Correlation between metabolic syndrome and periurethral prostatic fibrosis: results of a prospective study.

BACKGROUND: Prostatic fibrosis, characterized by the accumulation of myofibroblasts and collagen deposition, is closely associated with LUTS and may lead to mechanical obstruction of the urethra. Additionally, Metabolic Syndrome (MetS), characterized by central obesity, high blood sugar, lipid metabolism disorders, and hypertension, is increasingly recognized as a proinflammatory condition linked to prostate inflammation. METHODS: Clinical data from 108 subjects who underwent transurethral resection of the prostate or bipolar plasmakinetic enucleation of the prostate were prospectively collected between June 2021 and August 2022. Patients were divided in two groups according to whether or not they had a diagnosis of MetS. Specimens were stained with Masson trichrome and the periurethral prostatic fibrosis extent was evaluated using quantitative morphometry. RESULTS: Forty-three patients (39.8%) were diagnosed with MetS. Patients with MetS showed a significantly greater extent of prostatic fibrosis than the others (68.1 ± 17.1% vs. 42.5 ± 18.2%, P < 0.001), and there was a positive correlation between the number of positive MetS parameters and the extent of prostatic fibrosis (R2 = 0.4436, P < 0.001). Multivariate regression analysis revealed that central obesity (B = 2.941, 95% confidence interval, 1.700-3.283), elevated fasting glucose (B = 1.036, 95% confidence interval, 0.293-1.780), reduced HDL cholesterol (B = 0.910, 95% confidence interval, 0.183-1.636) and elevated triglycerides (B = 1.666, 95% confidence interval, 0.824-2.508) were positively correlated to prostatic fibrosis. Elevated blood pressure, however, was unrelated to prostatic fibrosis (B = 0.009, 95% confidence interval, -0.664-0.683). CONCLUSIONS: The present findings suggest that prostatic fibrosis is positively correlated with MetS and its components including central obesity, elevated fasting glucose, reduced high density lipoprotein cholesterol and elevated triglycerides.

The genetic associations of COVID-19 on genitourinary symptoms.

Background: Recently emerged reports indicated that patients with coronavirus disease 2019 (COVID-19) might experience novo genitourinary symptoms after discharge. Nevertheless, the causal associations and underlying mechanisms remain largely unclear. Methods: Genome-wide association study (GWAS) statistics for COVID-19 and 28 genitourinary symptoms with consistent definitions were collected from the COVID-19 Host Genetic Initiative, FinnGen, and UK Biobanks. Mendelian randomization (MR) analyses were applied to explore the causal effects of COVID-19 on genitourinary symptoms by selecting single-nucleotide polymorphisms as instrumental variables. Meta-analyses were conducted to evaluate the combined causal effect. Molecular pathways connecting COVID-19 and its associated disorders were evaluated by weighted gene co-expression network analysis (WGCNA) and enrichment analyses to extract insights into the potential mechanisms underlying the connection. Results: The MR and meta-analyses indicated that COVID-19 was causally associated with increased risk for calculus of the lower urinary tract (LUTC, OR: 1.2984 per doubling in odds of COVID-19, 95% CI: 1.0752-1.5680, p = 0.007) and sexual dysfunction (SD, OR: 1.0931, 95% CI: 1.0292-1.1610, p = 0.004). Intriguingly, COVID-19 might exert a slight causal protective effect on the progression of urinary tract infections (UTIs) and bladder cancer (BLCA). These results were robust to sensitivity analyses. Bioinformatic analyses indicated that the inflammatory-immune response module may mediate the links between COVID-19 and its associated disorders at the molecular level. Conclusions: In response to post-COVID-19 symptoms, we recommend that COVID-19 patients should strengthen the prevention of LUTC and the monitoring of sexual function. Meanwhile, the positive effects of COVID-19 on UTIs and BLCA should attach equal importance.

Connexin43 is associated with the progression of clear cell renal carcinoma and is regulated by tangeretin to sygergize with tyrosine kinase inhibitors.

