Cisplatin induces acute kidney injury by downregulating miR-30e-5p that targets Galnt3 to activate the AMPK signaling pathway.

Cisplatin nephrotoxicity is an etiological factor for acute kidney injury (AKI). MicroRNA (miRNA) expression is dysregulated in cisplatin-induced AKI (cAKI) although the underlying mechanisms are unclear. A cAKI model was established by intraperitoneally injecting cisplatin, and key miRNAs were screened using high-throughput miRNA sequencing. The functions of key miRNAs were determined using the cell viability, live/dead, reactive oxygen species (ROS), and 5-ethynyl-2'-deoxyuridine (EdU) proliferation assays. Additionally, the macrophage membrane was wrapped around a metal-organic framework (MOF) loaded with miRNA agomir to develop a novel composite material, macrophage/MOF/miRNA agomir nanoparticles (MMA NPs). High-throughput miRNA sequencing revealed that miR-30e-5p is a key miRNA that is downregulated in cAKI. The results of in vitro experiments demonstrated that miR-30e-5p overexpression partially suppressed the cisplatin-induced or lipopolysaccharide (LPS)-induced downregulation of cell viability, proliferation, upregulation of ROS production, and cell death. Meanwhile, the results of in vivo and in vitro experiments demonstrated that MMA NPs alleviated cAKI by exerting anti-inflammatory effects. Mechanistically, cisplatin downregulates the expression of miR-30e-5p, and the downregulated miR-30e-5p can target Galnt3 to activate the adenosine 5'-monophosphate activated protein kinase (AMPK) signaling pathway, which promotes the progression of AKI. Our study found that miR-30e-5p is a key downregulated miRNA in cAKI. The downregulated miR-30e-5p promotes AKI progression by targeting Galnt3 to activate the AMPK signaling pathway. The newly developed MMA NPs were found to have protective effects on cAKI, suggesting a potential novel strategy for preventing cAKI.

Reactive X (where X = O, N, S, C, Cl, Br, and I) species nanomedicine.

Reactive oxygen, nitrogen, sulfur, carbonyl, chlorine, bromine, and iodine species (RXS, where X = O, N, S, C, Cl, Br, and I) have important roles in various normal physiological processes and act as essential regulators of cell metabolism; their inherent biological activities govern cell signaling, immune balance, and tissue homeostasis. However, an imbalance between RXS production and consumption will induce the occurrence and development of various diseases. Due to the considerable progress of nanomedicine, a variety of nanosystems that can regulate RXS has been rationally designed and engineered for restoring RXS balance to halt the pathological processes of different diseases. The invention of radical-regulating nanomaterials creates the possibility of intriguing projects for disease treatment and promotes advances in nanomedicine. In this comprehensive review, we summarize, discuss, and highlight very-recent advances in RXS-based nanomedicine for versatile disease treatments. This review particularly focuses on the types and pathological effects of these reactive species and explores the biological effects of RXS-based nanomaterials, accompanied by a discussion and the outlook of the challenges faced and future clinical translations of RXS nanomedicines.

GAD1 contributes to the progression and drug resistance in castration resistant prostate cancer.

BACKGROUND: Prostate cancer is currently the second most lethal malignancy in men worldwide due to metastasis and invasion in advanced stages. Studies have revealed that androgen deprivation therapy can induce stable remission in patients with advanced prostate cancer, although most patients will develop castration-resistant prostate cancer (CRPC) in 1-2 years. Docetaxel and enzalutamide improve survival in patients with CRPC, although only for a short time, eventually patients develop primary or secondary resistance, causing disease progression or biochemical relapse. METHODS: The gene expression profiles of docetaxel-sensitive or -resistant prostate cancer cell lines, namely GSE33455, GSE36135, GSE78201, GSE104935, and GSE143408, were sequentially analyzed for differentially expressed genes and progress-free interval significance. Subsequently, the overall survival significance and clinic-pathological features were analyzed by the R package. The implications of hub genes mutations, methylation in prostate cancer and the relationship with the tumor immune cell infiltration microenvironment were assessed with the help of cBioPortal, UALCAN and TISIDB web resources. Finally, effects of the hub genes on the progression and drug resistance in prostate cancer were explored using reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, cell phenotype, and drug sensitivity. RESULT: Glutamate decarboxylase 1 (GAD1) was tentatively identified by bioinformatic analysis as an hub gene for the development of drug resistance, including docetaxel and enzalutamide, in prostate cancer. Additionally, GAD1 expression, mutation and methylation were significantly correlated with the clinicopathological features and the tumor immune microenvironment. RT-PCR, immunohistochemistry, cell phenotype and drug sensitivity experiments further demonstrated that GAD1 promoted prostate cancer progression and decreased the therapeutic effect of docetaxel or enzalutamide. CONCLUSION: This research confirmed that GAD1 was a hub gene in the progression and development of drug resistance in prostate cancer. This helped to explain prostate cancer drug resistance and provides new immune-related therapeutic targets and biomarkers for it.

