BACKGROUND:5-Fluorouracil (5-FU), one of the mostly commonly used chemotherapeutic agents, frequently induces intestinal mucositis, severely impacting patient quality of life and limiting treatment efficacy. Pectolinarigenin (PEC), a bioactive compound isolated from Chinese medicinal herb Dajitan, exhibits anti-inflammatory, antioxidative, and anticancer properties. However, its protective effect on 5-FU-induced mucositis and the underlying molecular mechanisms remains unclear. PURPOSES:To investigate the therapeutic effects and underlying mechanisms of PEC in 5-FU-induced intestinal mucositis. METHODS:Mouse models of ileal and colonic injury were used to study 5-FU-induced mucositis. Histological and biochemical assays assessed mucositis severity. A panel of 71 antioxidants was screened for their ability to inhibit 5-FU-induced cells death. Transcriptome sequencing, molecular docking, molecular dynamics simulations, and Western blotting explored PEC's mechanism of action, with a focus on its role in activating the PPARγ signaling pathway. Meanwhile, 5-aminosalicylic acid (5-ASA, the first-line therapeutic agent for treating ulcerative colitis) and pioglitazone (a known PPARγ agonist) were used as positive controls. RESULTS:5-FU induced ferroptosis and intestinal inflammation both in vivo and in vitro, characterized by increased iron and ROS accumulation, reduced GSH levels, and elevated lipid peroxidation biomarkers. Histological analysis showed severe intestinal mucosal damage. Among all tested phytochemicals, PEC demonstrated the best ameliorative effects on 5-FU-induced mucositis, showing impressive therapeutic efficacy in both cellular and animal models. PEC significantly mitigated 5-FU induced mucositis via reducing iron accumulation, lowering ROS and MDA levels, restoring GSH, and normalizing ferroptosis-related markers. Transcriptomic analysis combined cellular assays revealed that the PPARγ signaling plays a critical role in the protective effects of PEC against 5-FU-induced intestinal cellular injury. Further investigations showed that PEC could activate the PPARγ/GPX4 signaling pathway both in vitro and in vivo, which in turn, restored tight junction integrity and suppressed intestinal ferroptosis, ultimately providing protective effects against 5-FU-induced intestinal injury. CONCLUSIONS:This study uncovers a previously unrecognized ferroptosis-related mechanism underlying 5-FU-induced intestinal mucositis, while PEC significantly mitigates 5-FU-induced intestinal mucositis by activating the PPARγ/GPX4 axis. Our findings suggest that activating the PPARγ/GPX4 signaling pathway using phytochemicals represents a promising therapeutic strategy for mitigating chemotherapy-induced intestinal mucositis.

Genitourinary neoplasms, accounting for 20-25 % of all malignant tumors, are associated with high mortality rates and pose significant challenges to clinical treatment. Especially for young patients who have reproductive demands, pharmacotherapy is a promising non-surgical strategy to improve the survival rate and quality of life. However, the distinctive interface between physiological milieu complicates effective drug delivery. Nanomedicines offer distinct advantages, including mitigating clearance, enabling precise tumor targeting, and intracellular drug delivery. Unlike most reviews about the area, which focused on a specified tumor or nanomedicine, this review, for the first time, systematically summarized the application of extensively investigated nanomedicines in the entire genitourinary neoplasms, and provided the latest and most comprehensive insights. Furthermore, we proposed the shortage of therapeutic activity and challenges in nano-therapy, and highlighted the potential of innovative and functional nanomedicines as well as emerging technology.