BACKGROUND: The roles of Connexin43 (Cx43) in clear cell renal cell carcinoma (ccRCC) microenviroment remains to be poorly defined. METHODS: The expression profile, prognosis and immune analysis of Cx43 in various cancers, particularly in ccRCC were performed using TCGA database, and various biological function assays were applied to explore the physiological role of Cx43 and tangeretin in ccRCC. Western blot were applied to examine the protein expression and Kunming mice were used to evaluate preliminary safety or anti-tumor activity of tangeretin and sunitinib. RESULTS: Compared with the normal group, higher expression levels of Cx43 in ccRCC, and distinct associations between Cx43 expression and ccRCC prognosis or immune infiltration, were found. Notably, the expression of Cx43 was found to be highly correlated with that of receptor tyrosine kinases (RTKs), particularly with VEGFR1, VEGFR2 and VEGFR3. The expression of Cx43 and EGFR was also found to be higher in ccRCC than that in the para-cancerous specimens. Knocking down Cx43 expression decreased RCC cell viability, cell migration, p-EGFR, MMP-9 and survivin expression. Using 14 Chinese medicine monomers, tangeretin was screened and found to inhibit tumor cell viability and Cx43 expression. Tangeretin also enhanced the sensitivity of RCC cells to tyrosine kinase inhibitors (TKIs) sunitinib and sorafenib. However, the same concentration of tangeretin exerted a less prominent effect on normal renal cell viability. CONCLUSIONS: Cx43 is strongly associated with RTK expression and ccRCC progression, while tangeretin can inhibit RCC cell malignancy by inhibiting Cx43 expression and enhance the sensitivity of RCC cells to TKIs.

Distinct immune and inflammatory response patterns contribute to the identification of poor prognosis and advanced clinical characters in bladder cancer patients.

Due to the molecular heterogeneity, most bladder cancer (BLCA) patients show no pathological responses to immunotherapy and chemotherapy yet suffer from their toxicity. This study identified and validated three distinct and stable molecular clusters of BLCA in cross-platform databases based on personalized immune and inflammatory characteristics. H&E-stained histopathology images confirmed the distinct infiltration of immune and inflammatory cells among clusters. Cluster-A was characterized by a favorable prognosis and low immune and inflammatory infiltration but showed the highest abundance of prognosis-related favorable immune cell and inflammatory activity. Cluster-B featured the worst prognosis and high immune infiltration, but numerous unfavorable immune cells exist. Cluster-C had a favorable prognosis and the highest immune and inflammatory infiltration. Based on machine learning, a highly precise predictive model (immune and inflammatory responses signature, IIRS), including FN1, IL10, MYC, CD247, and TLR2, was developed and validated to identify the high IIRS-score group that had a poor prognosis and advanced clinical characteristics. Compared to other published models, IIRS showed the highest AUC in 5 years of overall survival (OS) and a favorable predictive value in predicting 1- and 3- year OS. Moreover, IIRS showed an excellent performance in predicting immunotherapy and chemotherapy's response. According to immunohistochemistry and qRT-PCR, IIRS genes were differentially expressed between tumor tissues with corresponding normal or adjacent tissues. Finally, immunohistochemical and H&E-stained analyses were performed on the bladder tissues of 13 BLCA patients to further demonstrate that the IIRS score is a valid substitute for IIR patterns and can contribute to identifying patients with poor clinical and histopathology characteristics. In conclusion, we established a novel IIRS depicting an IIR pattern that could independently predict OS and acts as a highly precise predictive biomarker for advanced clinical characters and the responses to immunotherapy and chemotherapy.

Allicin suppressed Escherichia coli-induced urinary tract infections by a novel MALT1/NF-κB pathway.

