Critical roles of lncRNA-mediated autophagy in urologic malignancies.

Urologic oncology is a significant public health concern on a global scale. Recent research indicates that long chain non-coding RNAs (lncRNAs) and autophagy play crucial roles in various cancers, including urologic malignancies. This article provides a summary of the latest research findings, suggesting that lncRNA-mediated autophagy could either suppress or promote tumors in prostate, kidney, and bladder cancers. The intricate network involving different lncRNAs, target genes, and mediated signaling pathways plays a crucial role in urological malignancies by modulating the autophagic process. Dysregulated expression of lncRNAs can disrupt autophagy, leading to tumorigenesis, progression, and enhanced resistance to therapy. Consequently, targeting particular lncRNAs that control autophagy could serve as a dependable diagnostic tool and a promising prognostic biomarker in urologic oncology, while also holding potential as an effective therapeutic approach.

Knockout of phosphatidylethanolamine binding protein4 (PEBP4) promotes chronic non-bacterial prostatitis by mediating the activation of NF-κB signaling.

BACKGROUND: The etiology of chronic prostatitis remains unclear; consequently, this disease is associated with recurrence and ineffective clinical therapy. Therefore, there is an urgent need to investigate the underlying pathogenesis of chronic prostatitis in order to develop more efficacious treatments. OBJECTIVE: The previous study found that knocking out of PEBP4 leads to chronic prostatitis in the male mice. This research aimed to identify the role of PEBP4 in prostatitis, determine the molecular pathogenic mechanisms associated with chronic prostatitis, and provide guidelines for the development of new treatment strategies for chronic prostatitis. MATERIALS AND METHODS: A PEBP4 exon knockout strain (PEBP4-/-) was established in C57BL/6 mice via the Cre-loxP system. Hematoxylin-eosin (H&E) staining was used to investigate histological changes. RNA-sequencing was used to investigate the gene expression signature of the prostate and the levels of inflammatory cytokines were determined by real-time polymerase chain reaction (RT-PCR). The expression of PEBP4 protein in prostate tissue was determined by immunohistochemistry in specimens from patients with BPH and BPH combined with chronic prostatitis. Finally, we used a CRISPR-Cas9 plasmid to knockout PEBP4 in RWPE-1 cells; western blotting was subsequently used to measure the level of activation in the NF-κB signaling pathway after activating with TNF-α. RESULTS: Hemorrhage and inflammatory cell infiltration were incidentally observed in the seminal vesicles and prostate glands of PEBP4-/- mice after being fed with a normal diet for 1 year. In addition, we found significantly lower (p < 0.001) expression levels of PEBP4 protein in prostate tissues from patients with benign prostate hyperplasia (BPH) and chronic and non-bacterial prostatitis (CNP) when compared to those with BPH only. The reduced expression of PEBP4 led to a higher risk of prostatitis recurrence in patients after 2 years of follow-up. Increased levels of NF-κB and IκB phosphorylation were observed in PEBP4-knockout RWPE-1 cells and prostate glands from PEBP4-/- mice. CONCLUSION: The knockout of PEBP4 in experimental mice led to chronic prostatitis and the reduced expression of PEBP4 in patients with higher risk of chronic and non-bacterial prostatitis suggested that PEBP4 might act as a protective factor against chronic prostatitis. The knockout of PEBP4 in RWPE-1 cells led to the increased activation of NF-κB and IκB, thus indicating that inhibition of PEBP4 faciliated the NF-κB signaling cascade. Our findings provide a new etiology and therapeutic target for chronic prostatitis.

Crosstalk between m6A modification and autophagy in cancer.

Autophagy is a cellular self-degradation process that plays a crucial role in maintaining metabolic functions in cells and organisms. Dysfunctional autophagy has been linked to various diseases, including cancer. In cancer, dysregulated autophagy is closely associated with the development of cancer and drug resistance, and it can have both oncogenic and oncostatic effects. Research evidence supports the connection between m6A modification and human diseases, particularly cancer. Abnormalities in m6A modification are involved in the initiation and progression of cancer by regulating the expression of oncogenes and oncostatic genes. There is an interaction between m6A modification and autophagy, both of which play significant roles in cancer. However, the molecular mechanisms underlying this relationship are still unclear. m6A modification can either directly inhibit autophagy or promote its initiation, but the complex relationship between m6A modification, autophagy, and cancer remains poorly understood. Therefore, this paper aims to review the dual role of m6A and autophagy in cancer, explore the impact of m6A modification on autophagy regulation, and discuss the crucial role of the m6A modification-autophagy axis in cancer progression and treatment resistance.