BackgroundCircular RNAs (circRNAs), which are covalently closed non-coding RNAs, are frequently dysregulated in cancer. However, their precise role in bladder cancer (BCa) remains largely unknown.MethodsExpression of hsa_circ_0005320 in tissues and cell lines was detected using quantitative real-time PCR. Proliferation and colony forming capacity of BCa cells were assessed using Cell Counting Kit-8, ethynyl-labeled deoxyuridine, and colony formation assays. The cell cycle was analyzed using flow cytometry. Protein expression of insulin-like growth factor II mRNA-binding protein 3 (IGF2BP3) and cyclin dependent kinase 2 (CDK2) was examined using western blots. The binding of RNA and protein was validated using RNA immunoprecipitation. Additionally, xenograft tumor models were established to validate the function of hsa_circ_0005320 in vivo.ResultsWe screened hsa_circ_0005320 from previous high-throughput sequencing and found that it was highly expressed in BCa tissues and associated with tumor differentiation and depth of invasion in BCa patients. Through functional experiments, we demonstrated that hsa_circ_0005320 promoted cell proliferation and regulated the cell cycle. Mechanistically, hsa_circ_0005320 interacted with and upregulated the expression of IGF2BP3, which binds to and enhances the stability of CDK2 mRNA. Furthermore, knockdown of hsa_circ_0005320 resulted in a reduction in tumor burden in vivo.ConclusionsCollectively, these findings highlight the pro-oncogenic role of hsa_circ_0005320 in BCa through the IGF2BP3/CDK2 axis, providing valuable insights into the mechanism of circRNAs in tumor progression.

In this study, a high-efficiency superparamagnetic drug delivery system was developed for preclinical treatment of bladder cancer in small animals. Two types of nanoparticles with magnetic particle imaging (MPI) capability, i.e., single- and multi-core superparamagnetic iron oxide nanoparticles (SPIONs), were selected and coupled with bladder anti-tumor drugs by a covalent coupling scheme. Owing to the minimal particle size, magnetic field strengths of 270 mT with a gradient of 3.2 T/m and 260 mT with a gradient of 3.7 T/m were found to be necessary to reach an average velocity of 2 mm/s for single- and multi-core SPIONs, respectively. To achieve this, a method of constructing an in vitro magnetic field for drug delivery was developed based on hollow multi-coils arranged coaxially in close rows, and magnetic field simulation was used to study the laws of the influence of the coil structure and parameters on the magnetic field. Using this method, a magnetic drug delivery system of single-core SPIONs was developed for rabbit bladder therapy. The delivery system consisted of three coaxially and equidistantly arranged coils with an inner diameter of Φ50 mm, radial height of 85 mm, and width of 15 mm that were positioned in close proximity to each other. CCK8 experimental results showed that the three types of drug-coupled SPION killed tumor cells effectively. By adjusting the axial and radial positions of the rabbit bladder within the inner hole of the delivery coil structure, the magnetic drugs injected could undergo two-dimensional delivery motions and were delivered and aggregated to the specified target location within 12 s, with an aggregation range of about 5 mm × 5 mm. In addition, the SPION distribution before and after delivery was imaged using a home-made open-bore MPI system that could realistically reflect the physical state. This study contributes to the development of local, rapid, and precise drug delivery and the visualization of this process during cancer therapy, and further research on MPI/delivery synchronization technology is planned for the future.

膀胱癌是一种常见的泌尿系统恶性肿瘤,其发病率在全球各地有所差异,但总体呈上升趋势.膀胱癌的组织学类型多样,其中以尿路上皮癌最为常见,占90％以上[1].尿路上皮癌又可分为移行细胞癌、鳞状细胞癌和腺癌等亚型[2].

目的:研究外周血肿瘤异常糖链糖蛋白(tumor abnormal protein,TAP)的表达对早期肾癌的诊断价值.方法:对45例肾癌患者(肾癌组)、32例肾脏良性病变患者(肾良性病变组)和42例体检健康人群(正常组)的外周血TAP值进行分析;绘制受试者工作特征(receiver operating characteristics,ROC)曲线评估TAP对肾癌的诊断效能;分析肾癌组中TAP阳性表达与患者临床病理特征的关系.结果:肾癌组中外周血TAP水平明显高于肾良性病变组和正常组.通过评估TAP对肾癌的诊断效能,发现TAP诊断肾癌的ROC曲线下面积为0.92(95％CI:0.82～0.95),其诊断肾癌的灵敏度和特异度分别为73％和91％.结论:肾癌患者外周血中TAP呈高表达,可作为肾癌早期诊断的肿瘤标志物.

