Anoikis resistance regulates immune infiltration and drug sensitivity in clear-cell renal cell carcinoma: insights from multi omics, single cell analysis and in vitro experiment.

Background: Anoikis is a form of programmed cell death essential for preventing cancer metastasis. In some solid cancer, anoikis resistance can facilitate tumor progression. However, this phenomenon is underexplored in clear-cell renal cell carcinoma (ccRCC). Methods: Using SVM machine learning, we identified core anoikis-related genes (ARGs) from ccRCC patient transcriptomic data. A LASSO Cox regression model stratified patients into risk groups, informing a prognostic model. GSVA and ssGSEA assessed immune infiltration, and single-cell analysis examined ARG expression across immune cells. Quantitative PCR and immunohistochemistry validated ARG expression differences between immune therapy responders and non-responders in ccRCC. Results: ARGs such as CCND1, CDKN3, PLK1, and BID were key in predicting ccRCC outcomes, linking higher risk with increased Treg infiltration and reduced M1 macrophage presence, indicating an immunosuppressive environment facilitated by anoikis resistance. Single-cell insights showed ARG enrichment in Tregs and dendritic cells, affecting immune checkpoints. Immunohistochemical analysis reveals that ARGs protein expression is markedly elevated in ccRCC tissues responsive to immunotherapy. Conclusion: This study establishes a novel anoikis resistance gene signature that predicts survival and immunotherapy response in ccRCC, suggesting that manipulating the immune environment through these ARGs could improve therapeutic strategies and prognostication in ccRCC.

Targeting ASK1 by CS17919 alleviates kidney- and liver-related diseases in murine models.

BACKGROUND: Apoptosis signal-regulating kinase 1 (ASK1) is a MAP3K kinase in the MAPK signaling pathway activated by stressors and triggers downstream biological effects such as inflammation and apoptosis; therefore, inhibition of ASK1 kinase activity can protect cells from pathological injury. In this study, we designed and synthesized a novel selective ASK1 inhibitor, CS17919, and investigated its pharmacological effects in various animal models of metabolic injury. METHODS: First, we validated the ability of CS17919 to inhibit ASK1 in vitro and then tested the safety profile of CS17919 in cell lines compared with Selonsertib (GS-4997), a phase III ASK1 inhibitor. We then conducted pharmacokinetic (PK) studies in mice. Finally, we tested the in vivo efficacy of CS17919 in murine models of chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH). RESULTS: Compared to GS-4997, CS17919 demonstrated comparable inhibition of ASK1 in vitro, exhibited lower toxicity, and provided greater protection in palmitic acid-treated LO2 cells. CS17919 also showed pronounced pharmacokinetic properties such as a high plasma concentration. In the unilateral ureteral obstruction model (UUO), CS17919 and GS-4997 preserved kidney function and showed a non-significant tendency to alleviate kidney fibrosis. In the diabetic kidney disease (DKD) model, CS17919 significantly improved serum creatinine and glomerular sclerosis. In the NASH model, the combination of CS17919 and a THRß agonist (CS27109) was found to significantly improve liver inflammation and substantially reduced liver fibrosis. CONCLUSIONS: CS17919 showed cell protective, anti-inflammatory, and antifibrotic effects in vitro and in vivo, suggesting its therapeutic potential for metabolic-related kidney and liver diseases.

UBE2N promotes cell viability and glycolysis by promoting Axin1 ubiquitination in prostate cancer cells.

