Exploring the Mechanism of Cardiorenal Protection with Finerenone Based on Network Pharmacology.

INTRODUCTION: Large prospective trials have demonstrated that finerenone could reduce the risk of cardiovascular death and progression of renal failure among patients with chronic kidney disease associated heart failure and/or type 2 diabetes mellitus (T2DM). The aim of this study was to explore the molecular mechanism of finerenone in the treatment of cardiorenal diseases through network pharmacology. METHODS: The STITH, SwissTargetPrediction, PharmMapper, DrugBank, and ChEMBL databases were used to screen the targets of finerenone. The disease-related targets were retrieved from the DisGeNET, GeneCards, CTD, OMIM, and MalaCards databases. The protein-protein interaction (PPI) network was conducted with STRING database and Cytoscape software. The clusterProfiler R package was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The interactions of key targets and finerenone were analyzed by molecular docking in Autodock software. Diabetes mellitus was induced by intraperitoneal injection of streptozotocin. Histopathology of myocardial and renal tissues was observed by hematoxylin-eosin (HE) staining, and detection of protein expressions was conducted using Western blotting. RESULTS: A total of 111 potential cardiorenal targets of finerenone were identified. The main mechanisms of action may be associated with lipids and atherosclerosis, fluid shear stress and atherosclerosis, AGE-RAGE signaling pathway in diabetic complications, and diabetic cardiomyopathy. The hub targets demonstrated by the PPI network were CASP3, ALB, MMP9, EGFR, ANXA5, IGF1, SRC, TNFRSF1A, IL2, and PPARG, and the docking results suggested that finerenone could bind to these targets with high affinities. HE staining revealed the cardiorenal protection of finerenone on diabetic mice. In addition, the protein expressions of CASP3 and EGFR were increased while ALB was decreased in myocardial and renal tissues in diabetic mice compared with control mice, which were reversed by finerenone. CONCLUSION: This study suggested that finerenone exerts cardiorenal benefits through multiple targets and pathways.

Asymptomatic adult Wilms' tumor: A case report.

Wilms' tumor, also called nephroblastoma, is an extremely uncommon kidney tumor of adulthood. We reported a adult man with a left kidney mass diagnosed as Wilms' tumor. Case presentation: A 25-year-old man was hospitalized due to injury of the anterior cruciate ligament of the right knee. Preoperative imaging accidentally revealed a mass measuring 53 × 46 mm involving the middle and lower segments of the left kidney without evidence supporting the invasion of the surrounding structures or metastasis. The patient didn't show any symptom commonly occurred in Wilms' tumor, such as flank pain or hematuria. After nephrectomy, the diagnosis of adult Wilms' tumor was confirmed based on the tumor morphology and immunohistochemical findings. Conclusion: In adult patients without any clinical manifestations or favorable imaging findings for low-stage renal cell carcinoma, the diagnosis of Wilms' tumor should be taken into consideration.

Loss of protocadherin-17 (PCDH-17) promotes metastasis and invasion through hyperactivation of EGFR/MEK/ERK signaling pathway in hepatocellular carcinoma.

Metastasis has been one of the major reasons for cancer-related mortality, with multiple genes and pathways being involved in this complex process. Given the molecular variations underlying metastasis of hepatocellular carcinoma (HCC) remains largely unknown; in our previous work, we found copying number of protocadherin-17 (PCDH-17) was significantly deleted in HCC tissues that occurred to metastasize compared with that in the primary HCC without metastasis. Therefore, we hypothesized that PCDH-17 may suppress the metastasis of HCC. There has been, however, no relevant literature available regarding PCDH-17 in HCC. In the present study, we have immunohistochemically detected and clinicopathologically analyzed the expression of PCDH-17 in vivo in clinical tissues; besides, we have explored the role of PCDH-17 ex vivo using a panel of HCC cell lines. It was discovered that PCDH-17 expression was clinically correlated with overall prognosis as well as metastasis in vivo and that PCDH-17 inhibited metastasis via EGFR/MEK/ERK signaling pathway ex vivo. Together, our results obtained both in vivo and ex vivo suggested that activation of EGFR/MEK/ERK signaling pathway through PCDH-17 promotes metastasis in HCC.

Downregulation of NUF2 inhibits tumor growth and induces apoptosis by regulating lncRNA AF339813.

Recent studies have shown that NUF2 (Ndc80 kinetochore complex component) play important roles in multiple human cancers. In our previous report, NUF2 expression was stronger in tumor tissues than in normal pancreatic tissues. However, whether and how NUF2 play a role in pancreatic cancer progression remains largely unknown. The aim of our study is to investigate the expression and functional role of NUF2 in human PC. NUF2 expression was measured in 10 pairs of PC cancerous and noncancerous tissue samples by quantitative real-time PCR. The effects of NUF2 on PC cells were studied by RNA interference. Apoptosis and cell cycle were analyzed by flow cytometry. Cells viability was evaluated using MTT. CDK4/CDK6 activity was measured by Western blot assay. LncRNAs regulated by NUF2 were gained from bioinformatics analysis. The role of LncRNA AF339813, regulated by NUF2, was finally characterized in PC cells by siRNA. Our results showed that NUF2 mRNA and protein were significantly overexpressed in Human PC tissues and several PC cell lines. Through bioinformatics analysis and knockdown NUF2 in PC cells, we found LncRNA AF339813 was positively regulated by NUF2. We further demonstrated that knockdown of AF339813 by siRNA in PC cells significantly reduced cell proliferation and promoted apoptosis. Thus, we conclude that NUF2 is consistently overexpressed in human PC and NUF2 is closely linked with human PC progression through the meditator LncRNA AF339813. Our studies may contribute to understand the molecular mechanism of PC pathogenesis and clinical therapy.

[Effects and mechanism of decorin on the proliferation of HuH7 hepatoma carcinoma cells in vitro].

AIM: To investigate the effects and mechanism of decorin( DCN) on the proliferation of HuH7 hepatoma carcinoma cell line in vitro. METHODS: Hepatoma carcinoma cells was cultured with DCN in different concentration (0, 25, 50, 75, 100, 125, 150, 200 microg/L) for different time(12, 24, 48, 72 h and 2 weeks). Cell activities were studied by MTT and clone test. The changes of cell cycle and apoptosis were analyzed by Flow cytometry. RESULTS: The proliferation of HuH7 cells could be inhibited by DCN in vitro and the inhibition effect was the time and dose dependent relationship. DCN could block cell cycle at G(1); phase. Apoptosis of hepatocarcinoma cells could be efficiently induced by DCN in a time/dose-dependent manner. CONCLUSION: DCN may be a negative regulatory protein inhibiting hepatoma carcinoma cell proliferation through inhibiting cell cycle and inducing apoptosis of cell in vitro.