目的:探讨术前白蛋白与纤维蛋白原比值(AFR)与非肌层浸润性膀胱癌患者预后的关系.方法:回顾性分析于我院行经尿道膀胱肿瘤切除术的205名非肌层浸润性膀胱癌患者的临床资料,根据受试者工作曲线确定AFR最佳临界值为12.127,并将患者分为高AFR组(n=136)和低AFR组(n=69).并分析AFR水平与膀胱癌患者临床资料及预后的关系.构建患者术后无复发列线图,并利用Bootstrap法计算一致性指数(C指数)以及校准曲线对其预测精准度及一致性进行验证.结果:低AFR组患者具有更高的糖尿病患病率、更大的肿瘤体积、更多肿瘤数量以及更差的组织学分级(P<0.05).低AFR组患者的无复发生存时间较高AFR组明显缩短.COX多因素分析提示肿瘤分化程度(HR=0.530,95％CI:0.314～0.895,P=0.017)及AFR<12.127(HR=0.275,95％CI:0.161～0.471,P<0.001)是影响患者术后复发的独立危险因素.结论:AFR是非肌层浸润性膀胱癌患者的预后不良因素,对预后有一定预测价值.

Long non-coding RNAs (lncRNAs) play a critical role in several human diseases, particularly in solid tumors. Specific lncRNAs are effective biological molecular markers for diagnosing diseases and determining patient prognosis for designing molecularly targeted therapies. HOTAIR is reportedly involved in several physiological emerging processes in solid tumor, such as unlocking phenotypic plasticity, polymorphic microbiome, and cellular senescence, and has been implicated in tumorigenesis and progression. This review summarizes the relationship between the levels of expression, biological features, clinical symptoms, and regulatory mechanisms of HOTAIR action in solid cancers and discusses the clinical applicability of HOTAIR as a biomarker for predicting risk, diagnosis, prognosis, and designing targeted therapy for cancer.

Abstract BackgroundThe urinary bladder's mixed neuroendocrine-non-neuroendocrine neoplasm is a sporadic malignant tumor. Because of its rare incidence rate, the optimal treatment options for patients with mixed neuroendocrine-non-neuroendocrine neoplasm of the urinary bladder remain unknown.Case presentationA 61-year-old man was diagnosed with bladder cancer by cystoscopy due to painless gross hematuria. The patient then underwent transurethral resection of the bladder tumor. The postoperative pathological and immunohistochemical examination confirmed a mixed neuroendocrine-non-neuroendocrine neoplasm of the urinary bladder with small cell carcinoma and urothelial. The patient finally received radical cystectomy and cisplatin plus etoposide chemotherapy. There was no recurrence and metastasis three months after the operation.ConclusionThis case is a rare and high-risk pathological type of bladder malignant tumor. After radical cystectomy and postoperative adjuvant treatment, there was no tumor recurrence and metastasis three months after the operation. Radical cystectomy is still the preferred treatment for high-risk bladder cancer without distant metastasis.

Bladder cancer has easy recurrence characteristics, but its occurrence and development mechanism are still unclear. Non-coding RNA is a kind of RNA that exists widely and cannot be translated into proteins, which has played a key role in the regulation of biological functions of tumor cells. However, the regulation mechanism of non-coding RNA on bladder tumors is not fully understood. By microarray analysis and database analysis, we found that LINC00511 was significantly highly expressed in bladder cancer. The expressions of LINC00511, miR-143-3p, and PCMT in bladder cancer tissues and cells were detected by quantitative reverse transcription–polymerase chain reaction. The relationship between the expressions of miR-143-3p and PCMT1 and the clinicopathological parameters of the tumor was analyzed. The proliferation and invasion of bladder cancer cells were detected by MTT assay and Transwell assay. The expression levels of E-cadherin and vimentin in bladder cancer cells were detected by Western blot. Cell apoptosis was detected by flow cytometry. In vivo, TCCSUP or SW780 cells were inoculated into BALB/c nude mice to detect tumor volume and weight. Bioinformatics and dual luciferase reporter gene were used to analyze the relationship between LINC00511 and miR-143-3p and its downstream target gene PCMT1. The results showed that LINC00511 could target miR-143-3p/PCMT1 to regulate the proliferation, migration, and apoptosis of bladder cancer TCCSUP or SW780 cells and promote the occurrence and development of bladder cancer.

