Network Pharmacology-Based Study on the Active Component and Mechanism of the Anti-Non-Invasive and Invasive Bladder Urothelial Carcinoma Effects of Zhuling Jisheng Decoction

Zhuling Jisheng decoction is employed for the treatment of bladder urothelial cancer in clinical practice of traditional Chinese medicine. However, there are few studies on its precise mechanism. For the antibladder cancer action of Zhuling Jisheng decoction, a network pharmacological technique was used to design a component/target/pathway molecular regulatory network. The TCMSP dataset was used to identify the chemical makeup of Zhuling Jisheng decoction, which was then analyzed and assessed for oral bioavailability and pharmacological similarity. The chemical composition of Zhuling Jisheng decoction was identified through the TCMSP database, and it was evaluated and screened based on oral bioavailability and drug similarity. The GEO database was searched for genes associated with urothelial bladder carcinoma, and gene targets associated with bladder urothelial cancer resistance were chosen by comparison. The function and linked pathways of the target genes were examined and screened using annotation, visualization, and a comprehensive discovery database. The impact of Zhuling Jisheng decoction on urothelial bladder cancer was studied using Cytoscape software to create a component/target/pathway network. Finally, 69 and 55 target genes were discovered for noninvasive bladder urothelial cancer and invasive bladder urothelial cancer, respectively. In noninvasive urothelial cancer, 118 pathways were highly enriched, including the TNF signaling pathway and the IL-17 signaling route. 103 pathways were highly enriched in invasive urothelial cancer, including the p53 signaling route, bladder cancer route, and calcium signaling route. There were 18 and 15 drug targets associated with noninvasive and invasive bladder urothelial carcinoma prognoses. Many signaling pathways directly act on tumours, and indirect pathways inhibit the development of bladder urothelial carcinoma. This research establishes a scientific foundation for further research into the framework of action of Zhuling Jisheng decoction in the therapy of bladder urothelial cancer.

Progress in the Research and Targeted Therapy of ErbB/HER Receptors in Urothelial Bladder Cancer

Bladder cancer is a lethal malignancy and a majority of bladder cancer arise from urothelial cells. Infiltration and metastasis are barriers for the radical cystectomy to achieve favored outcome and are the main cause of death. Systemic therapy, including chemotherapy, targeted therapy, and immunotherapy, is fundamental for these patients. erbB/HER receptors are found to be overexpressed in a subgroup of urothelial carcinoma, targeting erbB/HER receptors in these patients was found to be an efficient way in the era of genetic testing. To evaluate the role of erbB/HER receptors in bladder cancer, we reviewed the literature and ongoing clinical trials as regards to this topic to unveil the context of erbB/HER receptors in bladder cancer, which probably help to solidate the theoretical basis and might instruct further research.

Proteomics analysis in urinary bladder cancer patients identifies urinary SOD2 as a predictive marker of recurrence

Early non-invasive detection of tumor is an urgent clinical need for managing urothelial bladder cancer. Cystoscopy and cytology are the current standards for diagnosis of recurrence, but are limited by low sensitivity. Quantitative proteomics tool was employed to identify important deregulated molecules in bladder cancer tissues and validated using Western blot and immunohistochemistry analysis. A set of 1137 proteins were identified in four paired bladder cancer patients. Among these, 64 proteins were deregulated in all cases among which 9 were commonly up-regulated. The Ingenuity Pathway Analysis (IPA) generated top 11 Networks in which three commonly upregulated (SERPING1, SOD2 and HSPB6) proteins were involved and selected for further validation. Tissue expression of SOD2, SERPING1 and HSPB6 monitored in an independent sample set (n=18) by immuno-histochemical analysis showed similar profile. Western blot analysis of these proteins in urine of bladder cancer (n=26) and healthy subjects (n=10) showed a specificity and sensitivity of >80% for SOD2 and selected for further validation in a separate set (n=150) by ELISA. Significant elevation in urinary SOD2 level was found in urothelial bladder cancer patients compared to healthy controls and in recurrent cases compared to primary (p-value<0.001). Kaplan Meier survival analysis showed urinary SOD2 concentration >2,100 pg/ml was significantly associated with poorer survival and cumulative survival of patient with low SOD2 concentration was 34.4% compared to 18.9% in patient with high SOD2 at 24 months (p=0.025). The study identifies SOD2 as a non-invasive biomarker which may help to extend the period between cystoscopies during follow-up.

Identification of prognostic and therapeutic value of CC chemokines in Urothelial bladder cancer: evidence from comprehensive bioinformatic analysis

Background Urothelial bladder cancer (BC) is one of the most prevalent malignancies with high mortality and high recurrence rate. Angiogenesis, tumor growth and metastasis of multiple cancers are partly modulated by CC chemokines. However, we know little about the function of distinct CC chemokines in BC. Methods ONCOMINE, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan–Meier plotter, cBioPortal, GeneMANIA, and TIMER were used for analyzing differential expression, prognostic value, protein–protein interaction, genetic alteration and immune cell infiltration of CC chemokines in BC patients based on bioinformatics. Results The results showed that transcriptional levels of CCL2/3/4/5/14/19/21/23 in BC patients were significantly reduced. A significant relation was observed between the expression of CCL2/11/14/18/19/21/23/24/26 and the pathological stage of BC patients. BC patients with high expression levels of CCL1, CCL2, CCL3, CCL4, CCL5, CCL8, CCL13, CCL15, CCL17, CCL18, CCL19, CCL22, CCL25, CCL27 were associated with a significantly better prognosis. Moreover, we found that differentially expressed CC chemokines are primarily correlated with cytokine activity, chemokines receptor binding, chemotaxis, immune cell migration. Further, there were significant correlations among the expression of CC chemokines and the infiltration of several types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells). Conclusions This study is an analysis to the potential role of CC chemokines in the therapeutic targets and prognostic biomarkers of BC, which gives a novel insight into the relationship between CC chemokines and BC.

Sensitive identification of known and unknown protease activities by unsupervised linear motif deconvolution

The cleavage-site specificities for many proteases are not well-understood, restricting the utility of supervised classification methods. We present an algorithm and web interface to overcome this limitation through the unsupervised detection of overrepresented patterns in protein sequence data, providing insight into the mixture of protease activities contributing to a complex system. Here, we apply the RObust LInear Motif Deconvolution (RoLiM) algorithm to confidently detect substrate cleavage patterns for SARS-CoV-2 Mpro protease in N terminome data of an infected human cell line. Using mass spectrometry-based peptide data from a case-control comparison of 341 primary urothelial bladder cancer cases and 110 controls, we identified distinct sequence motifs indicative of increased MMP activity in urine from cancer patients. Evaluation of N terminal peptides from patient plasma post-chemotherapy detected novel Granzyme B/Corin activity. RoLiM will enhance unbiased investigation of peptide sequences to establish the composition of known and uncharacterized protease activities in biological systems.