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.

A rare case report of renal ewing sarcoma/primitive neuroectodermal tumor with ACTH production.

BACKGROUND: Ewing sarcoma/primitive neuroectodermal tumor (PNET) of the renal is extremely rare. The common cause of ectopic ACTH syndrome is pulmonary neuroendocrine tumors, such as small cell carcinomas and carcinoid tumors. Here, we present an unusual case of ectopic ACTH syndrome and hypothyroidism caused by Ewing sarcoma/PNET of the right kidney. CASE PRESENTATION: A 19-year-old girl presented with a history of right lumbar pain and discomfort for 2 months, aggravated for 2 days. Abdominal contrast-enhanced computed tomography and computed tomography angiography showed an upper pole occupancy of the right kidney occupancy with subepithelial hemorrhage. Preoperative hormone levels including plasma total cortisol (PTC), adrenocorticotrophic hormone (ACTH) and thyroid hormone measurements were abnormal, indicating that the patient had Cushing syndrome and hypothyroidism. The patient underwent right radical nephrectomy. Histopathological analysis revealed a renal small round blue cell tumor (consistent with a primitive neuroectodermal tumor), with positive immunohistochemistry for CD99 and Ki67 (about 10%) and molecular pathology for EWSR1 gene fusions. PTC, ACTH and thyroid hormone returned to normal after surgery. CONCLUSIONS: We report a rare ectopic ACTH syndrome and hypothyroidism due to renal Ewing sarcoma/PNET. The clinical manifestation of renal Ewing sarcoma/PNET is non-specific and the diagnosis relies on pathological morphology, immunohistochemistry and fusion gene detection. At present, surgery combined with radiotherapy and chemotherapy is used in the treatment, but the prognosis is still not optimistic.

ciRS-7 is a prognostic biomarker and potential gene therapy target for renal cell carcinoma.

Circular RNAs are a new class of non-coding RNAs that have been shown to play critical roles in the development and progression of renal cell carcinoma (RCC). However, little is known about the functional mechanisms and therapeutic role of ciRS-7 in RCC. A series of in vitro and in vivo experiments were performed to investigate the functional mechanism and therapeutic role of ciRS-7, such as real-time quantitative PCR, CCK-8, wound healing, transwell, colony formation, Edu, tumor xenograft and lung metastasis in NSG mice. RNA pull-down, dual luciferase reporter, fluorescence in situ hybridization (FISH) and rescue assays were used to determine the relationship between ciRS-7, miR-139-3p and TAGLN. In addition, we constructed PBAE/si-ciRS-7 nanocomplexes with PBAE material to evaluate the therapeutic effect of the nanocomplexes on tumor in vivo. ciRS-7 was highly expressed in RCC tumor tissues and cell lines, and high ciRS-7 expression correlated with tumor size, high Fuhrman grade and poor survival. Depletion of ciRS-7 significantly inhibited RCC cell proliferation, invasion, tumor growth and metastasis in vivo, while overexpression of ciRS-7 had the opposite effect. Mechanistically, ciRS-7 acts as a "ceRNA" for miR-139-3p to prevent TAGLN degradation and promoting RCC progression and metastasis via the PI3K/AKT signaling pathway. In addition, miR-139-3p mimics or inhibitor could reverse the altered malignant tumor behavior caused by ciRS-7 overexpression or silencing. Furthermore, the PBAE/siciRS-7 nanocomplexes could significantly inhibit RCC tumor progression and metastasis in vivo. ciRS-7 acts as a tumor promoter by regulating the miR-139-3p/TAGLN axis and activating the PI3K/AKT signaling pathway to promote RCC progression and metastasis. Drug development of PBAE/si-ciRS-7 nanocomplexes targeting ciRS-7 may represent a promising gene therapeutic strategy for RCC.

