Spermidine protects against acute kidney injury by modulating macrophage NLRP3 inflammasome activation and mitochondrial respiration in an eIF5A hypusination-related pathway.

BACKGROUND: Acute kidney injury (AKI) is still a critical problem in clinical practice, with a heavy burden for national health system around the world. It is notable that sepsis is the predominant cause of AKI for patients in the intensive care unit and the mortality remains considerably high. The treatment for AKI relies on supportive therapies and almost no specific treatment is currently available. Spermidine is a naturally occurring polyamine with pleiotropic effects. However, the renoprotective effect of spermidine and the underlying mechanism remain elusive. METHODS: We employed mice sepsis-induced AKI model and explored the potential renoprotective effect of spermidine in vivo with different administration time and routes. Macrophage depleting was utilized to probe the role of macrophage. In vitro experiments were conducted to examine the effect of spermidine on macrophage cytokine secretion, NLRP3 inflammasome activation and mitochondrial respiration. RESULTS: We confirmed that spermidine improves AKI with different administration time and routes and that macrophages serves as an essential mediator in this protective effect. Meanwhile, spermidine downregulates NOD-like receptor protein 3 (NLRP3) inflammasome activation and IL-1 beta production in macrophages directly. Mechanically, spermidine enhances mitochondrial respiration capacity and maintains mitochondria function which contribute to the NLRP3 inhibition. Importantly, we showed that eukaryotic initiation factor 5A (eIF5A) hypusination plays an important role in regulating macrophage bioactivity. CONCLUSIONS: Spermidine administration practically protects against sepsis-induced AKI in mice and macrophages serve as an essential mediator in this protective effect. Our study identifies spermidine as a promising pharmacologic approach to prevent AKI.

High-mobility group box 1 protein antagonizes the immunosuppressive capacity and therapeutic effect of mesenchymal stem cells in acute kidney injury.

BACKGROUND: Kidney ischemia reperfusion injury (IRI) is a common cause of acute kidney injury and an unavoidable consequence of kidney transplantation and still lacks specific therapeutics. Recently, mesenchymal stem cell (MSC) has been emerging as a promising cell-based therapy for IRI in the context of transplantation. MSC negatively regulates the secretion of pro-inflammatory as well as the activation of immune cells during IRI through its unique immunosuppressive property. METHODS: We employed mice kidney IRI model and MSC cell line to monitor the IRI related checkpoints. siRNAs were utilized to knock down the potential key factors for mechanistic analysis. Statistical analysis was performed by using one-way ANOVA with Tukey's post hoc procedure by SPSS. RESULTS: The expression of high-mobility group box 1 protein (HMGB1) is increased in the acute phase as well as the recovery stage of IRI. Importantly, the HMGB1 upregulation is correlated with the injury severity. HMGB1 diminishes the MSC induced immunosuppressive capacity in the presence of pro-inflammatory cytokines in vitro. Toll like receptor 4 (TLR4)-mediated inducible nitric oxide synthase (iNOS) inhibition contributes to the negative effect of HMGB1 on MSCs. HMGB1-TLR4 signaling inhibition augments the therapeutic efficacy of MSCs in mice renal IRI model. CONCLUSIONS: These findings demonstrate that HMGB1 plays a crucial role in shaping the immunoregulatory property of MSCs within the microenvironments, providing novel insights into the crosstalk between MSCs and microenvironment components, suggesting HMGB1 signals as a promising target to improve MSC-based therapy.

Plectin protects podocytes from adriamycin-induced apoptosis and F-actin cytoskeletal disruption through the integrin α6ß4/FAK/p38 MAPK pathway.

Podocyte injury is an early pathological change characteristic of various glomerular diseases, and apoptosis and F-actin cytoskeletal disruption are typical features of podocyte injury. In this study, we found that adriamycin (ADR) treatment resulted in typical podocyte injury and repressed plectin expression. Restoring plectin expression protected against ADR-induced podocyte injury whereas siRNA-mediated plectin silencing produced similar effects as ADR-induced podocyte injury, suggesting that plectin plays a key role in preventing podocyte injury. Further analysis showed that plectin repression induced significant integrin α6ß4, focal adhesion kinase (FAK) and p38 MAPK phosphorylation. Mutating Y1494, a key tyrosine residue in the integrin ß4 subunit, blocked FAK and p38 phosphorylation, thereby alleviating podocyte injury. Inhibitor studies demonstrated that FAK Y397 phosphorylation promoted p38 activation, resulting in podocyte apoptosis and F-actin cytoskeletal disruption. In vivo studies showed that administration of ADR to rats resulted in significantly increased 24-hour urine protein levels along with decreased plectin expression and activated integrin α6ß4, FAK, and p38. Taken together, these findings indicated that plectin protects podocytes from ADR-induced apoptosis and F-actin cytoskeletal disruption by inhibiting integrin α6ß4/FAK/p38 pathway activation and that plectin may be a therapeutic target for podocyte injury-related glomerular diseases.

