USP15 facilitates the progression of bladder cancer by amplifying the activation of the NF-κB signaling pathway.

USP15, a pivotal member of the deubiquitinase family, plays a crucial role in orchestrating numerous vital biological processes, including the regulation of NF-κB signaling pathway and deubiquitination of proto-oncogenes. In various cancers, USP15 has been validated to exhibit up-regulated expression, impacting the initiation and progression of cancer. However, its precise mechanism in bladder cancer remains elusive. Our study shed light on the significant overexpression of USP15 in bladder cancer cells compared to normal bladder cells, correlating with a poorer prognosis for bladder cancer patients. Strikingly, attenuation of USP15 expression greatly attenuated the proliferation, migration, and invasion of bladder cancer cells. Moreover, upregulation of USP15 was found to drive cancer progression through the activation of the NF-κB signaling pathway. Notably, USP15 directly deubiquitinates BRCC3, heightening its expression level, and subsequent overexpression of BRCC3 counteracted the antitumoral efficacy of USP15 downregulation. Overall, our findings elucidated the carcinogenic effects of USP15 in bladder cancer, primarily mediated by the excessive activation of the NF-κB signaling pathway, thereby promoting tumor development. These results underscore the potential of USP15 as a promising therapeutic target for bladder cancer in the future.

SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53.

Pancreatic cancer cells undergo intricate metabolic reprogramming to sustain their survival and proliferation. p53 exhibits a dual role in tumor cell ferroptosis. However, the precise role and mechanisms underlying wild-type p53 activation in promoting ferroptosis in pancreatic cancer cells remain obscure. In this study, we applied bioinformatics tools and performed an analysis of clinical tissue sample databases and observed a significantly upregulated expression of solute carrier family 35 member F2 (SLC35F2) in pancreatic cancer tissues. Our clinical investigations indicated that elevated SLC35F expression was related to adverse survival outcomes. Through multi-omics analyses, we discerned that SLC35F2 influences the transcriptome and inhibits ferroptosis in pancreatic cancer cells. Moreover, our findings reveal the pivotal involvement of p53 in mediating SLC35F2-mediated ferroptosis, both in vitro and in vivo. SLC35F2 inhibits ferroptosis by facilitating TRIM59-mediated p53 degradation. Further mechanistic investigations demonstrated that SLC35F2 competitively interacts with the E3 ubiquitin ligase SYVN1 of TRIM59, thereby stabilizing TRIM59 expression and consequentially promoting p53 degradation. Utilizing protein 3D structure analysis and drug screening, we identified irinotecan hydrochloride and lapatinib ditosylate as compounds targeting SLC35F2, augmenting the antitumor effect of imidazole ketone erastin (IKE) in a wild-type p53 patient-derived xenograft (PDX) model. However, in the p53 mutant PDX model, irinotecan hydrochloride and lapatinib ditosylate did not alter the sensitivity of the tumor xenograft model to IKE-triggered ferroptosis. In summary, our work establishes a novel mechanism wherein the SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53. Thus, SLC35F2 emerges as a promising therapeutic target for treating pancreatic cancer.

Laparoscopic bladder diverticulectomy in a child with situs inversus totalis: A case report and literature review.

Situs inversus totalis (SIT) is a rare internal laterality disorder characterized by the mirror arrangement of organs. Multiple gene mutations and maternal environmental factors are thought to cause this variation. It is usually challenging to perform laparoscopic surgery in these cases. Bladder diverticulum is uncommon in children, with an incidence of 1.7%. We report a 14-year-old male patient who was admitted to our department because of lower abdominal pain and frequent urination. A series of examinations confirmed the rare combination of giant bladder diverticulum and SIT. After extensive preoperative discussion, we performed laparoscopic bladder diverticulectomy. The operation was successful. To the best of our knowledge, this is the first report of successful laparoscopic bladder surgery on a case of SIT. This article summarizes the key technical points and the difficulties of performing this kind of operation. In addition, during the process of reviewing the literature, we found that SIT often coexists with some high-risk factors for bladder diverticulum in some rare syndromes. It is helpful to further understand and provide experience in the diagnosis and treatment of the rare combination of bladder diverticulum and SIT in children.