Polyfluoroalkyl chemicals and the risk of kidney stones in US adults: A population-based study.

The potential nephrotoxicity of polyfluoroalkyl chemicals (PFCs) have received extensive attention. However, the relationship between PFCs and the risk of kidney stones remain unclear. This study aimed to examine the level of PFCs in the US population and its relationship with the risk of kidney stones. We investigated the serum levels of six PFCs in 8453 adult participants (≥20 years) from the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2016, including perfluorodecanoic acid (PFDE), perfluorohexane sulfonic acid (PFHS), 2-(N-methyl-perfluorooctane sulfonamido) acetate (MPAH), perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUA), and perfluorododecanoic acid (PFDO). Logistic regression model was used to evaluate the correlation between PFCs and kidney stones. Of the 8453 participants, 787 self-reported a history of kidney stones. After adjusting for gender, age, race, education, marital status, body mass index (BMI), hypertension, diabetes and estimated glomerular filtration rate (eGFR), we found that total PFCs and PFHS were positively correlated with the risk of kidney stones. Compared with the lowest tertile, the odds ratios with 95% confidence intervals (CI) with increasing tertiles were 1.30 (95% CI,1.08-1.59, p = 0.007) and 1.25 (95 CI%,1.00-1.52, p = 0.024) for total PFCs and 1.24 (95 CI%,1.03-1.51, p = 0.032), and 1.35 (95 CI,1.10-1.68, p = 0.005) for PFHS. Our study shows that total PFCs and PFHS were associated with an increased risk of kidney stones.

Infiltration of inflammatory factors induced penile damage in chronic prostatitis.

The present study aimed to investigate the mechanism of penile damages in experimental autoimmune prostatitis (EAP) rat models to reveal the potential pathological mechanism of the relationship between CP and penile damages. Sprague-Dawley (SD) rats were administered with different concentrations of prostate tissue homogenate supernatant (PTHS) by multipoint subcutaneous injection to establish EAP models. IHC staining was done to assess the expression of inflammatory cytokines in prostate tissues and the corpus cavernosum of penis. Masson and Tunel staining was conducted to observe the fibrosis and apoptosis in the corpus cavernosum. Finally, the functional changes of corpus cavernosum were assessed by WB and IHC staining. The results revealed that EAP rats with different prostatitis severity were successfully established by PTHS. The expression of IL-1ß, IL-6 and TNF-α in prostate tissues increased with the concentration of PTHS. The results of Masson and Tunel staining indicated fibrosis and apoptosis gradually aggravated in corpus cavernosum among different subgroups. The function of cavernosum impaired by prostatitis from WB and IHC results and positively with the severity. In conclusion, there existed the infiltration of inflammatory factors and impaired function in the corpus cavernosum of EAP rats' penis and positively correlated with the severity of prostatitis.

Survival nomogram for patients with bone metastatic renal cell carcinoma: A population-based study.