Enhanced recovery after surgery for radical cystectomy with ileal urinary diversion: a multi-institutional, randomized, controlled trial from the Chinese bladder cancer consortium.

PURPOSE: Enhanced recovery after surgery (ERAS) has played an important role in recovery management for radical cystectomy with ileal urinary diversion (RC-IUD). This study is to evaluate ERAS compared with the conventional recovery after surgery (CRAS) for RC-IUD. METHODS: From October 2014 and July 2016, bladder cancer patients scheduled for curative treatment from 25 centers of Chinese Bladder Cancer Consortium were randomly assigned to either ERAS or CRAS group. Primary endpoint was the 30-day complication rate. Secondary endpoints included recovery of fluid and regular diet, flatus, bowel movement, ambulation, and length of stay (LOS) postoperatively. Follow-up period was 30-day postoperatively. RESULTS: There were 144 ERAS and 145 CRAS patients. Postoperative complications occurred in 25.7 and 30.3% of the ERAS and CRAS patients with 55 complications in each group, respectively (p = 0.40). There was no significant difference between groups in major complications (p = 0.82), or type of complications (p = 0.99). The ERAS group had faster recovery of bowel movements (median 88 versus 100 h, p = 0.01), fluid diet tolerance (68 versus 96 h, p < 0.001), regular diet tolerance (125 versus 168 h, p = 0.004), and ambulation (64 versus 72 h, p = 0.047) than the CRAS group, but similar time to flatus and LOS. CONCLUSIONS: ERAS did not increase 30-day complications compared with CRAS after RC. ERAS may be better than CRAS in terms of bowel movement, tolerance of fluid and regular diet, and ambulation.

[Effects of diabetic hyperlipidemia on bladder function and its possible mechanisms in a male rabbit model].

OBJECTIVE: To evaluate the effects of chronic hyperlipidemia on bladder function and its possible mechanisms and examine the functional and histological changes of bladder in a diabetic hyperlipidemic model. METHODS: A total of 30 male New Zealand white rabbits (2.5 to 3.0 kg) were numbered sequentially and randomly divided into 2 groups (hyperlipidemic group and control group). Then urodynamic test and detrusor strip contraction study were performed to assess bladder function.Histological studies of bladder and internal iliac arteries were performed with hematoxylin and eosin staining. The ultrastructure of bladder detrusor tissue was examined by transmission electron microscopy. Also the bladder tissue M2, 3-muscarinic receptor protein levels were examined by immunohistochemistry. RESULTS: After 12 weeks, the urodynamic test of the test group showed significantly increased non-voiding contractions (10/14 vs 1/13, P < 0.05) and decreased compliance ((2.16 ± 0.17) vs (4.18 ± 0.21) ml/cm H2O, P < 0.01) versus the control group. The functional experiments showed that carbachol-induced contractions significantly decreased in hyperlipidemic rabbits than those in controls. As to the relaxant actions of selective muscarinic receptor M3 antagonist solifenacin, the bladder strips of hyperlipidemic rabbits were significantly more sensitive than those of the controls.Histological examination showed thickened intima of internal iliac arteries, urothelial disruption and mild fibrosis in the hyperlipidemic rabbits. Transmission electron microscopy of hyperlipidemic bladder muscle tissues showed swollen mitochondrial damage. As to the immunohistochemical results, compared with the control group, the hyperlipidemic group showed significantly increased M3 receptor expression both in bladder urothelium (146 ± 14 vs 108 ± 9, P < 0.01) and smooth muscle layer (131 ± 17 vs 116 ± 15, P < 0.05) . And the expression was more obvious in urothelium layer. CONCLUSIONS: Involuntary detrusor overactivity with decreased bladder compliance and decreased contractions of detrusor are present in hyperlipidemic rabbits. And chronic bladder ischemia and increased M3 receptor expression may contribute to bladder dysfunction.

The effect of the enhanced recovery after surgery program on radical cystectomy: a meta-analysis and systematic review.