Renal cell carcinoma (RCC) is the third most frequent malignancy within urological oncology. Understanding mechanisms of chemoresistance in RCC cell is important for therapy and drug development. We established cisplatin (CDDP) resistant RCC cells by treating cells with increasing concentrations of CDDP. Nodal, an important embryonic morphogen, was increased in RCC/CDDP cells. Targeted inhibition of Nodal via its siRNA or neutralization antibody restored sensitivity of RCC resistant cells to CDDP treatment. It was due to that si-Nodal can decrease expression of P-glycoprotein (P-gp, encoded by ABCB1), one important ATP-binding cassette (ABC) membrane transporter for drug efflux. si-Nodal can decrease the transcription and promoter activity of ABCB1. Mechanistically, si-Nodal can decrease the phosphorylation of p65, which can bind to the promoter of ABCB1 and then trigger its transcription. Further, CDDP treatment decreased the expression of Nodal in culture medium of RCC cells. Collectively, we found that Nodal can regulate chemoresistance of RCC cells via regulating transcription of ABCB1.

肾集合管癌又称为Bellini导管癌,是起源于肾髓质的罕见恶性肿瘤[1],发病率低,但恶性程度很高,预后较差.本文就1 例肾集合管癌进行病例报道并文献复习,现报告如下.

Background: The inflammatory myofibroblastic tumor (IMT) of urinary bladder is very rare, this case and often misdiagnosed as bladder cancer. We report a patient with atypical clinical features with dysuria and lower abdominal pain. Case presentation: A 32-year-old man presented with dysuria and lower abdominal pain. Computed tomography (CT) demonstrated that a solitary non-papillary tumor was located at the wall of the bladder dome. Partial cystectomy was successfully managed. Immunohistochemically, positivity of the tumor cells for anaplastic lymphoma kinase (ALK), Actin (SM), vimentin, cytokine (CK), epithelial membrane antigen (EMA) and Ki-67. Based on the the above clinical features、histopathology and immunohistochemical, the tumor was definitively diagnosed as bladder’s IMT. After 24 months, there was no signs of recurrence and metastasis with CT and cystoscopy. Conclusion: A rare case of inflammatory myofibroblastic tumor of urinary bladder after partial cystectomy was reported. It is essential for urologists and scientists to entirely understand the characteristics of the inflammatory myofibroblastic tumor and make a better clinical guideline, to avoid over treatments.

PURPOSE:Using a rat model of hyperinsulinemia, the present study investigated the role of p-ERK1/2 in benign prostatic hyperplasia (BPH).MATERIALS AND METHODS:Forty male Sprague-Dawley rats were randomly selected and assigned to four groups: high fat diet (HFD)+BPH (n=10), HFD (n=10), BPH (n=10), and control (n=10) groups. Hyperinsulinemia was induced by HFD feeding, while BPH was induced using testosterone propionate. Plasma glucose, plasma insulin and bodyweight were examined weekly. Immunohistochemistry (IHC) and western blot analysis were used to analyze the expression of ERK1/2 and p-ERK1/2 in rat prostates.RESULTS:Plasma glucose and plasma insulin levels were significantly greater in the HFD+BPH and HFD groups, when compared to the other two groups (P<0.05). Prostate weights were significantly greater in the HFD+BPH, HFD and BPH groups, than in the control group (P<0.05). IHC and western blot analysis revealed that p-ERK1/2 expression was greater in the HFD+BPH group than in the other three groups (P<0.05).CONCLUSION:Androgens plus a hyperinsulinemic condition induced by HFD can result in prostatic cell hyperplasia, and this mechanism may be correlated to the upregulation of p-ERK1/2. Further investigations of this possibility are required.

