Curcumin strengthens a spontaneous self-protective mechanism-SP1/PRDX6 pathway, against di-n-butyl phthalate-induced testicular ferroptosis damage.

As one of the common plasticizers, di-n-butyl phthalate (DBP) has been using in various daily consumer products worldwide. Since it is easily released from products and exists in the environment for a long time, it has a lasting impact on human health, especially male reproductive health. However, the detailed mechanism of testicular damage from DBP and the protection strategy are still not clear enough. In this study, we found that DBP could induce dose-dependent ferroptosis in testicular tissue. Mechanism dissection indicates that DBP can upregulate SP1 expression, which could directly transcriptionally upregulate PRDX6, a negative regulator of ferroptosis. Overexpression of PRDX6 or adding SP1 agonist curcumin could suppress the DBP-induced ferroptosis on testicular cells. In vivo, rats were given 500 mg/kg/day DBP orally for 3 weeks; elevated levels of ferroptosis were detected in testicular tissue. When the above-mentioned doses of DBP and curcumin at a dose of 300 mg/kg/day were administered intragastrically simultaneously, the testicular ferroptosis induced by DBP was alleviated. Immunohistochemistry and quantitative real-time PCR of testis tissue showed that the expression of PRDX6 was upregulated under the action of DBP and curcumin. These findings suggest a spontaneous self-protection mechanism of testicular tissue from DBP damage by upregulating SP1 and PRDX6. However, it is not strong enough to resist the DBP-induced ferroptosis. Curcumin can strengthen this self-protection mechanism and weaken the level of ferroptosis induced by DBP. This study may help us to develop a novel therapeutic option with curcumin to protect the testicular tissue from ferroptosis and function impairment by DBP.

Deciphering the Role of Melatonin-Related Signatures in Tumor Immunity and the Prognosis of Clear Cell Renal Cell Carcinoma.

Methods: Adopting multiomics data from TCGA and other public datasets, we analysed the expression, mutation, and prognostic evaluation in multiple cancers. ccRCC patients were categorized into two subgroups by an unsupervised cluster algorithm: melatonin-pattern cancer subtype 1 (MPCS1) and subtype 2 (MPCS2). We then explored the immune microenvironment, immune therapy response, and tumor metabolic pathways between the two subtypes. The clinical characteristics, genomic mutation landscape, and molecular inhibitor response were further investigated. Finally, a melatonin regulator-related prognostic model was constructed to predict patient prognosis in ccRCC. Results: We found that melatonin regulators were dysregulated depending on distinct cancer types, which were associated with genomic variation. The two subtypes indicated different clinical characteristics and biological processes in ccRCC. MPCS2, an aggressive subtype, led an advanced clinical stage and poorer survival of ccRCC patients. The activated oncogenic signaling pathway and metabolic signatures were responsible for cancer progression in the MPCS2 subtype. The MPCS2 subgroup suggested a higher tumor mutational burden and immune dysfunction state, resulting in a lower response to immunotherapy. The copy number variations of MPCS2 were significantly more frequent than those of MPCS1. In addition, the two subgroups exhibited distinct drug responsiveness, with MPCS2 being less responsive to multiple drugs. Finally, we established a subtype biomarker-based prognostic risk model that exhibited satisfactory performance in ccRCC patients. Conclusion: Melatonin regulator-related features could remodel functional pathways and the tumor immune microenvironment through genomic mutations and pathway regulation. Melatonin regulator-associated molecular subtypes enhance the understanding of the molecular characteristics of renal cancer and can guide clinical treatment. Activating the melatonergic system axis may improve the effect of immunotherapy for ccRCC.

[Efficacy of Urapidil in treating lower urinary tract symptoms in patients with benign prostatic hyperplasia: A systematic review and meta-analysis].

