Background: Clear cell renal cell carcinoma (ccRCC) is closely associated with steroid hormones and their receptors affected by lipid metabolism. Recently, there has been growing interest in the carcinogenic role of NR3C1, the sole gene responsible for encoding glucocorticoid receptor. However, the specific role of NR3C1 in ccRCC remains unclear. The present study was thus developed to explore the underlying mechanism of NR3C1’s carcinogenic effects in ccRCC. Methods: Expression of NR3C1 was verified by various tumor databases and assessed using RT-qPCR and western blot. Stable transfected cell lines of ccRCC with NR3C1 knockdown were constructed, and a range of in vitro and in vivo experiments were performed to examine the effects of NR3C1 on ccRCC proliferation and migration. Transcriptomics and lipidomics sequencing were then conducted on ACHN cells, which were divided into control and sh-NR3C1 group. Finally, the sequencing results were validated using transmission electron microscopy, mitochondrial membrane potential assay, immunofluorescence co-localization, cell immunofluorescent staining, and Western blot. The rescue experiments were designed to investigate the relationship between endoplasmic reticulum stress (ER stress) and mitophagy in ccRCC cells after NR3C1 knockdown, as well as the regulation of their intrinsic signaling pathways. Results: The expression of NR3C1 in ccRCC cells and tissues was significantly elevated. The sh-NR3C1 group, which had lower levels of NR3C1, exhibited a lower proliferation and migration capacity of ccRCC than that of the control group (P < 0.05). Then, lipidomic and transcriptomic sequencing showed that lipid metabolism disorders, ER stress, and mitophagy genes were enriched in the sh-NR3C1 group. Finally, compared to the control group, ER stress and mitophagy were observed in the sh-NR3C1 group, while the expression of ATF6, CHOP, PINK1, and BNIP3 was also up-regulated (P < 0.05). Furthermore, Ceapin-A7, an inhibitor of ATF6, significantly down-regulated the expression of PINK1 and BNIP3 (P < 0.05), and significantly increased the proliferation and migration of ccRCC cells (P < 0.05). Conclusions: This study confirms that knockdown of NR3C1 activates ER stress and induces mitophagy through the ATF6-PINK1/BNIP3 pathway, resulting in reduced proliferation and migration of ccRCC. These findings indicate potential novel targets for clinical treatment of ccRCC. Graphical

Objective: Clinical treatment of erectile dysfunction (ED) caused by cavernous nerve (CN) injury during pelvic surgery is difficult. Low‐intensity pulsed ultrasound (LIPUS) can be a potential strategy for neurogenic ED (NED). However, whether Schwann cells (SCs) can respond to LIPUS stimulation signals is unclear. This study aims to elucidate the signal transmission between SCs paracrine exosome (Exo) and neurons stimulated by LIPUS, as well as to analyze the role and potential mechanisms of exosomes in CN repair after injury.Methods: The major pelvic ganglion (MPG) neurons and MPG/CN explants were stimulated with LIPUS of different energy intensities to explore the appropriate LIPUS energy intensity. The exosomes were isolated and purified from LIPUS‐stimulated SCs (LIPUS‐SCs‐Exo) and non‐stimulated SCs (SCs‐Exo). The effects of LIPUS‐SCs‐Exo on neurite outgrowth, erectile function, and cavernous penis histology were identified in bilateral cavernous nerve crush injury (BCNI)‐induced ED rats.Results: LIPUS‐SCs‐Exo group can enhance the axon elongation of MPG/CN and MPG neurons compared to SCs‐Exo group in vitro. Then, the LIPUS‐SCs‐Exo group showed a stronger ability to promote the injured CN regeneration and SCs proliferation compared to the SCs‐Exo group in vivo. Furthermore, the LIPUS‐SCs‐Exo group increased the Max intracavernous pressure (ICP)/mean arterial pressure (MAP), lumen to parenchyma and smooth muscle to collagen ratios compared to the SCs‐Exo group in vivo. Additionally, high‐throughput sequencing combined with bioinformatics analysis revealed the differential expression of 1689 miRNAs between the SCs‐Exo group and the LIPUS‐SCs‐Exo group. After LIPUS‐SCs‐Exo treatment, the phosphorylated levels of Phosphatidylinositol 3‐kinase (PI3K), protein kinase B (Akt) and forkhead box O (FoxO) in MPG neurons increased significantly compared to negative control (NC) and SCs‐Exo groups.Conclusion: Our study revealed that LIPUS stimulation could regulate the gene of MPG neurons by changing miRNAs derived from SCs‐Exo, then activating the PI3K‐Akt‐FoxO signal pathway to enhance nerve regeneration and restore erectile function. This study had important theoretical and practical significance for improving the NED treatment.