PURPOSE: Increased attention has been focused on the survival of renal cell carcinoma (RCC) patients with bone metastasis. This study proposed to establish and evaluate a nomogram for predicting the overall survival (OS) and cancer-specific survival (CSS) of RCC patients with bone metastasis. MATERIALS AND METHODS: RCC patients with bone metastasis between 2010 and 2015 were captured from the surveillance, epidemiology and end results (SEER) database. Univariate and multivariate cox regressions were performed to assess the effects of clinical variables on OS and CSS. The nomogram based on the Cox hazards regression model was developed. Concordance index (C-index) and calibration curve were performed to evaluate the accuracy of nomogram models, receiver operating characteristic (ROC) curves and decision curve analysis (DCA) were conducted to assess the predict performance. RESULTS: A total of 2.471 eligible patients were enrolled in this study. The patients were assigned to primary (n=1.672) and validation (n=799) cohorts randomly. The 1-, 2-, and 3-year OS and CSS nomogram models were constructed based on age at diagnosis, sex, marital status, pathological grade, T-stage, N-stage, brain/liver/lung metastasis, surgery, radiotherapy and chemotherapy. The c for OS and CSS prediction was 0.730 (95% confidence interval [CI]: 0.719-0.741) and 0.714 (95%CI:0.702-0.726). The calibration curves showed significant agreement between nomogram models and actual observations. ROC and DCA indicated nomograms had better predict performance. CONCLUSIONS: The nomograms for predicting prognosis provided an accurate prediction of OS and CSS in RCC patients with bone metastasis, and contributed clinicians to optimize individualized treatment plans.

Clinicopathological study of organ metastasis in endometrial cancer.

Aim: Our aim was to analyze the clinicopathological features of lung, liver, bone and brain metastasis in patients with endometrial cancer (EC). Patients & methods: We screened patients diagnosed with EC between 2010 and 2015 from the Surveillance, Epidemiology and End Results database. Results: Among 69,027 eligible EC patients, lung metastasis was the most common. Patients with lung or liver metastasis were at higher risk of bone and brain metastases than those without lung and liver metastasis. Brain metastasis has the lowest survival time (5.0 months) in single organ metastasis. Liver and brain metastasis have the highest death rate in two organ metastasis, and lung, liver and brain metastasis had the lowest survival time (1.0 month) in multi-sites metastasis. Conclusion: Lung metastasis was the most common in EC patients. Assessing distant organ metastasis may help clinicians to determine appropriate follow-up strategy for patients with EC.

Cystatin C in Evaluating Renal Function in Ureteral Calculi Hydronephrosis in Adults.

BACKGROUND: Serum cystatin C (CysC) is still becoming used as a marker of renal function but is far from being commonly used worldwide. The purpose of this study was to characterize the ureteral calculi patients with hydronephrosis-caused CysC changes in renal function. METHODS: To better reflect the changes of renal function, we constructed models of ureteral obstruction in rats to mimic the hydronephrosis caused by human ureteral calculi. Moreover, our study included 200 patients diagnosed with ureteral calculi in our hospital between June 2017 and 2018. We compared the estimated glomerular filtration rate using different equations based on CysC and/or serum creatinine (SCr). RESULTS: We found that the expression of CysC and SCr increased with the prolonged obstruction time by enzyme linked immunosorbent assay. Moreover, quantitative real-time polymerase chain reaction, Western blot and immunohistochemistry further demonstrated that the expression of CysC increases with the degree of hydronephrosis. Among 200 patients with ureteral calculi, 40 (20.0%) had no hydronephrosis, 110 (55.0%) had mild hydronephrosis, 32 (16.0%) had moderate hydronephrosis and 18 (9.0%) had severe hydronephrosis. As the degree of hydronephrosis increased, the expression of neutrophil percentage, CysC, blood urea nitrogen, SCr and serum uric acid also increased. Multivariate analyses demonstrated that only CysC was an independent risk factor for hydronephrosis (p = 0.003). In addition, CysC and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) CysC equation showed the highest veracity in renal function estimation of patients with hydronephrosis caused by ureteral calculus. CONCLUSION: For patients with hydronephrosis caused by ureteral calculi, CysC better reflects the changes in renal function, and the CKD-EPI CysC equation has the highest accuracy.

Knockdown of Glycolysis-Related LINC01070 Inhibits the Progression of Breast Cancer.