OBJECTIVE: To investigate the potential application of α-1 blocker (urapidil) in the treatment of lower urinary tract symptoms (LUTS) in male patients with benign prostatic hypertrophy (BPH), we conducted a comprehensive meta-analysis. METHODS: Our study involved identifying and collecting randomized controlled trials (RCT) and clinical observational studies from databases including PubMed、MEDLINE、Web of science、CNKI and Wanfang database. We performed meta-analysis using RevMan 5.2.0 software for both fixed effects model and random effects model. RESULTS: Our analysis included 3 short-term (within 1 month) observational studies and 1 RCT involving 142 patients. We found that urapidil significantly improved the International Prostate Symptom Score (IPSS, MD=－5.57, 95%CI: －7.98～－3.16，P<0.00001), nocturia（MD=－0.7, 95%CI: －1.16～－0.24，P=0.003）, residual urine rate（MD=－6.97；95%CI: －12.57～－1.37，P=0.01）, average flow rate（MD=2.04；95%CI: 0.52～3.56，P=0.008）, and maximum flow rate （MD=4.29；95%CI: 0.58～8.01，P=0.02）of patients. However, there was no significant difference in the residual urine volume（MD=－35.93；95%CI: －78.62～6.76，P=0.10）between pre-treatment and post-treatment groups. CONCLUSION: Urapidil is an effective medication for relieving LUTS in BPH patients. However, due to the limited quantity and quality of current RCT studies, high-quality and large-scale RCT studies are still needed to further confirm this conclusion.

KCNN4 may weaken anti-tumor immune response via raising Tregs and diminishing resting mast cells in clear cell renal cell carcinoma.

BACKGROUND: Studies over the past decade have shown that competitive endogenous RNA (ceRNA) plays an essential role in the tumorigenesis and progression of clear cell renal cell carcinoma (ccRCC). Meanwhile, immune checkpoint blocker is gradually moving towards the first-line treatment of ccRCC. Hence, it's urgent to develop a new prediction model for the efficiency of immunotherapy. At present, there is no study to reveal the effect of ceRNA network on the efficiency of immunotherapy for ccRCC. METHODS: To systematically analyze the effect of ceRNA hub genes in ccRCCon immune response, we constructed prognosis models based on ceRNAs and immune cells, respectively. We constructed ceRNA network using hypergeometric distribution test and correlation analysis with R script based on The Cancer Genome Atlas (TCGA) database. We then applied the Cibersort algorithm to simulate the infiltration overview of immune cells in kidney renal clear carcinoma (KIRC) samples. Prognosis-related immune cells were screened and a predictive model of these cells was constructed. Prognosis-related immune cells and ceRNA hub genes were performed with co-expression analysis. Finally, qRT-PCR and immunofluorescence assays were performed to validate the results. RESULTS: The construction of ceRNA related prognosis model contained 8 hub genes, including RELT, MYO9B, KCNN4, SIX1, OTOGL, MALAT1, hsa-miR-130b-3p, and hsa-miR-21-5p. The area under the receiver operating characteristic curve (AUC) was 0.77 at 5 years. For the construction of immune cells prognosis model, 3 immune cells (T cells regulatory, Macrophages, Mast cells resting) were adopted, and the AUC was 0.65 at 5 years. We then merged the two models by correlation analysis and co-expression analysis. Finally, we found that KCNN4 positively correlates with T cells regulatory (Tregs) and negatively correlates with mast cells resting significantly. Furthermore, higher expression of KCNN4 may lead to a higher potential for immune evasion and lower efficiency for immune checkpoint inhibitors (ICIs). CONCLUSIONS: Generally, this is the first study to assess the prognostic value of immune related ceRNA hub genes in ccRCC, and KCNN4 was finally demonstrated to be a key regulatory factor with strong correlation with Tregs and mast cells resting.

Clusterin suppresses invasion and metastasis of testicular seminoma by upregulating COL15a1.