Testicular germ cell tumours (TGCTs) rank as the most common malignancy in men aged 20‐34 years, and seminomas are the most type of TGCTs. As a crucial anti‐tumour agent with explicit toxicity, cisplatin may render resistance through intertwined mechanisms, even in disease entities with high curative ratio, such as seminoma. Previously, we established cisplatin‐resistant seminoma TCam‐2 (TCam‐2/CDDP) cells and showed that epigenetic regulations, such as non‐coding RNA (ncRNA) interactions, might orchestrate cell fate decisions in the cisplatin treatment context in seminoma. N6‐methyladenosine (m6A) is the most prevalent internal modification in mRNA. In the present study, we assessed cisplatin resistance in seminoma from the perspective of m ⁶ A, another manner of epigenetic modification. The global m ⁶ A enrichment of TCam‐2 and TCam‐2/CDDP was depicted. Then, we elucidated whether transcription factor‐activating enhancer‐binding protein 2C (TFAP2C) was functionally m ⁶ A‐modified by methyltransferase‐like protein 3 (METTL3), which acted as an m ⁶ A ‘writer’, and insulin‐like growth factor 2 mRNA‐binding protein 1 (IGF2BP1), which acted as an m ⁶ A ‘reader’. Enhanced stability of TFAP2C mRNA promoted seminoma cell survival under cisplatin treatment burden probably through up‐regulation of DNA repair‐related genes. Hopefully, this study will help improve our understanding of the subtleties of the tumour cellular coping strategy in response to chemotherapy. Targeting factors that are involved in m ⁶ A methylation may be an effective strategy for circumventing cisplatin resistance in seminoma.

The simplified International Index of Erectile Function (IIEF-5) is a convenient, reliable and validated diagnostic tool for erectile dysfunction (ED). However, few studies focused on IIEF-5 in ED patients with different pathophysiological causes. ,We aim to compare the IIEF-5 score among ED patients with specific pathophysiologies in this study.

MicroRNA (miRNA)–gene interactions are well-recognized as involved in the progression of almost all cancer types including prostate cancer, which is one of the most common cancers in men. This study explored the significantly dysregulated genes and miRNAs and elucidated the potential miRNA–gene regulatory network in prostate cancer. Integrative analysis of prostate cancer and normal prostate transcriptomic data in The Cancer Genome Atlas dataset was conducted using both differential expression analysis and weighted correlation network analysis (WGCNA). Thirteen genes (RRM2, ORC6, CDC45, CDKN2A, E2F2, MYBL2, CCNB2, PLK1, FOXM1, CDC25C, PKMYT1, GTSE1, and CDC20) were potentially correlated with prostate cancer based on functional enrichment analyses. MiRNAs targeting these genes were predicted and eight miRNAs were intersections between those miRNAs and the hub miRNAs obtained from miRNA WGCNA analysis. Three genes (E2F2, RRM2, and PKMYT1) and four miRNAs (hsa-mir-17-5p, hsa-mir-20a-5p, hsa-mir-92a-3p, and hsa-mir-93-5p) were key factors according to the interaction network. RRM2 and PKMYT1 were significantly related to survival. These findings partially elucidated the dysregulation of gene expressions in prostate cancer. Efficient manipulations of the miRNA–gene interactions in prostate cancer may be exploited as promising therapeutics.

The role of TDRG1 in tumorigenesis and the progression of seminoma, as well as its role in regulating chemosensitivity of seminoma to cisplatin through the PI3K/Akt/mTOR signaling pathway, has been previously defined. However, the detailed mechanism underlying TDRG1 expression and concomitant chemoresistance conditions are unknown. Furthermore, it has been reported that non‐protein‐coding RNAs play an important role in a variety of vital processes including cellular chemosensitivity. However, the role of non‐protein‐coding RNAs in regulating the chemosensitivity of seminoma remains unknown. In this study, using microarray analysis, we found that long non‐coding RNA H19 was upregulated while miRNA‐106b‐5p was downregulated in an established cisplatin‐resistant TCam‐2 cell line. Moreover, H19 acts as a miRNA‐106b‐5p sponge and thus impairs the function of miRNA‐106b‐5p on its target gene, TDRG1. Based on these findings, we propose that H19 promotes the expression of TDRG1 by sequestering miRNA‐106b‐5p and uses this mechanism to facilitate cell survival in cisplatin‐based chemotherapeutic conditions. These findings elucidate the mechanisms, at least partially, applied to deregulate TDRG1 and cisplatin sensitivity, and may provide new therapeutic possibilities for chemoresistant seminoma.