Accumulative evidence confirms that glycolysis and long non-coding RNAs (lncRNAs) are closely associated with tumor development. The aim of this study was to construct a novel prognostic model based on glycolysis-related lncRNAs (GRLs) in breast cancer patients. By performing Pearson correlation analysis and Lasso regression analysis on differentially expressed genes and lncRNAs associated with glycolysis in the Cancer Genome Atlas (TCGA) and Gene Set Enrichment Analysis (GSEA) datasets, we identified nine GRLs and constructed associated prognostic risk signature. Kaplan-Meier survival analysis and univariate and multivariate Cox analysis showed that patients in the low-risk group had a better prognosis. The receiver operator characteristics (ROC) curves showed that the area under the curve (AUC) of the prognostic risk signature predicting patients' overall survival at 1-, 3- and 5- years was 0.78, 0.71, and 0.71, respectively. Moreover, the validation curves also showed that the signature had better diagnostic efficacy and clinical predictive power. Furthermore, clone formation assay, EdU assay, and Transwell assay showed that knockdown of LINC01070 inhibited breast cancer progression. We developed a prognostic risk-associated GRLs signature that can accurately predict the breast cancer patient's prognostic status, and LINC01070 can be used as a potential biomarker for the prognosis of breast cancer patients.

Single-cell combined bioinformatics analysis: construction of immune cluster and risk prognostic model in kidney renal clear cells based on CD8+ T cell-associated genes.

BACKGROUND: Kidney cancer is an immunogenic solid tumor, characterized by high tumor burden and infiltration of CD8+ T cells. Although immunotherapy targeting the PD1/CTLA-4 axis has demonstrated excellent clinical efficacy, clinical outcomes in most patients are poor. METHODS: We used the RNA sequencing data from the GEO database for KIRC GSE121636 and normal kidney tissue GSE131685, and performed single-cell analysis for cluster identification, pathway enrichment, and CD8+ T cell-associated gene identification. Subsequently, the significance of different CD8+ T-cell associated gene subtypes was elucidated by consensus clustering, pathway analysis, mutated gene analysis, and KIRC immune microenvironment analysis in the TCGA-KIRC disease cohort. Single gene analysis identified LAG3 as the most critical CD8+ T-cell-associated gene and its function was verified by cell phenotype and immunohistochemistry in KIRC. RESULTS: In the present study, CD8+ T-cell associated genes in KIRC were screened, including GZMK, CD27, CCL4L2, FXYD2, LAG3, RGS1, CST7, DUSP4, CD8A, and TRBV20-1 and an immunological risk prognostic model was constructed (risk score = - 0.291858656434841*GZMK - 0.192758342489394*FXYD2 + 0.625023643446193*LAG3 + 0.161324477181591*RGS1 - 0.380169045328895*DUSP4 - 0.107221347575037*TRBV20-1). LAG3 was identified and proved as the most critical CD8+ T cell-associated gene in KIRC. CONCLUSION: We proposed and constructed an immunological risk prognostic model for CD8+ T cell-associated genes and identified LAG3 as a pivotal gene for KIRC progression and CD8+ T-cell infiltration. The model comprehensively explained the immune microenvironment and provided novel immune-related therapeutic targets and biomarkers in KIRC.

Lycopene intake and the risk of erectile dysfunction in US adults: NHANES 2001-2004.

BACKGROUND: Erectile dysfunction is a condition with a high incidence among adult men. Lycopene has been shown to lower blood glucose and reduce weight in diabetic patients because of its antioxidant and anti-inflammatory properties. However, the association between lycopene and the incidence of erectile dysfunction is unclear. OBJECTIVE: The aim of this study was to examine the dietary lycopene intake and its association with erectile dysfunction risk in the US population. MATERIALS AND METHODS: We investigated the lycopene intake of adult participants with complete information on clinical variables from the National Health and Nutrition Examination Survey between 2001 and 2004. Dose-response curve analysis was applied to explore the association between lycopene intake and erectile dysfunction. Logistic regression models were used to adjust for confounders. Different ethnicities, body mass index level, hypertension status, diabetes status, and smoking status were analyzed as subgroups. Propensity score matching was employed to eliminate the effects of potential confounders to confirm the reliability of the results. RESULTS: A total of 3265 participants with lycopene consumption data were included in our study, including 931 individuals with erectile dysfunction and 2334 without erectile dysfunction during National Health and Nutrition Examination Survey 2001-2004. We found more consumption of lycopene in the non-erectile dysfunction group than in the erectile dysfunction group. Dose-response curve analysis revealed a significant negative association between lycopene intake and erectile dysfunction prevalence. After adjusting for age, race, cigarette smoking, body mass index, annual family income, education, physical activity, hypertension, diabetes, depression, and testosterone level, we found that increased lycopene intake reduced the odds ratio of erectile dysfunction. Low lycopene intake was positively related to erectile dysfunction in almost all subgroups, especially in Mexican American, non-Hispanic white, body mass index <25, hypertension positive, diabetes mellitus negative, and smoke negative. Furthermore, the results were confirmed in the 1:1 matched group. CONCLUSION: Our national data suggest that lower dietary lycopene intake is positively associated with an increased risk of erectile dysfunction in US men.