Seminoma is the most common subtype of testicular germ cell tumor, with an increasing incidence worldwide. Clusterin (CLU) expression was found to be downregulated in testicular seminoma in our previous study. We now expanded the sample size, and further indicated that CLU expression correlates with tumor stage. Tcam-2 cell line was used to investigate the CLU function in testicular seminoma, and CLU was found to inhibit the proliferation and metastasis abilities. Besides, extracellular matrix protein COL15a1 was demonstrated as the downstream of CLU to affect the epithelial-mesenchymal transition (EMT) process via competitively binding to DDR1 with COL1A1 and inhibiting the phosphorylation of PYK2. MEF2A was found to interact with CLU and bind to the promoter of COL15a1 and so upregulate its expression. This is the first study using testicular xenografts in situ to simulate testicular seminoma metastatic and proliferative capacities. In conclusion, CLU acts as a tumor suppressor to inhibit the metastasis of testicular seminoma by interacting with MEF2A to upregulate COL15a1 and blocking the EMT process.

Identification of autophagy-related long non-coding RNA prognostic and immune signature for clear cell renal cell carcinoma.

BACKGROUND: Studies over the past decade have shown that long non-coding RNAs (lncRNAs) play an essential role in the tumorigenesis and progression of kidney renal clear cell carcinoma (KIRC). Meanwhile, autophagy has been demonstrated to regulate KIRC pathogenesis and targeting therapy resistance. However, the prognostic value of autophagy-related lncRNAs in KIRC patients has not been reported before. METHODS: In this study, we obtained transcriptome data of 611 KIRC cases from the TCGA database and 258 autophagy-related mRNAs from the HADb database to identify autophagy-related lncRNAs by co-expression network. A prognostic model was then established basing on these autophagy-related lncRNAs, dividing patients into high-risk and low-risk groups. Survival analysis, clinical variables dependent receiver operating characteristic (ROC) analyses, univariate/multivariate Cox analyses, and clinical correlation analysis were performed based on risk signature with R language. Gene set enrichment analysis (GSEA) was then performed to investigate the potential mechanism of the risk signature promoting KIRC progression with GSEA software. CIBERSORT algorithm was performed to assess the impact of these lncRNAs on the infiltration of immune cells. RESULTS: A total of 17 lncRNAs were screened out and all these lncRNAs were found significantly related to KIRC patients' overall survival in subsequent survival analyses. Besides, the overall survival time in the high-risk group was much poorer than in the low-risk group. The ROC analysis revealed that the prognostic value of risk signature was better than age, gender, grade, and N stage. Univariate/multivariate analyses suggested that the risk signature was an independent predictive factor for KIRC patients. Immune and autophagy related pathways were dramatically enriched in high-risk and low-risk groups, respectively, and lncRNAs related immune cells were identified by CIBERSORT. CONCLUSIONS: In summary, our identified 17 autophagy-related lncRNAs had prognostic value for KIRC patients which may function in immunomodulation.

TRIM37 orchestrates renal cell carcinoma progression via histone H2A ubiquitination-dependent manner.

BACKGROUND: Ubiquitylation modification is one of the multiple post-transcriptional process to regulate cellular physiology, including cell signaling, cycle regulation, DNA repair and transcriptional regulation. Members of TRIM family proteins could be defined as E3 ubiquitin ligases as they contain a RING-finger domain, and alterations of TRIM proteins are involved into a broad range of diverse disorders including cancer. TRIM37 is a novel discovered E3 ubiquitin ligase and acts as a oncoprotein in multiple human neoplasms, however its biological role in RCC still remains elusive. METHODS: RCC microarray chips and public datasets were screened to identify novel TRIMs member as TRIM37, which was dysregulated in RCC. Gain or loss of functional cancer cell models were constructed, and in vitro and in vivo assays were performed to elucidate its tumorigenic phenotypes. Interactive network analyses were utilized to define intrinsic mechanism. RESULTS: We identified TRIM37 was upregulated in RCC tumors, and its aberrant function predicted aggressive neoplastic phenotypes, poorer survival endings. TRIM37 promoted RCC cells EMT and malignant progression via TGF-ß1 signaling activation, as a consequence of directly mediated by ubiquitinating-H2A modifications. CONCLUSIONS: Our findings identified a previously unappreciated role of TRIM37 in RCC progression and prognostic prediction. Importantly, we declared a novel ubiquitination-dependent link between TRIM ubiquitin ligases and TGF-ß1 signaling in regulating cancerous malignancies.

