risk of kidney stones after adjusting for confounding factors. Compared with the low group, an increased risk of kidney stones was observed in the high group of total PAHs [OR (95% CI), 1.32 (1.06-1.64), P=0.013], 2-hydroxynaphthalene [OR (95% CI), 1.37 (1.10-1.71), P=0.005], 1-hydroxyphenanthrene [OR (95% CI), 1.24 (1.00-1.54), P=0.046] and 9-hydroxyfluorene [OR (95% CI), 1.36 (1.09-1.70), P=0.007]. CONCLUSION: High levels of PAHs were positively associated with the risk of kidney stones in the US population.

Association Between Preoperative Blood Glucose Level and Hospital Length of Stay in Patients With Kidney Stones Undergoing Percutaneous Nephrolithotomy.

AIM: To assess the effect of preoperative blood glucose (POBG) levels on the length of stay (LOS) in patients with kidney stones undergoing percutaneous nephrolithotomy (PCNL). METHODS: We conducted a retrospective study of patients who underwent PCNL at the Zhongda Hospital of Southeast University from 2013 to 2019. The relationship between POBG level and LOS was investigated by dose-response analysis curves of restricted cubic spline function. RESULTS: We included 310 patients and divided them into three groups (<5.04, 5.04 to <6.88, ≥6.88 mmol/L) according to the POBG levels. Patients with POBG levels ≥6.88 mmol/L (adjusted odds risk [aOR] 1.67; 95% CI 0.83-3.33) had a 67% higher risk of LOS > 2 weeks than patients with POBG levels <5.04 mmol/L. A positive dose-response analysis curve was observed between POBG and the adjusted risk of LOS >2 weeks. Similar results were observed in the subgroups analysis. CONCLUSION: We demonstrated that higher POBG levels were significantly associated with longer LOS in patients with kidney stones undergoing PCNL.