The efficacy and safety of Hyperthermia intravesical chemotherapy in the treatment non-muscle invasive bladder cancer:A meta analysis.

Background：The current treatment of non-muscle-invasive bladder cancer is suboptimal. However, in recent years, hyperthermia intravesical chemotherapy has emerged as a more effective alternative to conventional bladder perfusion. This novel treatment approach appears to have a similar therapeutic effect as BCG perfusion. Objective: This study aims to evaluate the safety and effectiveness of hyperthermia intravesical chemotherapy compared to conventional bladder perfusion chemotherapy for non-muscle-invasive bladder cancer. Additionally, it aims to evaluate the safety and effectiveness of hyperthermia intravesical chemotherapy in comparison to BCG perfusion therapy for non-muscle-invasive bladder cancer. Methods：We conducted a comprehensive search of PubMed, Embase, Cochrane Library, and Web of Science databases to gather relevant studies on hyperthermia intravesical chemotherapy for non-muscle-invasive bladder cancer. The analysis of the collected data was carried out using RevMan 5.3 software. Results：A total of 8 randomized controlled trials (RCTs) were included in this meta-analysis, involving 1203 patients. Among them, 629 cases received hyperthermia intravesical chemotherapy (HIVEC), 419 cases received conventional bladder perfusion chemotherapy with mitomycin C (MMC), and 155 cases received Bacillus Calmette-Guérin (BCG). The combined analysis revealed that the recurrence rate of bladder hyperthermic perfusion was significantly lower than that of conventional perfusion chemotherapy (RR=0.65, 95%CI 0.52-0.82, P=0.0003). However, there was no significant difference in recurrence rate between hyperthermia intravesical chemotherapy and BCG perfusion (RR=0.78, 95%CI 0.56-1.09, P=0.14). Furthermore, no significant difference was found in the progression rate between the hyperthermia intravesical chemotherapy group and either the conventional bladder chemotherapy group (RR=1.08, 95%CI 0.52-2.26, P=0.83) and the BCG perfusion group (RR=0.48, 95%CI 0.19-1.25, P=0.13). However, Compared with the conventional bladder perfusion chemotherapy group, there was no significant statistical difference in adverse events between the bladder hyperthermia chemotherapy group and the conventional bladder perfusion chemotherapy group (RR1.08, 95% CI 0.80,1.45, p=0.63). No significant difference in the incidence of adverse events was observed between hyperthermia intravesical chemotherapy and BCG perfusion (RR1.03, 95% CI 0.83,1.29, p=0.79).

The role of the methyltransferase METTL3 in prostate cancer: a potential therapeutic target.

The incidence of prostate cancer (PCa), the most prevalent malignancy, is currently at the forefront. RNA modification is a subfield of the booming field of epigenetics. To date, more than 170 types of RNA modifications have been described, and N6-methyladenosine (m6A) is the most abundant and well-characterized internal modification of mRNAs involved in various aspects of cancer progression. METTL3, the first identified key methyltransferase, regulates human mRNA and non-coding RNA expression in an m6A-dependent manner. This review elucidates the biological function and role of METTL3 in PCa and discusses the implications of METTL3 as a potential therapeutic target for future research directions and clinical applications.

Prognostic significance and relationship of SMAD3 phospho-isoforms and VEGFR-1 in gastric cancer: A clinicopathological study.