BACKGROUND: Ubiquitin-conjugating enzyme E2 N (UBE2N) is recognized in the progression of some cancers; however, little research has been conducted to describe its role in prostate cancer. The purpose of this paper is to explore the function and mechanism of UBE2N in prostate cancer cells. METHODS: UBE2N expression was detected in Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) data, prostate cancer tissue microarrays, and prostate cancer cell lines, respectively. UBE2N knockdown or overexpression was used to analyze its role in cell viability and glycolysis of prostate cancer cells and tumor growth. XAV939 or Axin1 overexpression was co-treated with UBE2N overexpression to detect the involvement of the Wnt/ß-catenin signaling and Axin1 in the UBE2N function. UBE2N interacting with Axin1 was analyzed by co-immunoprecipitation assay. RESULTS: UBE2N was upregulated in prostate cancer and the UBE2N-high expression correlated with the poor prognosis of prostate cancer. UBE2N knockdown inhibited cell viability and glycolysis in prostate cancer cells and restricted tumor formation in tumor-bearing mice. Wnt/ß-catenin inhibition and Axin1 overexpression reversed the promoting viability and glycolysis function of UBE2N. UBE2N promoted Axin1 ubiquitination and decreased Axin1 protein level.

Immunotherapeutic value of NUSAP1 associated with bladder cancer through a comprehensive analysis of 33 human cancer cases.

To investigate the correlation between nucleolar spindle-associated protein 1 (NUSAP1) and cancer immunotherapy across 33 different types of human cancers. We conducted an analysis of The Cancer Genome Atlas (TCGA) database to retrieve gene expression data and clinical characteristics for 33 different cancer types. The immunotherapy cohorts encompassed GSE67501, GSE78220, and IMvigor210. Relevant information was extracted from the gene expression repository. We assessed the prognostic significance of NUSAP1 by examining various clinical parameters. The single-sample gene-set enrichment analysis (ssGSEA) method was utilized to gauge NUSAP1 activity and to contrast NUSAP1 transcriptome and protein levels. We delved into the correlation between NUSAP1 and various immune processes and components to gain insights into NUSAP1's role. We also discussed coherent pathways associated with NUSAP1 signal transduction and its impact on immunotherapy biomarkers. To authenticate and validate the differential expression patterns of NUSAP1 in bladder tumor tissues versus normal bladder counterparts, we utilized Western blotting (WB), real-time quantitative polymerase chain reaction (RT-qPCR), and immunohistochemistry (IHC) techniques. NUSAP1 exhibits overexpression across a spectrum of malignancies, and its expression levels correlate with overall survival (OS), disease-specific survival, and tumor stage in specific cancer types. Furthermore, NUSAP1 expression is linked to mutations, methylation patterns, and immunotherapy responses in human cancers. Meanwhile, our experiments, involving WB, RT-qPCR, and IHC, consistently demonstrated significantly higher NUSAP1 expression in bladder tumor tissues compared to normal controls. Our study underscores the potential of NUSAP1 as a promising prognostic indicator and immunotherapeutic target for a range of malignant tumors.

Experimental study on integrated desulfurization and denitrification of low-temperature flue gas by oxidation method.

In this paper, TiO2 catalysts doped with different Fe contents (Fe-TiO2 catalysts) were prepared by coprecipitation method and the Fe loading capacity was optimized, and then the integrated pollutant removal experiment was conducted, in which TiO2 doped with Fe as catalyst and H2O2 as oxidant. The results show that under the condition of constant H2O2/(SO2 + NO) molar ratio, low concentration of SO2 can promote the oxidation and removal efficiency of NO, while high concentration of SO2 can inhibit the removal of NOx. The pollutant removal efficiency is proportional to the amount of catalyst, liquid-gas ratio and pH value of the absorbing solution. The optimal experimental conditions are H2O2/(SO2 + NO) molar ratio 1.5, space velocity ratio 10,000 h-1, H2O2 mass fraction 10 wt%, liquid gas ratio 10, pH 10. Correspondingly, NO oxidation efficiency reaches 88%, NOx removal efficiency 85.6%, and SO2 is almost completely removed. The microstructure of the catalyst before and after the reaction was characterized, and the crystal structure did not change obviously. However, with the deepening of the reaction, the specific surface area of the catalyst decreases, and the catalytic effect decreases slightly.