Prognostic value of preoperative combined neutrophil, monocyte, and lymphocyte scores in patients with renal cell carcinoma undergoing laparoscopic nephrectomy: A retrospective study.

BACKGROUND: In a multi-institutional clinical study, we assessed the prognostic significance of a novel indicator preoperative peripheral blood immune (PBIS) scores that combined ratios of preoperative lymphocyte, monocyte, and neutrophil of renal cell carcinoma (RCC) patients undergoing laparoscopic nephrectomy. METHODS: Between January 2014 and December 2019, 438 patients with RCC were retrospectively analyzed in three centers. We used X-tile software to obtain the optimum cut-off values for neutrophils, monocytes, and lymphocytes to classify the patients. To assess the relationship between PBIS score and overall survival (OS), and cancer-specific survival (CSS) in patients with RCC by Kaplan-Meier survival curves and Cox regression analyses. In addition, predictive OS and CSS nomograms were constructed. The discriminative ability of nomogram and predictive performance accuracy were verified with consistency index (C-index), calibration curves, receiver operating curve (ROC) curves, decision curve analysis (DCA) curves, and time-dependent ROC curves. RESULTS: The optimum cutoff values for monocytes, lymphocytes, and neutrophils were 0.46, 1.01, and 4.50, respectively. We divided patients into four subgroups according to PBIS scores, which were significantly associated with M-stage (p = 0.008), T-stage (p < 0.001), N-stage (p = 0.006), and AJCC stage (p < 0.001). Multivariate Cox regression analysis revealed that RCC patients with lower PBIS scores showed a worse postoperative prognosis and served as an independent predictor of OS (p = 0.002) and CSS (p < 0.001). Ultimately, the nomograms based on PBIS scores demonstrated excellent predictive performance for OS (C-index: 0.770) and CSS (C-index: 0.828) through the analysis of calibration curves, ROC curves, DCA curves, and time-dependent ROC curves. CONCLUSION: PBIS score served as novel and effective predictor to accurately predict OS and CSS in patients with RCC receiving laparoscopic nephrectomy.

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.

Identification of MUC1-C as a Target for Suppressing Progression of Head and Neck Squamous Cell Carcinomas.

The MUC1-C protein is aberrantly expressed in adenocarcinomas of epithelial barrier tissues and contributes to their progression. Less is known about involvement of MUC1-C in the pathogenesis of squamous cell carcinomas (SCC). Here, we report that the MUC1 gene is upregulated in advanced head and neck SCCs (HNSCC). Studies of HNSCC cell lines demonstrate that the MUC1-C subunit regulates expression of (i) RIG-I and MDA5 pattern recognition receptors, (ii) STAT1 and IFN regulatory factors, and (iii) downstream IFN-stimulated genes. MUC1-C integrates chronic activation of the STAT1 inflammatory pathway with induction of the ∆Np63 and SOX2 genes that are aberrantly expressed in HNSCCs. In extending those dependencies, we demonstrate that MUC1-C is necessary for NOTCH3 expression, self-renewal capacity, and tumorigenicity. The findings that MUC1 associates with ∆Np63, SOX2 and NOTCH3 expression by single-cell RNA sequencing analysis further indicate that MUC1-C drives the HNSCC stem cell state and is a target for suppressing HNSCC progression. SIGNIFICANCE: This work reports a previously unrecognized role for MUC1-C in driving STAT1-mediated chronic inflammation with the progression of HNSCC and identifies MUC1-C as a druggable target for advanced HNSCC treatment.