Background: Bladder cancer is the ninth most common malignant tumor worldwide. As an effective evidence-based multidisciplinary protocol, the enhanced recovery after surgery (ERAS) program is practiced in many surgical disciplines. However, the function of ERAS after radical cystectomy remains controversial. This systematic review and meta-analysis aims to research the impact of ERAS on radical cystectomy. Methods: A systematic literature search on PubMed, EMBASE, SCOPUS, and the Cochrane Library databases was conducted in April 2022 to identify the studies that performed the ERAS program in radical cystectomy. Studies were selected, data extraction was performed independently by two reviewers, and quality was assessed using a random effects model to calculate the overall effect size. The odds ratio and standardized mean difference (SMD) with a 95% confidence interval (CI) served as the summary statistics for the meta-analysis. A sensitivity analysis was subsequently performed. Results: A total of 25 studies with 4,083 patients were enrolled. The meta-analysis showed that the complications (OR = 0.76; 95% CI: 0.63-0.90), transfusion rate (OR = 0.59; 95% CI: 0.39-0.90), readmission rate (OR = 0.79; 95% CI: 0.64-0.96), length of stay (SMD = -0.79; 95% CI: -1.41 to -0.17), and time to first flatus (SMD = -1.16; 95% CI: -1.58 to -0.74) were significantly reduced in the ERAS group. However, no significance was found in 90-day mortality and urine leakage. Conclusion: The ERAS program for radical cystectomy can effectively decrease the risk of overall complications, postoperative ileus, readmission rate, transfusion rate, length of stay, and time to first flatus in patients who underwent radical cystectomy with relative safety. Systematic Review Registration: https://inplasy.com/, identifier INPLASY202250075.

[Distribution characteristics of cancerous foci in the prostate among patients undergoing single positive core biopsy].

OBJECTIVE: To determine the distribution characteristics of cancerous foci in the prostate by retrospective analysis on the radical prostatectomy (RP) samples from patients with prostate cancer diagnosed by single positive core biopsy and treated by RP. METHODS: Thirty-seven patients with prostate cancer diagnosed by ultrasound-guided biopsy and single positive core biopsy underwent RP. We reviewed the pre- and post-operative data of the patients, compared the results of biopsies and pathological examination of the RP samples, and analyzed the factors that led to the underestimation of the overall prostate cancer risks. RESULTS: Post-operative pathological results showed multifocal distribution of the tumors in 70% of the patients (26/37) and obviously increased Gleason score (7-9) in 56% (21/37). The clinical stages of the tumors had been significantly underestimated preoperatively. The underestimation of their clinical stages might be due to a larger proportion of cancer tissues in a single positive core biopsy, and that of the overall cancer risks attributed to PSAD > 0.2 microg/L. Larger prostate volume (> or = 40 ml) increased the possibility of multifocal distribution. CONCLUSION: The risk of prostate cancer diagnosed by single positive core biopsy might be underestimated, and the cancerous foci were characterized by multifocal distribution in the prostate.

"Two-zone and Three-segment" Laparoscopic Radical Cystectomy vs Conventional Laparoscopic Radical Cystectomy for Male Patients With Bladder Urothelial Carcinoma: A Retrospective Analysis.

PURPOSE: The aim of this study was to introduce an advanced surgical technique for laparoscopic radical cystectomy (LRC), evaluate the perioperative outcome and compare it to that of conventional LRC (CLRC). MATERIALS AND METHODS: Between March 2018 and March 2020, sixty patients were divided into the "two-zone and three-segment" laparoscopic radical cystectomy (TTLRC) group or the CLRC group. Patient baseline characteristics, preoperative characteristics and postoperative complications were collected. RESULTS: The TTLRC technique was developed based on the pelvic anatomy of six formalin fixed male cadavers. None of the patient baseline characteristics, including ECOG-PS score, comorbidity, ASA score and Hb, were significantly different between the two groups (p>0.05). There were significant differences in the operating time and estimated blood loss (total time: 3±0.2 vs 3.8±0.4, p<0.001; time to cystectomy and lymph node dissection: 1.7±0.2 vs 2.2±0.3, p<0.001; estimated blood loss 182.1±18.8 vs 264.3±27.4, p<0.001). Although there were no differences in late complications, early complications were significantly different between the two groups (p = 0.033). No statistically significant differences were found between the two groups in other outcomes (p>0.05). CONCLUSION: The TTLRC technique achieves a clearer surgical field, has a shorter operating time and produces less blood loss than CLRC. It is safe and feasible for urologists to perform this improved LRC procedure.

miR-184-5p inhibits cell proliferation, invasion and predicts prognosis of clear cell renal cell carcinoma by targeting NUS1 dehydrodolichyl diphosphate synthase subunit: Results from large-scale comprehensive identification and validation.