RING-finger protein 6 enhances c-Myc-mediated Warburg effect by promoting MAD1 degradation to facilitate pancreatic cancer metastasis.

Aerobic glycolysis (the Warburg effect) promotes tumor metastasis; hence, drugs targeting its regulators are being developed. c-Myc, a critical transcription factor that regulates the Warburg effect, is involved in the tumorigenesis of many cancers, including pancreatic cancer (PC). However, the upstream regulating mechanisms of c-Myc in PC are unclear. Herein, we reported that E3 ubiquitin ligase RING-finger protein 6 (RNF6) was upregulated in PC tissues, and an elevated RNF6 level was closely associated with metastasis and poor prognosis in patients with PC. In functional experiments, RNF6 over-expression accelerated the metastatic ability of PC cells, whereas RNF6 knockdown impaired PC cell motility and invasiveness along with metastasis in an orthotopic mouse model. Furthermore, we found that RNF6 promoted PC cell metastasis by enhancing c-Myc-mediated aerobic glycolysis. Mechanistically, RNF6 increased the expression level of c-Myc by catalyzing the ubiquitination of Max-dimerization protein-1 (MAD1), a cellular antagonist of c-Myc. Lastly, RNF6 promoted the degradation of MAD1 via the ubiquitin-proteasome pathway, and this reduction in the MAD1 levels enabled c-Myc to promote the Warburg effect in PC. Our results demonstrate that RNF6 may be a novel biomarker in PC carcinogenesis, thereby indicating that targeting the RNF6/MAD1/c-Myc axis is a potential strategy for PC therapy.

Bovine Serum Albumin Nanoparticle-Mediated Delivery of Sorafenib for Improving Hepatocellular Carcinoma Therapy.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. The majority of patients with HCC are diagnosed with advanced-stage disease. Sorafenib is a frontline therapy drug approved by the Food and Drug Administration for advanced HCC. However, the poor aqueous solubility of sorafenib limits its applications. The present study aimed to overcome this limitation of sorafenib. Thus, bovine serum albumin (BSA)-based nanoparticles were developed to encapsulate hydrophobic sorafenib. The resultant sorafenib-loaded BSA nanoparticles (Sf-BSA-NPs) were thoroughly characterized for size distribution, encapsulation efficiency and morphology. Previous studies on HepG2 cells in vitro have demonstrated that Sf-BSA-NPs exhibit remarkable superiority to free sorafenib in cytocompatibility, cytotoxicity and proapoptotic effect. The results of the present study demonstrated that Sf-BSA-NPs were effective in improving aqueous solubility, and enhanced drug cytotoxicity, suggesting its therapeutic potential for HCC.

MiR-340 regulates the growth and metabolism of renal cell carcinoma cells by targeting frizzled class receptor 3.

MicroRNA(miR)-340 is known as a multifunctional miRNA related to various types of cancer while its role in renal cell carcinoma (RCC) remains to be further investigated. In the present study, an apparent increase in miR-340 expression was observed in both clear cell RCC tissues and RCC cell line 786-O and Caki-1. Functionally, the overexpression of miR-340 promoted cell proliferation, migration, invasion, extracellular alanine (Ala) level, and glycolysis level in 786-O cells. Then, frizzled class receptor 3 (FZD3) was determined as the target gene of miR-340 and its expression level was negatively regulated by miR-340. The FZD3 silencing abrogated the inhibitory effect of miR-340 knockdown on cell proliferation, migration, invasion, Ala level, and glycolysis level in 786-O cells. In conclusion, miR-340 promotes proliferation, migration, and invasion of RCC cells via suppressing FZD3 expression, and the promotion effect of miR-340 on RCC progression may be due to its regulatory effect on glycolysis and Ala level.