Escherichia coli (E. coli) strains cause the majority of urinary tract infections (UTIs) and are resistant to various antibiotics. Therefore, it is imperative to explore novel host-target therapies. As a famous food and condiment, garlic (Allium sativum L.) is widely used in medicine, but its exact key targets in UTIs remain elusive. To identify the major active ingredient of garlic and its molecular target against UTIs, a network pharmacology analysis was carried out, and allicin was revealed to be a key active component in garlic acting on UTIs. By molecular docking, allicin showed a good binding affinity to mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1). The possible regulatory mechanisms of allicin against UTIs were based on the modules of immune and inflammatory responses mainly through AKT/NF-κB signaling. Next, an E. coli-stimulated human uroepithelial cell (HUC) model was established to confirm the anti-infective effect of allicin. The results showed that allicin could significantly inhibit the upregulation of MALT1, the AKT/NF-κB pathway, and cytokines (IL-6 and IL-1ß). HUCs pretreated with the PI3K inhibitor or transfected with MALT-siRNA also partly suppressed the activation of the AKT/NF-κB pathway and cytokines. Furthermore, by establishing the PCA algorithm to evaluate the therapeutic score, allicin was proved to achieve the optimal therapeutic effects compared with the PI3K inhibitor and siRNA-MALT1. Moreover, in rats with an E. coli-induced UTI model, allicin significantly alleviated the infection and up-regulation of MALT1 expression in the bladders, a marked increase in the bacterial load of urine, and deviations in serum biochemical parameters. In conclusion, allicin exerts anti-infective effects in UTIs mainly via the MALT1/NF-κB axis or AKT/NF-κB pathway, which provides a theoretical basis for understanding the function of allicin against UTIs and facilitates its clinical application.

Citrus Flavone Tangeretin Inhibits CRPC Cell Proliferation by Regulating Cx26, AKT, and AR Signaling.

Prostate cancer (PCa) progression depends on the action of androgen receptors (AR). Therefore, preventing ligand-mediated activation of AR is the first-line treatment strategy for metastatic PCa. Androgen deprivation therapy (ADT) can inhibit ligand binding to AR and alleviate PCa progression initially. However, due to the adaptation of PCa and recovery of AR signaling, castration-resistant prostate cancer (CRPC) eventually develops. Exploring novel dietary compounds that can target AR signaling appears to be a viable alternative therapeutic option for CRPC. In the present study, compounds from the citrus fruits were focused upon, which contain various flavonoid ingredients. Key components contained within orange peel, which is frequently used in traditional Chinese medicine, and downstream targets were first analyzed using network pharmacology approach. Notably, it was found that tangeretin, an active ingredient from orange peel, can significantly inhibit CRPC cell (C4-2 and Du145 cells) proliferation and migration whilst also synergistically increasing the sensitivity of CRPC cells to anti-tumor drugs sorafenib or cisplatin. Tangeretin also significantly reduced AR and AKT expressions in C4-2 cells and signal transducer and activator of transcription 3 expression in the androgen-insensitive cell line Du145. In addition, tangeretin increased the expression of both connexin26 (Cx26) and gap junction function, which may mediate the bystander effects of cisplatin or sorafenib. Taken together, the present study revealed a novel molecular mechanism by which tangeretin may inhibit the proliferation of CRPC cells, by affecting the Cx26/AKT/AR pathway, to synergistically increase the sensitivity of CRPC cells to sorafenib and cisplatin.

A novel mouse model simulating transurethral laser vaporization prostatectomy.

Benign prostatic hyperplasia (BPH) is a common disease in elderly men, and transurethral laser prostatectomy (TULP) has been widely used in the clinic to remove bladder outlet obstruction caused by BPH. Previous animal models for wound repair after prostatectomy have many limitations, and there have been no previous reports of a mouse model of TULP. Therefore, this study aimed to establish a novel mouse model of TULP. Twelve healthy adult Kunming (KM) mice received transurethral laser vaporization prostatectomy with a 200-µm thulium laser. The mice were sacrificed, and wound specimens from the prostatic urethra and bladder neck were harvested at 1 day, 3 days, 5 days, and 7 days after surgery. Hematoxylin-eosin (HE) and immunohistochemistry were applied to confirm the establishment of the mouse TULP model. One day after the surgery, urothelium expressing uroplakin (UPK) was absent in the urethral wound site, and a large number of necrotic tissues were found in the wound site. There was no UPK-positive urothelium in the wound 3 days after surgery. At 5 days after surgery, monolayer urothelium expressing UPK was found in the wound site, indicating that the re-epithelization of the wound had been completed. On the 7th day after surgery, there were multiple layers of urothelium with UPK expression, indicating that the repair was completed. It is feasible to establish a mouse TULP model by using a microcystoscope system and a 200-µm thulium laser.