Clear cell renal cell carcinoma (ccRCC) has become a common malignant cancer with increasing incidence rate and high recurrence risk in genitourinary oncology around the world. Recently, miRNAs were identified to affect pathogenesis, development, molecular functions, and prognosis of ccRCC. In this study, microRNA-184-5p (miR-184-5p) was identified from three independent ccRCC cohorts and was determined as a significantly distinct prognostic biomarker. Relative miR-184-5p expression was found in A-498 and 786-O ccRCC cells compared with HK-2 cells. After ccRCC cells were transfected with miR-184-5p mimics or inhibitor, biological abilities of miR-184-5p in tumor cell proliferation, cycle, apoptosis and invasion were determined. Additionally, we confirmed the direct relationship between miR-184-5p and NUS1 dehydrodolichyl diphosphate synthase subunit (NUS1) by using the Luciferase reporter and rescue assays. These results indicated that the expression level of miR-184-5p in human ccRCC cells and tissues was reduced, and the up-regulation of miR-184-5p regulated A-498 and 786-O cell proliferation, invasion and apoptosis by directly targeting NUS1. These findings may provide new theoretical targets for treatment strategies and drug development of ccRCC.

Identification of potential novel differentially-expressed genes and their role in invasion and migration in renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) remains one of the most common cancer types globally, and while it has been extensively studied, the molecular basis for its pathology remains incompletely understood. Herein, we profiled three previously published datasets (GSE66272, GSE100666, and GSE105261) in a single integrated analysis aimed at identifying disease-associated patterns of gene expression that may offer mechanistic insight into the drivers of this disease. We pooled expression data from 39 normal kidney samples and 39 kidney tumors, leading us to identify 310 differentially expressed genes (DEGs) that were linked to kidney cancer in all three analyzed datasets. Of these genes, 133 and 177 were up- and down-regulated, respectively, in cancer samples. We then incorporated these DEGs into a protein-protein interaction network with the STRING and Cytoscape tools, and we were able to identify signaling pathways significantly enriched for these DEGs. The relationship between DEG expression and ccRCC patient survival was further evaluated using a Kaplan-Meier approach, leading us to identify TIMP1 as an independent prognostic factor in ccRCC patients. When TIMP1 expression was disrupted in ccRCC cell lines, this impaired their migratory and invasive capabilities. In summary, we employed an integrative bioinformatics approach to identify ccRCC-related DEGs and associated signaling pathways. Together these findings offer novel insight into the mechanistic basis for ccRCC, potentially helping to identify novel therapeutic targets for the treatment of this deadly disease.

WITHDRAWN: Identification of abnormally expressed genes and their roles in invasion and migration of hepatocellular carcinoma.

This paper was originally published in Aging Advance Online Publications on February 2, 2020. In compliance with Aging's withdrawal policy, the paper was withdrawn in its entirety. It will not appear in Aging internal or any external indexes or archives.

Scrotal elephantiasis associated with follicular occlusion triad: A case report and literature review.

RATIONALE: Follicular occlusion triad (FOT) is an autosomal recessive inherited disease and no more than 3 variants of the triad have been reported. We give a report in which scrotal elephantiasis is a variant of FOT and further perform a literature review. PATIENT CONCERNS: A 41-year-old man came to us because of a large scrotal cyst and generalized skin lesions that had occurred over the past 10 years. The generalized skin lesions consisted of hidradenitis suppurativa on the perineum and back, acne conglobata in the armpit, and dissecting cellulitis of the scalp. He took antibiotics for a long time but achieved poor effect. Furthermore, he told his father and elder brother also manifested such skin lesions. DIAGNOSES: Magnetic resonance showed a mass in the left scrotum with clear boundaries. A routine blood test showed a high leukocyte level of 12 × 10/L and a hemoglobin content of 78 g/L. C-reactive-protein increased. Series of autoimmune antibody tests were negative. The postoperative pathologic findings showed that the mass was an epidermoid cyst, and hematoxylin and eosin staining showed hyperkeratosis of the skin as well as inflammatory and edematous changes. A diagnosis of a variant of FOT was made. INTERVENTIONS: We removed skin abscesses and lesioned the inner part with hydrogen peroxide. Then we performed an excision of the scrotal lesion. OUTCOME: The patient recovered well and had no evidence of recurrence at a 16-month follow-up. LESSONS: We reported a case in which scrotal elephantiasis was a variant of FOT and surgical intervention played an important role in secondary urologic diseases.