Exploring serum metabolic markers for the discrimination of ccRCC from renal angiomyolipoma by metabolomics.

Aim: The discrimination of renal cell carcinoma from renal angiomyolipoma (RAML) is crucial for the effective treatment of each. Materials & methods: Serum samples were analyzed by nuclear magnetic resonance spectroscopy-based metabolomics and a number of metabolites were further quantified by HPLC-UV. Results: Clear-cell renal carcinoma (ccRCC) was characterized by drastic disruptions in energy, amino acids, creatinine and uric acid metabolic pathways. A logistic model for the differential diagnosis of RAML from ccRCC was established using the combination of serum levels of uric acid, the ratio of uric acid to hypoxanthine and the ratio of hypoxanthine to creatinine as variables with area under the curve of the receiver operating characteristic curve value of 0.907. Conclusion: Alterations in serum purine metabolites may be used as potential metabolic markers for the differential diagnosis of ccRCC and RAML.

Recent Developments in Pharmacological Effect, Mechanism and Application Prospect of Diazeniumdiolates.

Nitric oxide (NO) is a simple structured and unstable free radical molecule, which participates in the regulation of many pathophysiological processes. It functions both as a second messenger and as an endogenous neurotransmitter. Diazeniumdiolates (NONOates) are a series of compounds containing the functional parent nuclear structure of [N(O)NO]-, which are the most widely studied NO donors. NONOates are unstable and easy to release NO in physiological conditions. The biomedical applications and drug development of NO donor have attracted the scientists' attention in recent years. In this review, recent advances in NONOates research are highlighted in terms of chemical structures, molecular characteristics, pharmacological effects, and biomedical application prospects.

[Eukaryotic translation elongation factor 1A1 positively regulates NOB1 expression to promote invasion and metastasis of hepatocellular carcinoma cells in vitro].

OBJECTIVE: To explore the role of eukaryotic translation elongation factor 1A1 (eEF1A1) in regulating the invasion and metastasis of hepatocellular carcinoma (HCC) cells and the possible mechanism. METHODS: qRT-PCR and Western blotting were used to detect the mRNA and protein expression of eEF1A1 and NOB1 in different HCC cell lines and normal liver cells. The invasion and migration abilities of HCC cells with eEF1A1 knockdown or overexpression were examined using Transwell chamber assay and RTCA assay, and the changes in NOB1 mRNA and protein expressions in the cells were detected. The effects of increasing NOB1 expression in HCCLM3-sheEF1A1 cells and decreasing NOB1 expression in eEF1A1-overexpressing MHCC97h cells on eEF1A1 expression and cell invasion and migration abilities were analyzed using Western blotting, Transwell chamber assay and RTCA assay. RESULTS: The expressions of eEF1A1 and NOB1 were significantly increased in positive correlation in HCC cells as compared with normal hepatocytes. Knockdown of eEF1A1 significantly decreased the invasion and migration of HCC cells and reduced the mRNA and protein expression of NOB1 (P < 0.01). Overexpression of eEF1A1 significantly enhanced invasion and migration of HCC cells and increased NOB1 mRNA and protein expressions (P < 0.01). Increasing NOB1 expression in HCCLM3-sheEF1A1 cells led to the restoration of NOB1 expression and cell invasion and migration abilities (P < 0.01), whereas decreasing NOB1 in MHCC97h-eEF1A1 cells resulted in inhibition of NOB1 expression and cell invasion and migration (P < 0.01). CONCLUSIONS: eEF1A1 positively regulates the expression of NOB1 to promote the invasion and migration of HCC cells in vitro.

Synergistic active targeting of dually integrin αvß3/CD44-targeted nanoparticles to B16F10 tumors located at different sites of mouse bodies.