Background Sirtuin 3 (SIRT3) has been reported to share an association with mitochondrial metabolic reprogramming. However, the molecular mechanism underlying is not well understood, especially in benign prostatic hyperplasia (BPH). Therefore, the purpose of this study was to research whether SIRT3 can affect the progression of BPH via the regulation of mitochondrial metabolic reprogramming. Methods Following the development of a rat model of BPH using testosterone propionate (TP), we extracted prostate tissues from sham-operated and BPH rats. Subsequently, bioinformatics prediction was used to screen the genes differentially expressed in BPH. To verify the role played by SIRT3 in BPH, we injected AAV9-SIRT3 into rats, followed by TP treatment. Prostate epithelial cells (PEC) were treated with TP to assess the mitochondrial morphology, mitochondrial membrane potential, and expression of enzymes related to the oxidative phosphorylation pathway after SIRT3 expression alteration. Finally, we examined the expression of AMPK-PGC-1 alpha pathway in tissues and cells. Results SIRT3 was reduced in the prostate tissues of BPH rats. After overexpression of SIRT3, mitochondrial morphology was more stable in prostate tissues of BPH rats and in TP-treated PEC, with significant increases in mitochondrial membrane potential and in the expression of oxidative phosphorylation-related enzymes in the cytoplasm. Moreover, SIRT3 significantly activated the AMPK-PGC-1 alpha signaling pathway, which maintained the stability of mitochondrial membrane potential as well as mitochondrial structure, thus alleviating the symptoms of BPH. Conclusion SIRT3 maintained the stability of mitochondrial membrane potential as well as mitochondrial structure by activating the AMPK-PGC-1 alpha pathway, thereby alleviating the symptoms of BPH.

目的 探讨SRSF1在膀胱尿路上皮癌中的表达情况及与临床预后的关系.方法 应用免疫组化方法检测55例膀胱尿路上皮癌及10例正常膀胱组织中SRSF1蛋白的表达情况,Western blot方法检测膀胱癌组织中SRSF1蛋白的表达水平,并对55例患者进行随访,结合相关临床指标和随访指标,采用x2检验、Kaplan-Meier法、Cox回归进行统计分析.结果 SRSF1在膀胱尿路上皮细胞癌中阳性表达率为72.73％,明显高于正常膀胱组织表达(P＜0.01),SRSF1蛋白在膀胱癌组织中高表达与病理分级、是否转移显著相关.膀胱癌中SRSF1蛋白阳性表达组的总体生存率显著低于阴性表达组(P＜0.05),病理分级、临床分期、SRSF1的表达是患者预后的独立因素.结论 SRSF1可能作为膀胱癌预测、治疗的新靶点.

Objective:To investigate the effect of NOB1 gene interference on apoptosis and Wnt/beta-catenin signaling pathway in bladder cancer cells.Methods:Bladder cancer T-24 cells were divided into control group (CON group), without transfection, siRNA-CON negative control group(siRNA-CON) and NOB1-siRNA group.The expression levels of NOB1 mRNA and protein were detected by RT-PCR and Western blot, cell viability was detected by MTT, cell apoptosis was detected by flow cytometry, and the expression levels of beta-catenin and c-Myc protein were detected by Western blot.NOB1-siRNA cells were treated with Wnt/β-catenin signaling pathway inhibitor FH535.The cells were divided into NOB1-siRNA-FH535 group.Cell viability, apoptosis and expression of beta-catenin and c-Myc protein were detected.Results:The level of NOB1 gene and protein expression in NOB1-siRNA group was lower than that in siRNA-CON group and CON group, and the difference was significant ( P<0.05). The cell viability of NOB1-siRNA group was lower than that of siRNA-CON group and CON group, the difference was significant( P<0.05). The results of flow cytometry showed that the apoptotic rate of NOB1-siRNA group was higher than that of siRNA-CON group and CON group( P<0.05). The expression levels of beta-catenin and c-Myc protein in NOB1-siRNA group were lower than those in siRNA-CON group and CON group( P<0.05). The cell viability of NOB1-siRNA-FH535 group was lower than that of NOB1-siRNA group( P<0.05). Flow cytometry showed that the apoptotic rate of NOB1-siRNA-FH535 group was higher than that of NOB1-siRNA group( P<0.05). Conclusions:Interference of NOB1 expression may promote apoptosis of bladder cancer cells by inhibiting the activation of Wnt/β-catenin signaling pathway.

