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.

Platelet-derived extracellular vesicles aggravate septic acute kidney injury via delivering ARF6.

Circulating plasma extracellular vesicles (EVs) mostly originate from platelets and may promote organ dysfunction in sepsis. However, the role of platelet-derived EVs in sepsis-induced acute kidney injury (AKI) remains poorly understood. The present study extracted EVs from the supernatant of human platelets treated with phosphate buffer saline (PBS) or lipopolysaccharide (LPS). Then, we subjected PBS-EVs or LPS-EVs to cecal ligation and puncture (CLP) mice in vivo or LPS-stimulated renal tubular epithelial cells (RTECs) in vitro. Our results indicated that LPS-EVs aggravate septic AKI via promoting apoptosis, inflammation and oxidative stress. Further, ADP-ribosylation factor 6 (ARF6) was identified as a differential protein between PBS-EVs and LPS-EVs by quantitative proteomics analysis. Mechanistically, ARF6 activated ERK/Smad3/p53 signaling to exacerbate sepsis-induced AKI. LPS upregulated ARF6 in RTECs was dependent on TLR4/MyD88 pathway. Both genetically and pharmacologically inhibition of ARF6 attenuated septic AKI. Moreover, platelets were activated by TLR4 and its downstream mediator IKK controlled platelet secretion during sepsis. Inhibition of platelet secretion alleviated septic AKI. Collectively, our study demonstrated that platelet-derived EVs may be a therapeutic target in septic AKI.

Association between grip strength and stress urinary incontinence of NHANES 2011-2014.

OBJECTIVES: To investigate the association between grip strength (GS) and relative grip strength (rGS) with the prevalence and severity risk of SUI. METHODS: Female patients were retrieved from the NHANES 2011-2014. GS was measured using a digital hand dynamometer, rGS was defined as grip strength divided by BMI. Samples were classified into four groups based on quartiles of GS and rGS distribution (Q1-Q4)。Logistic regression models were established to detect the relationship between GS or rGS and SUI. The potential bias of baseline variables between SUI and non-SUI groups was controlled by performing the propensity score matching (PSM). RESULTS: A total of 4263 samples were included, with 3085 (85%) people in non-SUI group and 1178 (27.6%) people in SUI group. GS and rGS levels of people without SUI were higher than that of SUI patients. Monthly SUI patients' GS and rGS levels were higher than weekly SUI patients' level. Logistic regression analysis showed that risks of prevalence and severity of SUI decreased with increasing levels of GS and rGS. rGS was found to have a stronger association with SUI than GS [prevalence: GS: Q4 vs. Q1: aOR = 0.633, 95%CI = 0.508-0.789, p < 0.001; rGS: Q4 vs. Q1: aOR = 0.365, 95%CI = 0.290-0.459, p < 0.001; severity: GS: Q4 vs. Q1: aOR = 0.727, 95%CI = 0.600-0.881, p = 0.001; rGS: Q4 vs. Q1: aOR = 0.371, 95%CI = 0.282-0.488, p < 0.001]. The results of PSM confirmed that GS and rGS were correlated with SUI. CONCLUSIONS: Lower levels of GS and rGS are associated with an increased prevalence and severity risk of SUI.

Fibrinogen Is Associated with Prognosis of Critically Ill Patients with Sepsis: A Study Based on Cox Regression and Propensity Score Matching.

Introduction: Sepsis is a common syndrome in critically ill patients. Fibrinogen was reported to be associated with the prognosis of sepsis patients. Materials and Methods: Data was acquired from Multiparameter Intelligent Monitoring in Intensive Care Database IV (MIMIC-IV) version 1.0. Cox proportional hazards regression was utilized to estimate the relationship between fibrinogen and inhospital mortality. The cumulative incidence of mortality by fibrinogen level was estimated through the Kaplan-Meier curve. Restricted cubic spline (RCS) was used to assess nonlinear relationship. Subgroup analysis was also conducted to evaluate the robustness of the association between fibrinogen and inhospital mortality. Propensity score matching (PSM) was applied to adjust for confounding factors. Results: A total of 3365 patients, including 2031 survivors and 1334 nonsurvivors, were enrolled in our study. The survivors had a significantly elevated levels of fibrinogen compared with the deceased. The elevated level of fibrinogen was significantly associated with a decrease in mortality in multivariate Cox regression before and after PSM (HR 0.66, P < 0.001 and HR 0.73, P < 0.001, respectively). RCS showed a nearly linear relationship. Subgroup analysis demonstrated the robustness of the association in most subpopulations. However, the association between decreased levels of fibrinogen and increased inhospital mortality was denied after PSM. Conclusion: The elevated level of fibrinogen hints at better overall survival in critically ill patients with sepsis. Decreased levels of fibrinogen may be of little value in identifying patients with a high risk of death.