Conventional enhanced permeation and retention (EPR) mediates the effects of many drugs, including the accumulation of nanocarriers at tumor sites, but its efficiency remains low. In this study, this limitation was overcome by developing a dual-targeting delivery system based on hyaluronan (HA, a major ligand of CD44) and tetraiodothyroacetic acid (tetrac, a specific ligand of αvß3), which was exploited to carry docetaxel (DTX) for the synergistic active targeting to tumors. First, a tetrac-HA (TeHA) conjugate was synthesized and grafted onto the surfaces of solid lipid nanoparticles (SLNs) (TeHA-SLNs/DTX), with a high encapsulation efficiency of >91.6%. The resulting SLNs exhibited an approximately toroid morphology revealed using TEM. The cellular uptake and cytotoxicity of various formulations on CD44/αvß3-enriched B16F10 cells were then assessed, and both results confirmed the selective uptake and high cytotoxicity of the TeHA-SLNs/DTX in a TeHA-dependent manner. In vivo imaging and vessel distribution tests revealed the efficiency of synergistic active targeting was higher than that of EPR-mediated passive targeting by the TeHA-SLNs to αvß3-expressing tumor blood vessels and CD44-expressing tumor cells via selective targeting. Finally, in both xenograft tumor mice and in situ lung metastasis tumor mice, tumor growth was significantly inhibited by TeHA-SLNs/DTX. Therefore, TeHA-SLNs are an efficient system for the dual-targeted delivery of drugs to treat cancer in vivo.

Reduction of urinary uric acid excretion in patients with proteinuria.

Serum uric acid (UA) concentration is positively associated with proteinuria. However, the relationship between proteinuria and urinary metabolites of purine metabolism remains unknown. This study developed a hydrophilic interaction chromatography (HILIC)-based HPLC method with ultraviolet detection (UV) to quantify creatinine (Cr), UA, xanthine, and hypoxanthine in human urine simultaneously. The urinary concentrations of UA and Cr obtained by our method are consistent with those measured by an autoanalyzer. The HPLC-HILIC-UV method was validated as selective and robust with simple sample preparation for measuring UA, xanthine, hypoxanthine and Cr, which is suitable for large clinical studies. The UA/Cr ratios in random urine samples were 5.5 times lower in proteinuria patients (0.077±0.008) than in healthy individuals (0.424±0.037). Moreover, the UA/hypoxanthine ratio in proteinuria patients was approximately 10 times lower than that in healthy individuals. Our findings revealed a reduced urinary UA excretion, which is one of the factors leading to increased serum UA in proteinuria patients.

Enhancement of fractionated bone marrow transplantation on hematopoietic cell homing in a mouse allogeneic model.

BACKGROUND: The conventional method of bone mar row transplantation (BMT) requires a large quantity of bone marrow cells (BMC) transplanted by a single injection. However, the homing efficiency of BMC is low, because the emptying of available niches might be a continuous process after stem-cell death after irradiation. In this article, the death character of CD34 stem cells was directly detected, and a novel method of fractionated (Fr) BMT that aimed to better use each niche that was continuously emptied was developed. METHODS: Apoptosis and necrosis were detected using trivariate fluorescence-activated cell sorting after labeling cells with phycoerythrin-CD34-fluorescein isothiocyanate-Annix V-7-aminoactinomycin D. Fr-BMT was conducted in a model of allogeneic BMT, where the total dosage of BMC was divided into four doses, and each dose was administrated for 4 consecutive days at 24-hr intervals after lethal irradiation. RESULTS: CD34 cells underwent a continuous death process after lethal irradiation and presented three death peaks within a week. Fr-BMT decreased the BMC transplanted but increased the accumulatively homed BMC and enhanced the survival rates of recipients. CONCLUSIONS: Fr-BMT is able to enhance hematopoietic cell homing and engraftment, and this method might prove to be a solution to the previous clinical problem that a single unit of umbilical cord blood is not sufficient for engraftment in adults.