BACKGROUND: The TGF-ß/SMAD3 and VEGFR-1 signaling pathways play important roles in gastric cancer metastasis. SMAD3 phosphorylation is a crucial prognostic marker in gastric cancer. AIM: To determine the prognostic value and relationship of SMAD3 phospho-isoforms and VEGFR-1 in gastric cancer. METHODS: This was a single-center observational study which enrolled 98 gastric cancer patients and 82 adjacent normal gastric tissues from patients aged 32-84 years (median age 65) between July 2006 and April 2007. Patients were followed up until death or the study ended (median follow-up duration of 28.5 mo). The samples were used to generate tissue microarrays (TMAs) for immunohistochemical (IHC) staining. The expressions of TGF-ß1, pSMAD3C(S423/425), pSMAD3L(S204), and VEGFR-1 in gastric cancer (GC) tumor tissue and normal tissue were measured by IHC staining using TMAs obtained from 98 GC patients. Prognosis and survival information of the patients was recorded by Outdo Biotech from May 2007 to July 2015. The relationship between TGF-ß1, pSMAD3C(S423/425), pSMAD3L(S204), and VEGFR-1 protein expression levels was analyzed using Pearson's correlation coefficient. The relationship between protein expression levels and clinicopathological parameters was analyzed using the Chi-squared test. A survival curve was generated using the Kaplan-Meier survival analysis. RESULTS: TGFß-1 and VEGFR-1 expression was significantly upregulated in gastric cancer tissue compared to adjacent non-cancerous tissue. The positive expression of phosphorylated isoforms of Smad3 varied depending on the phosphorylation site [pSMAD3C(S423/425): 51.0% and pSMAD3L(S204): 31.6%]. High expression of pSMAD3L(S204) was significantly correlated with larger tumors (P = 0.038) and later N stages (P = 0.035). Additionally, high expression of VEGFR-1 was closely correlated with tumor size (P = 0.015) and pathological grading (P = 0.013). High expression of both pSMAD3L(S204) and VEGFR-1 was associated with unfavorable outcomes in terms of overall survival (OS). Multivariate analysis indicated that high expression of pSMAD3L(S204) and VEGFR-1 were independent risk factors for prognosis in GC patients. VEGFR-1 protein expression was correlated with TGF-ß1 (r = 0.220, P = 0.029), pSMAD3C(S423/425) (r = 0.302, P = 0.002), and pSMAD3L(S204) (r = 0.201, P = 0.047), respectively. Simultaneous overexpression of pSMAD3L(S204) and VEGFR-1 was associated with poor OS in gastric cancer patients. CONCLUSION: Co-upregulation of pSMAD3L(S204) and VEGFR-1 can serve as a predictive marker for poor gastric cancer prognosis, and pSMAD3L(204) may be involved in enhanced gastric cancer metastasis in a VEGFR-1-dependent manner.

Autonomic Nervous System Dysfunction Is Related to Chronic Prostatitis/Chronic Pelvic Pain Syndrome.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common and non-lethal urological condition with painful symptoms. The complexity of CP/CPPS's pathogenesis and lack of efficient etiological diagnosis results in incomplete treatment and recurrent episodes, causing long-term mental and psychological suffering in patients. Recent findings indicate that the autonomic nervous system involves in CP/CPPS, including sensory, sympathetic, parasympathetic, and central nervous systems. Neuro-inflammation and sensitization of sensory nerves lead to persistent inflammation and pain. Sympathetic and parasympathetic alterations affect the cardiovascular and reproductive systems and the development of prostatitis. Central sensitization lowers pain thresholds and increases pelvic pain perception in chronic prostatitis. Therefore, this review summarized the detailed processes and mechanisms of the critical role of the autonomic nervous system in developing CP/CPPS. Furthermore, it describes the neurologically relevant substances and channels or receptors involved in this process, which provides new perspectives for new therapeutic approaches to CP/CPPS.

The role of RNA modification in urological cancers: mechanisms and clinical potential.

RNA modification is a post-transcriptional level of regulation that is widely distributed in all types of RNAs, including mRNA, tRNA, rRNA, miRNA, and lncRNA, where N6-methyladenine (m6A) is the most abundant mRNA methylation modification. Significant evidence has depicted that m6A modifications are closely related to human diseases, especially cancer, and play pivotal roles in RNA transcription, splicing, stabilization, and translation processes. The most common urological cancers include prostate, bladder, kidney, and testicular cancers, accounting for a certain proportion of human cancers, with an ever-increasing incidence and mortality. The recurrence, systemic metastasis, poor prognosis, and drug resistance of urologic tumors have prompted the identification of new therapeutic targets and mechanisms. Research on m6A modifications may provide new solutions to the current puzzles. In this review, we provide a comprehensive overview of the key roles played by RNA modifications, especially m6A modifications, in urologic cancers, as well as recent research advances in diagnostics and molecularly targeted therapies.