Escherichia coli Aggravates Calcium Oxalate Stone Formation via PPK1/Flagellin-Mediated Renal Oxidative Injury and Inflammation.

Escherichia coli (E. coli) is closely associated with the formation of kidney stones. However, the role of E. coli in CaOx stone formation is not well understood. We explored whether E. coli facilitate CaOx stone formation and its mechanism. Stone and urine cultures were reviewed from kidney stone formers. The ability of calcium oxalate monohydrate (COM) aggregation was detected to evaluate the influence of uropathogenic E. coli, then gel electrophoresis and nanoLC-MS/MS to detect the crystal-adhered protein. Flagellin (Flic) and polyphosphate kinase 1 (PPK1) were screened out following detection of their role on crystal aggregation, oxidative injury, and inflammation of HK-2 cell in vitro. By transurethral injection of wild-type, Ppk1 mutant and Flic mutant strains of E. coli and intraperitoneally injected with glyoxylate in C57BL/6J female mice to establish an animal model. We found that E. coli was the most common bacterial species in patients with CaOx stone. It could enhance CaOx crystal aggregation both in vitro and in vivo. Flagellin was identified as the key molecules regulated by PPK1, and both of them could facilitate the crystal aggregation and mediated HK-2 cell oxidative injury and activated the inflammation-related NF-κB/P38 signaling pathway. Wild-type strain of E. coli injection significantly increased CaOx deposition and enhanced oxidative injury and inflammation-related protein expression, and this effect could be reversed by Ppk1 or Flic mutation. In conclusion, E. coli promotes CaOx stone formation via enhancing oxidative injury and inflammation regulated by the PPK1/flagellin, which activated NF-κB/P38 pathways, providing new potential drug targets for the renal CaOx calculus precaution and treatment.

Extracellular matrix-related genes play an important role in the progression of NMIBC to MIBC: a bioinformatics analysis study.

Bladder cancer is the 11th most common cancer in the world. Bladder cancer can be roughly divided into muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC). The aim of the present study was to identify the key genes and pathways associated with the progression of NMIBC to MIBC and to further analyze its molecular mechanism and prognostic significance. We analyzed microarray data of NMIBC and MIBC gene expression datasets (GSE31684) listed in the Gene Expression Omnibus (GEO) database. After the dataset was analyzed using R software, differentially expressed genes (DEGs) of NMIBC and MIBC were identified. These DEGs were analyzed using Gene Ontology (GO) enrichment, KOBAS-Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and protein-protein interaction (PPI) analysis. The effect of these hub genes on the survival of bladder cancer patients was analyzed in The Cancer Genome Atlas (TCGA) database. A total of 389 DEGs were obtained, of which 270 were up-regulated and 119 down-regulated. GO and KEGG pathway enrichment analysis revealed that DEGs were mainly involved in the pathway of protein digestion and absorption, extracellular matrix (ECM) receiver interaction, phantom, toll-like receptor (TLR) signaling pathway, focal adhesion, NF-κB signaling pathway, PI3K/Akt signaling pathway, and other signaling pathways. Top five hub genes COL1A2, COL3A1, COL5A1, POSTN, and COL12A1 may be involved in the development of MIBC. These results may provide us with a further understanding of the occurrence and development of MIBC, as well as new targets for the diagnosis and treatment of MIBC in the future.