Long non-coding RNA (lncRNA) is characterized by biological function in diverse cancers. LncRNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) is well acknowledged to regulate various cancers, while its role in bladder cancer remains unclear. In the present study, we aimed at probing into the impact and detailed mechanisms of KCNQ1OT1 in bladder cancer progression. In this study, we demonstrated that KCNQ1OT1 expression in bladder cancer tissues was notably up-regulated compared with in normal adjacent tissues, and KCNQ1OT1 modulated the malignant phenotypes of bladder cancer cells. Moreover, it was validated that KCNQ1OT1 could specifically bind to miR-218-5p and reduce its expression. Overexpressed miR-218-5p would inhibit the proliferation and metastasis of bladder cancer cells while facilitating apoptosis. In terms of Mechanism, Heparan Sulfate-Glucosamine 3-Sulfotransferase 3B1 (HS3ST3B1) was validated as a target gene of miR-218-5p, and could be regulated by KCNQ1OT1 indirectly. In conclusion, KCNQ1OT1 can promote the progression of bladder cancer through regulation of miR-218-5p/HS3ST3B1, which is expected to serve as a new therapeutic target for bladder cancer.

目的 探讨丝氨酸/富含精氨酸剪接因子(serine/arginine-rich splicing factor 1,SRSF1)对人膀胱癌BIU-87细胞增殖的作用,分析吡柔比星对BIU-87细胞SRSF1表达的影响.方法 对数生长期人膀胱癌BIU-87细胞随机分为空白对照组(不转染)、阴性对照组(转染siRNA-NC)、SRSF1干扰组(转染siRNA-SRSF1),采用Western blot法检测3组转染6h时SRSF1相对表达量,CCK-8法检测3组转染后培养24、48 h细胞增殖.取对数生长期空白对照组细胞,随机分为对照组、0.4 mg/L吡柔比星组、0.8 mg/L吡柔比星组、1.6 mg/L吡柔比星组、3.2 mg/L吡柔比星组,分别加入吡柔比星浓度为0、0.4、0.8、1.6、3.2 mg/L的培养液1 mL培养24 h,采用Western blot法检测5组SRSF1蛋白相对表达量.结果 转染6h,SRSF1干扰组SRSF1蛋白相对表达量(0.070±0.053)低于空白对照组(0.692±0.069)、阴性对照组(0.776±0.088)(P＜0.05),空白对照组与阴性对照组比较差异无统计学意义(P＞0.05).转染后培养24、48 h,SRSF1干扰组细胞增殖吸光度值(1.624±0.265、2.025±0.314)低于空白对照组(2.071±0.014、3.145±0.104)、阴性对照组(2.332±0.053、3.234±0.158)(P＜0.05),空白对照组与阴性对照组比较差异无统计学意义(P＞0.05).SRSF1蛋白相对表达量在0.4 mg/L吡柔比星组(1.672±0.055)、0.8 mg/L吡柔比星组(1.963±0.028)、1.6 mg/L吡柔比星组(1.432±0.026)均高于对照组(1.036±0.065)(P＜0.05),3.2 mg/L吡柔比星组(0.996±0.085)与对照组比较差异无统计学意义(P＞0.05),0.4 mg/L、0.8 mg/L、1.6 mg/L、3.2 mg/L吡柔比星组SRSF1蛋白相对表达量呈先增高后降低趋势,峰值在0.8 mg/L吡柔比星组(P＜0.05).结论 抑制SRSF1表达可抑制人膀胱癌BIU-87细胞增殖,低浓度吡柔比星可促讲BIU-87细胞SRSF1表达,高浓度吡柔比星可抑制BIU-87细胞SRSF1表达.

Although accumulating evidence has shown the important function of long non-coding RNAs (lncRNAs) in tumor progression and chemotherapy resistance, the role of lncRNA DLEU1 in regulating proliferation, invasion, and chemoresistance of bladder cancer (BCA) cells remains largely unknown. Here, we found that DLEU1 was upregulated in BLCA tissues and BCA patients with high DLEU1 expression exhibited a shorter survival time. Furthermore, mechanistic analysis and functional assays validated that DLEU1 induced cell proliferation, invasion, and cisplatin resistance of BCA cells by de-repressing the expression of HS3ST3B1 through sponging miR-99b. Low miR-99b and high HS3ST3B1 levels were correlated with worse prognosis in patients with BCA. Ectopic expression of HS3ST3B1 or inhibition of miR-99b reversed DLEU1 knockdown-mediated suppression of cell proliferation, invasion, and cisplatin resistance. Thus, our study revealed a novel role for the DLEU1/miR-99b/HS3ST3B1 axis in regulating proliferation, invasion, and cisplatin resistance of BCA cells.