CS27109, A Selective Thyroid Hormone Receptor-ß Agonist Alleviates Metabolic-Associated Fatty Liver Disease in Murine Models.

Background/Aim: Thyroid hormone receptor-ß (THR-ß) agonists play crucial roles in dyslipidemia and metabolic associated fatty liver disease (MAFLD). We developed a novel oral and liver-targeted THR-ß agonist, CS27109, and evaluated its efficacy in the treatment of metabolic disorders. Materials and Methods: We evaluated in vitro and in vivo efficacy and/or safety of CS27109 along with MGL3196 (a phase III THR-ß agonist). Results: CS27109 showed pronounced activity and selectivity to THR-ß and favorable PK properties, which was equivalent to MGL3196. In the hamster model, animals treated with a high dose of CS27109 showed equivalent reductions in serum TC and LDL-c with groups treated with MGL3196. In the rat model, CS27109 and MGL3196 reduced serum ALT, TC, TG, LDL-c, liver weight ratio, and liver steatosis. CS27109 simultaneously decreased liver TG and TC, and MGL3196 additionally reduced AST. In the mouse model, CS27109 dose-dependently reduced serum AST, ALT, liver inflammation, and NAS score, and also downregulated TC, LDL-c, liver steatosis, and fibrosis, but not in a dose-dependent manner. MGL3196 revealed an equivalent effect with CS27109 in that model. CS27109 also exhibited tolerable toxicity to the heart. Conclusions: CS27109 shows comparative in vitro and in vivo efficacy with MGL3196, suggesting its potential therapeutic application in the treatment of MAFLD such as dyslipidemia and steatohepatitis.

ARHGAP6 inhibits bladder cancer cell viability, migration, and invasion via ß-catenin signaling and enhances mitomycin C sensitivity.

The Rho/ROCK pathway regulates diverse cellular processes and contributes to the development and advancement of several types of human cancers. This study investigated the role of specific Rho GTPase-activating proteins (RhoGAP), ARHGAP6, in bladder cancer (BC). In this study, ARHGAP6 expression in BC and its clinical significance were investigated. In vitro and in vivo assays were used to explore the tumor-related function and the underlying molecular mechanism ARHGAP6 of in BC. The mRNA and protein levels of ARHGAP6 significantly reduced in human BC tissues and cell lines compared with corresponding adjacent non-cancerous tissues and normal urothelial cells. In vitro, ARHGAP6 overexpression markedly decreased the viability, migration, and invasion of BC cells. Interestingly, low ARHGAP6 expression in BC strongly correlated with poor patient survival and was highly associated with metastasis and ß-catenin signaling. Furthermore, ARHGAP6 expression strongly influenced the sensitivity of BC cells to mitomycin C treatment. Together, our results demonstrate that ARHGAP6 plays critical roles in regulating the proliferation, migration, invasion, and metastasis of BC cells possibly via the modulation of ß-catenin and strongly influences the chemosensitivity of BC cells.

Qici Sanling Decoction Suppresses Glutamine Consumption and Bladder Cancer Cell Growth through Inhibiting c-Myc Expression.

Traditional Chinese medicine (TCM) is widely used as an alternative therapy for cancer treatment in China. Glutamine catabolism plays an important role in cancer development. Qici Sanling decoction (QCSL) suppresses bladder cancer growth. However, the association between QCSL and glutamine catabolism remains unknown. In this study, different doses of QCSL were applied to T24 cells, followed by the measurements of cell viability and apoptosis using CCK-8 and Annexin V/PI assay, respectively. Furthermore, glutamine consumption was detected using the glutamine assay kit. QCSL was observed to inhibit cell growth and induced cell apoptosis in a dose-dependent manner. Analysis of glutamine consumption revealed that QCSL suppressed glutamine consumption in T24 cells. Furthermore, QCSL decreased the mRNA and protein levels of c-Myc, GLS1, and SLC1A5. All these effects induced by QCSL could be alleviated by c-Myc overexpression, indicating c-Myc was involved in the protective role of QCSL in bladder cancer. In addition, QCSL was found to inhibit tumor growth in the xenograft tumor model. The similar results were obtained in tumor samples that protein levels of c-Myc, GLS1, and SLC1A5 were decreased upon treatment with QCSL. In conclusion, QCSL suppresses glutamine consumption and bladder cancer cell growth through inhibiting c-Myc expression.