Therapeutic potential of vasculogenic mimicry in urological tumors.

Angiogenesis is an essential process in the growth and metastasis of cancer cells, which can be hampered by an anti-angiogenesis mechanism, thereby delaying the progression of tumors. However, the benefit of this treatment modality could be restricted, as most patients tend to develop acquired resistance during treatment. Vasculogenic mimicry (VM) is regarded as a critical alternative mechanism of tumor angiogenesis, where studies have demonstrated that patients with tumors supplemented with VM generally have a shorter survival period and a poorer prognosis. Inhibiting VM may be an effective therapeutic strategy to prevent cancer progression, which could prove helpful in impeding the limitations of lone use of anti-angiogenic therapy when performed concurrently with other anti-tumor therapies. This review summarizes the mechanism of VM signaling pathways in urological tumors, i.e., prostate cancer, clear cell renal cell carcinoma, and bladder cancer. Furthermore, it also summarizes the potential of VM as a therapeutic strategy for urological tumors.

Insights into vitamin A in bladder cancer, lack of attention to gut microbiota?

Vitamin A has long been associated with bladder cancer, and many exogenous vitamin A supplements, vitamin A derivatives, and synthetic drugs have been investigated over the years. However, the effectiveness of these strategies in clinical practice has not met expectations, and they have not been widely adopted. Recent medical research on intestinal flora has revealed that bladder cancer patients exhibit reduced serum vitamin A levels and an imbalance of gut microbiota. In light of the close relationship between gut microbiota and vitamin A, one can speculate that a complex regulatory mechanism exists between the two in the development and occurrence of bladder cancer. As such, further exploration of their interaction in bladder cancer may help guide the use of vitamin A for preventive purposes. During the course of this review, attention is paid to the influence of intestinal microbiota on the vitamin A metabolism and the RA signaling pathway, as well as the mutual promotion relationships between them in the prevention of bladder cancer, In addition, it emphasizes the importance of intestinal microbiota for bladder cancer prevention and treatment.

Pharmacotherapy of urethral stricture.

ABSTRACT: Urethral stricture is characterized by the chronic formation of fibrous tissue, leading to the narrowing of the urethral lumen. Despite the availability of various endoscopic treatments, the recurrence of urethral strictures remains a common challenge. Postsurgery pharmacotherapy targeting tissue fibrosis is a promising option for reducing recurrence rates. Although drugs cannot replace surgery, they can be used as adjuvant therapies to improve outcomes. In this regard, many drugs have been proposed based on the mechanisms underlying the pathophysiology of urethral stricture. Ongoing studies have obtained substantial progress in treating urethral strictures, highlighting the potential for improved drug effectiveness through appropriate clinical delivery methods. Therefore, this review summarizes the latest researches on the mechanisms related to the pathophysiology of urethral stricture and the drugs to provide a theoretical basis and new insights for the effective use and future advancements in drug therapy for urethral stricture.

Targeting integrin α5ß1 in urological tumors: opportunities and challenges.

Urological tumors, such as prostate cancer, renal cell carcinoma, and bladder cancer, have shown a significant rise in prevalence in recent years and account for a significant proportion of malignant tumors. It has been established that metastasis to distant organs caused by urological tumors is the main cause of death, although the mechanisms underlying metastasis have not been fully elucidated. The fibronectin receptor integrin α5ß1 reportedly plays an important role in distant metastasis and is closely related to tumor development. It is widely thought to be an important cancer mediator by interacting with different ligands, mediating tumor adhesion, invasion, and migration, and leading to immune escape. In this paper, we expound on the relationship and regulatory mechanisms of integrin α5ß1 in these three cancers. In addition, the clinical applications of integrin α5ß1 in these cancers, especially against treatment resistance, are discussed. Last but not least, the possibility of integrin α5ß1 as a potential target for treatment is examined, with new ideas for future research being proposed.