AQP9 Is a Prognostic Factor for Kidney Cancer and a Promising Indicator for M2 TAM Polarization and CD8+ T-Cell Recruitment.

BACKGROUND: It is undeniable that the tumor microenvironment (TME) plays an indispensable role in the progression of kidney renal clear cell carcinoma (KIRC). However, the precise mechanism of activities in TME is still unclear. METHODS AND RESULTS: Using the CIBERSORT and ESTIMATE calculation methods, the scores of the two main fractions of tumor-infiltrating immune cells (TICs) from The Cancer Genome Atlas (TCGA) database of 537 KIRC patients were calculated. Subsequently, differentially expressed genes (DEGs) were drawn out by performing an overlap between Cox regression analysis and protein-protein interaction (PPI) network. Aquaporin 9 (AQP9) was identified as a latent predictor through the process. Following research revealed that AQP9 expression was positively correlated with the pathological characteristics (TNM stage) and negatively connected with survival time. Then, by performing gene set enrichment analysis (GSEA), it can be inferred that genes with high expression level of AQP9 were mainly enriched in immune-related activities, while low AQP9 group was associated with functions of cellular metabolism. Further studies have shown that regulatory T cells (Tregs), macrophages M2, macrophages M0, CD4+ T cells, and neutrophils were positively correlated with AQP9 expression. While the levels of mast cells, natural killer (NK) cells, and CD8+ T cells are negatively correlated with AQP9. The result of multiple immunohistochemistry (mIHC) suggests a negative relevance between AQP9 and CD8+ T cells and reveals a trend of consistent change on AQP9 and M2 macrophages. CONCLUSION: The expression level of AQP9 may be helpful in predicting the prognosis of patients with KIRC, especially to the TME state transition, the mechanism of which is possibly through lipid metabolism and P53, Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways that affect M2 polarization. AQP9 was associated with the expression levels of M2, tumor-associated macrophages (TAMs), and the recruitment of CD8+ T cells in tumor environment. The research result indicates that AQP9 may be an obstacle to maintain the immune activity of TME.

Combination of Albumin-Globulin Score and Sarcopenia to Predict Prognosis in Patients With Renal Cell Carcinoma Undergoing Laparoscopic Nephrectomy.

We conducted a multicenter clinical study to construct a novel index based on a combination of albumin-globulin score and sarcopenia (CAS) that can comprehensively reflect patients' nutritional and inflammatory status and assess the prognostic value of CAS in renal cell carcinoma (RCC) patients. Between 2014 and 2019, 443 patients from 3 centers who underwent nephrectomy were collected (343 in the training set and 100 in the test set). Kaplan-Meier curves were employed to analyze the impact of albumin-globulin ratio (AGR), albumin-globulin score (AGS), sarcopenia, and CAS on overall survival (OS) and cancer-specific survival (CSS) in RCC patients. Receiver operating characteristic (ROC) curves were used to assess the predictive ability of AGR, AGS, sarcopenia, and CAS on prognosis. High AGR, low AGS, and nonsarcopenia were associated with higher OS and CSS. According to CAS, the training set included 60 (17.5%) patients in grade 1, 176 (51.3%) patients in grade 2, and 107 (31.2%) patients in grade 3. Lower CAS was linked to longer OS and CSS. Multivariate Cox regression analysis revealed that CAS was an independent risk factor for OS (grade 1 vs. grade 3: aHR = 0.08; 95% CI: 0.01-0.58, p = 0.012; grade 2 vs. grade 3: aHR = 0.47; 95% CI: 0.25-0.88, p = 0.018) and CSS (grade 1 vs. grade 3: aHR = 0.12; 95% CI: 0.02-0.94, p = 0.043; grade 2 vs. grade 3: aHR = 0.31; 95% CI: 0.13-0.71, p = 0.006) in RCC patients undergoing nephrectomy. Additionally, CAS had higher accuracy in predicting OS (AUC = 0.687) and CSS (AUC = 0.710) than AGR, AGS, and sarcopenia. In addition, similar results were obtained in the test set. The novel index CAS developed in this study, which reflects patients' nutritional and inflammatory status, can better predict the prognosis of RCC patients.