Expression of mir-143 in serum of bladder cancer patients and its correlation with clinical features and prognosis.

PURPOSE: To explore the expression of mir-143 in the serum of bladder cancer patients and its correlation with clinical pathological features and prognosis. METHODS: A retrospective study was performed on 68 patients (observation group) diagnosed with bladder cancer and treated in the Qilu Hospital of Shandong University from June 2013 to January 2014 and another 40 healthy individuals (control group) in the physical examination center at the same period. Real-time PCR (RT-PCR) was used to detect the expression levels of mir-143 in the serum of bladder cancer patients and healthy subjects. The expression of mir-143 in the serum of bladder cancer patients and its correlation with clinical pathological indicators and prognosis were explored. RESULTS: The expression level of mir-143 in the serum of bladder cancer patients was significantly lower than that of healthy people (p<0.05). There was no statistically significant difference in age and sex (p>0.05). There was a correlation between the expression level of mir-143 and differentiation grade, lymph node metastasis, distant metastasis and clinical stage (p<0.05). The median expression level of mir-143 in the serum of bladder cancer patients was 0.652. Thirty four patients with lower expression than the median of mir-143 were in the low expression group, and 34 patients with higher expression than the median of mir-143 were in the high expression group. The mean survival time of bladder cancer patients with the low expression of mir-143 was 37.32±1.26 months, significantly lower than that with the high expression of mir-143 (46.17±1.54;p<0.05). CONCLUSION: mir-143 is lowly expressed in the serum of bladder cancer patients. Its expression level is correlated with clinical stage, lymph node metastasis, distant metastasis and prognosis.

Prognostic scores based on the preoperative plasma fibrinogen and serum albumin level as a prognostic factor in patients with upper urinary tract urothelial carcinoma.

This study is to clarify the prognostic value of preoperative plasma fibrinogen and serum albumin level, as known as FA score, in a cohort of Chinese patients with upper urinary tract urothelial carcinoma (UTUC). We retrospectively evaluated clinicopathological data on 169 patients who underwent surgery between 2006 and 2013. The FA score was calculated based on cutoff values of 3.53g/L for fibrinogen and 43.56 g/L for albumin. Overall survival and cancer specific survival was assessed using the Kaplan-Meier method and the equivalences of the curves were tested by log-rank tests. The Cox proportional hazards regression model was applied in univariate and multivariate analyses. In univariate analysis, tumor size, tumor grade, pathological T stage and FA score were significantly associated with overall survival and cancer specific survival, and multivariate Cox proportional hazards regression analysis identified FA score (score 1: HR=3.486, 95%CI 1.358-8.948, p=0.009; HR=3.485, 95%CI 1.363-8.913, p=0.009, respectively; score 2: HR=5.509, 95%CI 2.144-14.158, p<0.001; HR=5.521, 95%CI 2.074-14.697, p=0.001, respectively) was an independent predictor for overall survival and cancer specific survival. The evaluation of preoperative FA score can be regarded as an independent prognostic factor for predicting overall survival and cancer specific survival in UTUC. The fibrinogen and albumin levels are low cost and easy accessibility in clinical practice.

Pelvic Floor Reconstruction After Radical Prostatectomy: A Systematic Review and Meta-analysis of Different Surgical Techniques.

Radical prostatectomy (RP) is the gold standard for the treatment of localized PCa. A meta-analysis was conducted to evaluate the effect of different techniques of pelvic floor reconstruction on urinary continence. A comprehensive search was made for trials that evaluated the efficacy of pelvic floor reconstruction. Relevant databases included PubMed, Embase, Cochrane, Ovid, Web of Science databases and relevant trials from the references. Random-effects model was used to estimate risk ratios (RRs) statistics. Pooled results of patients treated with posterior reconstruction (PR) demonstrated complete urinary continence improved at 1-4, 28-42, 90, 180 and 360 days following catheter removal. Anterior suspension (AS) was associated with improvement only at 28-42 days. The anterior reconstruction (AR) + PR was associated with urinary continence at 1-4, 90 and 180 days. AS + PR was not associated with any benefit. And PR improved social urinary continence at 7-14 and 28-42 days. No benefit was associated with AS. AR + PR had better outcomes at 90 and 180 days. AS + PR was significant improved at 28-42 and 90 days. Patients who underwent RP and PR had the least urinary incontinence. No significant benefit was observed after AS. AR + PR and AS + PR had little benefit in the post-operative period.