Oxalate as a potent promoter of kidney stone formation.

Kidney stones are among the most prevalent urological diseases, with a high incidence and recurrence rate. Treating kidney stones has been greatly improved by the development of various minimally invasive techniques. Currently, stone treatment is relatively mature. However, most current treatment methods are limited to stones and cannot effectively reduce their incidence and recurrence. Therefore, preventing disease occurrence, development, and recurrence after treatment, has become an urgent issue. The etiology and pathogenesis of stone formation are key factors in resolving this issue. More than 80% of kidney stones are calcium oxalate stones. Several studies have studied the formation mechanism of stones from the metabolism of urinary calcium, but there are few studies on oxalate, which plays an equally important role in stone formation. Oxalate and calcium play equally important roles in calcium oxalate stones, whereas the metabolism and excretion disorders of oxalate play a crucial role in their occurrence. Therefore, starting from the relationship between renal calculi and oxalate metabolism, this work reviews the occurrence of renal calculi, oxalate absorption, metabolism, and excretion mechanisms, focusing on the key role of SLC26A6 in oxalate excretion and the regulatory mechanism of SLC26A6 in oxalate transport. This review provides some new clues for the mechanism of kidney stones from the perspective of oxalate to improve the understanding of the role of oxalate in the formation of kidney stones and to provide suggestions for reducing the incidence and recurrence rate of kidney stones.

Essential role of bromodomain proteins in renal cell carcinoma (Review).

Histone alterations are a hallmark of kidney cancer. Histone acetylation modification mediated by bromodomain proteins (BRD) has been indicated to be related to a variety of cancer types and several targeted inhibitors have been proven to be promising modalities for cancer adjuvant therapy. As renal cell carcinoma (RCC) is not sensitive to radiotherapy or chemotherapy, the exploration of effective adjuvant therapies remains an important research direction for advanced RCC. At present, studies on bromodomain family proteins in RCC are limited and the roles of bromodomain family proteins in RCC have remained to be fully elucidated. The present review discussed the role of bromodomain family proteins in RCC, aiming to explore possible potential therapeutic targets of BRD­related drugs in this type of cancer.

Preclinical models and evaluation criteria of prostatitis.

Prostatitis is a common urological condition that affects almost half of all men at some point in their life. The prostate gland has a dense nerve supply that contributes to the production of fluid to nourish sperm and the mechanism to switch between urination and ejaculation. Prostatitis can cause frequent urination, pelvic pain, and even infertility. Long-term prostatitis increases the risk of prostate cancer and benign prostate hyperplasia. Chronic non-bacterial prostatitis presents a complex pathogenesis, which has challenged medical research. Experimental studies of prostatitis require appropriate preclinical models. This review aimed to summarize and compare preclinical models of prostatitis based on their methods, success rate, evaluation, and range of application. The objective of this study is to provide a comprehensive understanding of prostatitis and advance basic research.

Lower SLC7A2 expression is associated with enhanced multidrug resistance, less immune infiltrates and worse prognosis of NSCLC.

BACKGROUND: Solute carrier family 7 member 2 (SLC7A2), a cationic amino acid transporter, is lowly expressed in ovarian and hepatocellular cancers, which is associated with their worse prognosis. However, its roles in the prognosis, drug resistance and immune infiltration in non-small-cell lung cancer (NSCLC) are unclear. METHODS: We chose SLC7A2 from RNA-Seq of paclitaxel/cisplatin-resistant A549 cells, then bioinformatics, cell lines construction, RT-qPCR, and CCK8 were performed to investigate SLC7A2 role. RESULT: We analyzed the 223 differentially expressed genes (DEGs) from RNA-Seq of paclitaxel/cisplatin-resistant A549 cells and found that SLC7A2 expression was down-regulated in NSCLC. Lower SLC7A2 expression was associated with worse recurrence-free survival (RFS) in NSCLC. SLC7A2 silencing enhanced the proliferation of NSCLC cells and their insensitivity to paclitaxel, cisplatin, and gemcitabine in vitro. Activation of AMPK has up-regulated SLC7A2 expression and enhanced the sensitivity of NSCLC cells to anti-tumor drugs, which could be attributed to E2F1's regulation. In addition, the levels of SLC7A2 expression were correlated to the numbers of infiltrated neutrophils, macrophages, dendritic cells and their marker genes, like CD86, HLA-DPA1 and ITGAM. CONCLUSIONS: SLC7A2 may act as a tumor suppressor to modulate drug sensitivity, immune infiltration and survival in NSCLC. Video abstract.