Nuclear magnetic resonance spectroscopy as a new approach for improvement of early diagnosis and risk stratification of prostate cancer.

Prostate cancer (PCa) is the second most common male cancer worldwide and the fifth leading cause of death from cancer in men. Early detection and risk stratification is the most effective way to improve the survival of PCa patients. Current PCa biomarkers lack sufficient sensitivity and specificity to cancer. Metabolite biomarkers are evolving as a new diagnostic tool. This review is aimed to evaluate the potential of metabolite biomarkers for early detection, risk assessment, and monitoring of PCa. Of the 154 identified publications, 27 and 38 were original papers on urine and serum metabolomics, respectively. Nuclear magnetic resonance (NMR) is a promising method for measuring concentrations of metabolites in complex samples with good reproducibility, high sensitivity, and simple sample processing. Especially urine-based NMR metabolomics has the potential to be a cost-efficient method for the early detection of PCa, risk stratification, and monitoring treatment efficacy.

Overexpression of high mobility group box 1 with poor prognosis in patients after radical prostatectomy.

UNLABELLED: What's known on the subject? and What does the study add? Recent studies have indicated that high mobility group box 1 (HMGB1) is related to the development and progression of human carcinomas. However, further studies were required to confirm the roles played by HMGB1 in clinical prostate cancer treatment. We investigated the relationship between HMGB1 expression and the characteristics of prostate cancer, and also evaluated the significance of HMGB1 as a prognostic factor for biochemical recurrence-free survival after radical prostatectomy. OBJECTIVE: • To investigate high mobility group box 1 (HMGB1) expression in human prostate cancer (PC) cell lines and its prognostic significance after radical prostatectomy (RP). PATIENTS AND METHODS: • Quantitative reverse-transcription polymerase chain reaction and western blotting were used to detect HMGB1 mRNA and protein expression in PC cell lines. • Immunohistochemistry coupled with the tissue microarray technique was performed to evaluate HMGB1 protein expression in 168 primary prostatectomy tissue samples. • Clinicopathological features were compared between positive and negative HMGB1 protein expression groups. • Kaplan-Meier and multivariate Cox analyses were applied to determine the prognostic value of HMGB1 protein expression on biochemical recurrence (BCR) for patients with PC who were undergoing RP. RESULTS: • There were three PC cells (DU145, PC-3 and LNCaP) with overexpression of HMGB1 mRNA and protein compared to the non-transformed immortalized prostate cell RWPE-1. • A total of 60.1% (101/168) of the PC samples appeared to have positive protein expression of HMGB1. • HMGB1 protein expression was correlated with some clinicopathological parameters, such as pathological stage (pT) (P= 0.011), Gleason score, preoperative prostate-specific antigen concentration and BCR (P < 0.001, respectively). • Positive HMGB1 immunostaining in patients with PC who were undergoing RP was significantly associated with poor median BCR-free survival (23.1 months vs 15.6 months) (P < 0.001). • Multivariate analysis indicated that HMGB1 protein expression was an independent prognostic factor for BCR-free survival after RP (hazard ratio = 2.348, 95% confidence interval = 1.373-6.361, P= 0.001). CONCLUSIONS: • Up-regulation of HMGB1 mRNA and protein concentrations was confirmed in PC cells. • HMGB1 expression may contribute to the malignant progression of PC. • HMGB1 presents as a novel prognostic factor for BCR after RP.