Acinar with ductal and mucinous adenocarcinoma of prostate cancer complicated with lung metastasis: a case report and literature review.

Acinar adenocarcinoma, ductal adenocarcinoma and mucinous adenocarcinoma are the subtypes of prostate cancer (PCa). Most of the pathological types of PCa are acinar adenocarcinoma, while ductal adenocarcinoma and mucinous adenocarcinoma are uncommon. The case of acinar adenocarcinoma with ductal and mucinous adenocarcinoma has not been reported before. Herein, we report a treatment experience involving a 72-year-old man who presented similarly as most PCa patients, but the pathologic diagnosis was acinar adenocarcinoma with focal ductal and mucinous adenocarcinoma differentiating. Besides, this case is associated with lung metastasis, after radical prostatectomy (RP) and endocrine therapy the pulmonary nodule exerted a shrinking trend and the PSA level of this patient is still maintained at 0 ng/ mL till now. Through literature review, we found that patients who diagnosed as mixed pathological type of PCa had a lower survivor than pure PCa patients. Furthermore, there is no corresponding consensus or guideline for treating such multiple differentiated PCa patients. Surprisingly, this patient showed a high sensitivity to androgen deprivation therapy (ADT). Although the tumor presented aggressiveness, the followup results were satisfactory and we will continue to pay attention to his physical condition. We report this case to provide a treatment strategy for the patients with multi-differentiated PCa complicated with organ metastases.

Apolipoprotein C1 (APOC1): A Novel Diagnostic and Prognostic Biomarker for Clear Cell Renal Cell Carcinoma.

Background: Apolipoprotein C1 (APOC1) has been proved to play a critical role in gastric, breast, lung, and pancreatic cancer. However, the relationship between APOC1 and urinary tumors remains unclear. This study aimed to assess the diagnostic and prognostic value of APOC1 in urinary tumors. Methods: We performed a pan analysis of APOC1 mRNA expression in urinary cancer using the Gene Expression Profiling Interactive Analysis (GEPIA) database. To further investigate the prognostic value of APOC1 expression in urinary cancers, the Kaplan-Meier plotter database was used. Furthermore, we collected the tumor and adjacent normal samples of 32 ccRCC patients to perform qRT-PCR and western blotting assays. A total of 72 cases with ccRCC were analyzed using tissue microarrays (TMAs). Results: Our results based on Kaplan-Meier plotter database indicated that a high expression of APOC1 may lead to poor overall survival (OS, p = 0.0019) in patients with ccRCC. Furthermore, the cancer stages and tumor grade of ccRCC appeared to be strongly linked with APOC1 expression according to UALCAN database. Hence, we reached a preliminary conclusion that APOC1 may play a key role in the tumorigenesis and progression of ccRCC. Furthermore, the Kaplan-Meier survival curve analyses of 72 clinical patients indicated that high expression of APOC1 was associated with poor progression-free survival (PFS, p = 0.007) and OS (p = 0.022). In addition, univariate Cox regression analysis confirmed the significant relationship between APOC1 expression and survival (p = 0.038). The TMAs analysis in combination with the patients' clinicopathological features was also performed. The expression of APOC1 was found to be significantly correlated with the tumor size (p = 0.018) and histological grade (p = 0.016). Conclusions: In conclusion, the findings of our study suggest that APOC1 may serve as a novel diagnostic and prognostic biomarker for ccRCC. Further evidence on the mechanism of APOC1 promoting tumor progression may transform it to a new therapeutic target for the treatment of ccRCC.