Urethral Lift as a Safe and Effective Procedure for Prostatic Hyplasia Population: A Systematic Review and Meta-Analysis.

Background: Prostatic urethral lift (PUL) is a relatively new minimally invasive treatment procedure for benign prostatic hyperplasia (BPH). In order to analyze the sustainability of this new protocol, a systematic review and meta-analysis is performed based on the published articles. Methods: We performed a critical review according to the preferred reporting items for systematic review and meta-analysis (PRISMA) and MOOSE guidelines. A total of 818 published articles matched our search terms, and 11 studies met the inclusion criteria. Data of each follow-up time point (1, 3, 6, 12, and 24 months) were analyzed in terms of baseline characteristics and functional and sexual health outcomes. The merged means of each time point were calculated using R package meta and shown in the tendency plot. Results: A total of 1,443 patients who underwent PUL are available for the research. At 24 months, the changes of the three indicators are statistically significant (IPSS 9.40 points, p < 0.001; Qmax 3.39 ml/s, p < 0.001; QoL 1.99 points, p < 0.001) but were not as effective as TURP (from literature). The trend plot shows that, as time goes on, the effect of PUL tends to increase first and then weaken. Three items fitted a meaningful curve: IPSS (slope = -1.378 t = -12.395, p < 0.001), Qmax (slope = -1.382 t = -6.429, p < 0.001), and QoL (slope = -0.218, t = -10.058, p < 0.001). Fitted curves of SHIM and PVR are not statistically significant. The regression reveals that IPSS, Qmax, and QoL could be predicted after accepting PUL. Conclusion: PUL appears to be a safe and effective procedure in selected patients with BPH and can improve the symptoms of urinary tract obstruction. However, it is not as effective as TURP and shows no influence to the objective indicators like PVR.

Diagnostic Accuracy of Multi-Parametric Magnetic Resonance Imaging for Tumor Staging of Bladder Cancer: Meta-Analysis.

Purpose: Evaluate the diagnostic accuracy of multi-parametric magnetic resonance imaging (mp-MRI) for local staging of bladder cancer (BCa). Materials and Methods: The databases of PubMed, Web of Science, Wanfang, and CNKI were searched for related literatures about BCa diagnosed by mp-MRI from January 1, 2000 to April 12, 2019. The strict inclusion and exclusion criteria were set up to extract records. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 was used to evaluate quality of the candidate studies. The pooled sensitivity, specificity, positive likelihood ratio (+LR), negative likelihood ratio (-LR), and diagnostic odds ratio (DOR) were calculated to assess the diagnostic authenticity of mp-MRI. The summarized receiver operating characteristic (SROC) curve corresponding with the area under the curve (AUC) were analyzed to comprehensively evacuate the diagnostic value of mp-MRI. Results: A total of 140 studies were retrieved by computer-based searching. After quality control, 4 studies with 259 patients were enrolled for meta-analysis. The pooled results showed 0.84 of sensitivity [95% confidence interval (CI) = 0.79-0.89], 0.91 of specificity (95% CI = 0.87-0.93), 8.24 of +LR (95% CI = 4.87-13.92), 0.18 of -LR (95% CI = 0.10-0.31), 49.42 of DOR (95% CI = 19.07-128.09), and 0.946 of AUC. The Spearman correlation analysis found no threshold effect (p = 0.684). A significant heterogeneity existed among 4 included studies with sensitivity (I2 = 65.7%), specificity (I 2 = 60.0%) and diagnostic OR (I 2 = 67.5%). The Begg's test (p = 0.497) and the egger's test (p = 0.337) found no publication bias. Conclusion: mp-MRI acts a good diagnostic performance for bladder cancer. It is plausible that mpMRIs can be used as an important method for bladder cancer staging.