Physical activity can influence the relationship between ethylene oxide and risk of kidney stones: A cross-sectional study from the NHANES 2013-2016.

Ethylene oxide (EO) is known to cause inflammatory damage, and suitable physical activity can reportedly affect the risk of kidney stones. In this study, we aimed to investigate the relationship between EO and kidney stones and whether physical activity can potentially influence the relationship between EO and kidney stones. Overall, 3,336 adult participants were included; of them, 330 (9.9%) had a self-reported history of kidney stones. Data were obtained from the National Health and Nutrition Examination Survey 2013-2016. Physical activity was calculated using metabolic equivalent, weekly frequency, and duration. Logistic regression and restricted cubic spline (RCS) curves were used to explore the association between physical activity, EO, and kidney stones. Dose-response curves from the RCS showed a nonlinear positive association between EO and kidney stones. Multivariate logistic regression analysis revealed an adjusted odds ratio (aOR) of 1.548 (95% confidence interval 1.123-2.135, P = 0.008) for the risk of kidney stones among participants in the highest quartile (Q4) group compared with those in the lowest quartile (Q1) group. Furthermore, compared to the Q1 group, the aOR for risk of kidney stones in the Q4 group was 1.326 in participants without physical activity, a decreased risk (aOR 1.239) in participants with low physical activity, and an increased risk (aOR 1.981) in those with high physical activity. This study suggests that EO is a risk factor for kidney stones and that suitable physical activity may moderate this relationship to some extent; however, excessive physical activity can exacerbate this relationship.

LMNTD2-AS1 regulates immune cell infiltration and promotes prostate cancer progression by targeting FUS to regulate NRF2 signal pathway.

Numerous studies have demonstrated that long non-coding RNAs (lncRNAs) play crucial roles in tumor progression. This study aimed to identify lncRNAs associated with overall survival (OS) and progression-free interval (PFI) in prostate cancer (PCa) patients and to elucidate the driving mechanisms and functions of these lncRNAs. We utilized the TCGA database to screen for lncRNAs linked with OS and PFI. KM survival analysis, ROC curve analysis, and Cox survival analysis were employed to assess the prognostic significance of lncRNAs in PCa patients. We conducted a loss-of-function assay to explore the role of lncRNAs in PCa. Correlation analysis was performed to study the relationship between lncRNAs and immune cell infiltration. Lasso regression analysis was performed to screen proteins which might interact with lncRNAs, while rescue experiments verified the integrity of the signaling pathway. LMNTD2-AS1 was found to be the only lncRNA in PCa patients associated with both OS and PFI with significantly elevated levels in PCa. Elevated LMNTD2-AS1 expression was significantly linked to advanced stage, grade, primary treatment outcomes, residual tumors, and Gleason scores in PCa patients. Moreover, multivariate Cox regression analysis revealed that high LMNTD2-AS1 expression independently predicted PFI in PCa patients. The AUC of LMNTD2-AS1 for predicting 3-year OS and 5-year OS in PCa patients was 0.877 and 0.807, respectively, while for 3-year PFI and 5-year PFI it was 0.751 and 0.727, respectively. Overexpression of LMNTD2-AS1 correlated with infiltration of neutrophils, macrophages, pDC, NK CD56bright cells, and other immune cells. Furthermore, FUS and NRF2 are both potential binding proteins and related signaling pathways downstream of LMNTD2-AS1. Functional experiments demonstrated that LMNTD2-AS1 knockdown significantly inhibited migration, invasion, and proliferation of PCa cells while overexpression of FUS was found to rescue the functional inhibition caused by LMNTD2-AS1 knockdown. LMNTD2-AS1 functions as an oncogene in PCa, influencing patient prognosis and the immune microenvironment; it may regulate immune cell infiltration and promote PCa progression by interacting with the NRF2 signaling pathway via FUS binding.