Protective Effects and Mechanisms of Flavonoids in Renal Ischemia-Reperfusion Injury.

BACKGROUND: Acute kidney injury (AKI) is a common and potentially fatal complication encountered during a variety of kidney surgeries. Renal ischemia/reperfusion (I/R) injury is the predominant mechanism of AKI in this setting. Hence, controlling I/R injury is a key research imperative as it is directly related to the prognosis of patients. SUMMARY: In the last decade, studies in vitro and in animal models have demonstrated that flavonoids can significantly alleviate I/R-induced AKI through a variety of pathways, including anti-oxidative stress, anti-inflammation, anti-cell death, inhibition of endoplasmic reticulum stress, and alleviation of mitochondrial dysfunction. Based on the extensive role of flavonoids in ischemia-reperfusion injury, the lack of drugs entering the clinic so far is a question worthy of consideration. KEY MESSAGES: This review summarizes the available evidence pertaining to the protective effect of flavonoids against renal I/R injury and discusses their potential clinical application in renal I/R injury.

Overexpression of SATB1 correlates with epithelial-mesenchymal transition and lymphatic metastasis in gastric cancer.

BACKGROUND: Gastric cancer (GC) is a malignant tumor with a high mortality rate, and lymphatic metastasis is the main mode of GC metastasis. The nuclear transcriptional regulatory protein SATB1 has been confirmed to be closely related to GC metastasis, but the mechanism has not been elucidated. METHODS: Epithelial-mesenchymal transition (EMT) is known as the pivotal process of GC metastasis. To evaluate the relationship between SATB1 and EMT in GC metastasis, the immunohistochemical method was used to detect the expression of SATB1, E-cadherin, N-cadherin, Vimentin protein in 52 paraffin-embedded specimens of gastric cancer, and analyze the relationship between their expression and pathological parameters. RESULTS: Abnormal positive expression of SATB1 protein in paraffin-embedded tumor tissues was positively correlated with local invasion, lymph node metastasis, and TNM staging in gastric cancer. There was a statistically significant difference in the expression of SATB1 between the early stage of gastric cancer (stage I) and the advanced stage (stageII, III, IV). Moreover, SATB1 expression was positively correlated to N-cadherin and Vimentin but negatively to E-cadherin from Stages I to IV. CONCLUSION: The GC patients with overexpression of SATB1 tended to have advanced stage and lymph node metastasis. SATB1 was positively correlated with EMT in Gastric Cancer.

CD36 and Its Role in Regulating the Tumor Microenvironment.

CD36 is a transmembrane glycoprotein that binds to a wide range of ligands, including fatty acids (FAs), cholesterol, thrombospondin-1 (TSP-1) and thrombospondin-2 (TSP-2), and plays an important role in lipid metabolism, immune response, and angiogenesis. Recent studies have highlighted the role of CD36 in mediating lipid uptake by tumor-associated immune cells and in promoting tumor cell progression. In cancer-associated fibroblasts (CAFs), CD36 regulates lipid uptake and matrix protein production to promote tumor proliferation. In addition, CD36 can promote tumor cell adhesion to the extracellular matrix (ECM) and induce epithelial mesenchymal transition (EMT). In terms of tumor angiogenesis, CD36 binding to TSP-1 and TSP-2 can both inhibit tumor angiogenesis and promote tumor migration and invasion. CD36 can promote tumor angiogenesis through vascular mimicry (VM). Overall, we found that CD36 exhibits diverse functions in tumors. Here, we summarize the recent research findings highlighting the novel roles of CD36 in the context of tumors.