ALYREF m5C RNA methylation reader predicts bladder cancer prognosis by regulating the tumor immune microenvironment.

BACKGROUND: 5-Methylcytidine (m5C) methylation is a recently emerging epigenetic modification that is closely related to tumor proliferation, occurrence, and metastasis. This study aimed to investigate the clinicopathological characteristics and prognostic value of m5C regulators in bladder cancer (BLCA), and their correlation with the tumor immune microenvironment. METHODS: Thirteen m5C RNA methylation regulators were analyzed using RNA-sequencing and corresponding clinical information obtained from the TCGA database. The Cluster Profiler package was used to analyze the gene ontology function of potential targets and enriched the Kyoto Encyclopedia of Genes and Genomes pathway. Kaplan-Meier survival analysis was used to compare survival differences using the log-rank test and univariate Cox proportional hazards regression. The correlation between signature prognostic m5C regulators and various immune cells was analyzed. Univariate and multivariate Cox regression analyses identified independence of the ALYREF gene signature. RESULTS: Nine out of the 13 m5C RNA methylation regulators were differentially expressed in BLCA and normal samples and were co-expressed. These 9 regulators were associated with clinicopathological tumor characteristics, particularly high or low tumor risk, pT or pTNM stage, and migration. Consensus clustering analysis divides the BLCA samples into 4 clusters. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment annotation and gene ontology function analysis identified 273 upregulated and 594 downregulated genes in BLCA. Notably, only ALYREF was significantly correlated with OS (P < .05). ALYREF exhibited significant infiltration levels in macrophage cells. Therefore, we constructed a nomogram for ALYREF as an independent prognostic factor. Additionally, we observed that both the mRNA and protein levels of ALYREF were upregulated, and immunofluorescence showed that ALYREF was mainly distributed in nuclear speckles. ALYREF overexpression was significantly associated with poor OS. CONCLUSION: Our findings demonstrated the potential of ALYREF to predict clinical prognostic risks in BLCA patients and regulate the tumor immune microenvironment. As such, ALYREF may serve as a novel prognostic indicator in BLCA patients.

An analysis of the relationship between donor and recipient biomarkers and kidney graft function, dysfunction, and rejection.

BACKGROUND: The study aimed to find predictive biomarkers to evaluate donor kidney function to predict graft dysfunction as well as to assess an early signs of acute graft rejection. METHOD: Twenty-seven deceased donors and 54 recipients who underwent a successful kidney transplantation were enrolled in the study. An assessment was made in serum and urine from donors and recipients to measure the following biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinase 2 (TIMP-2) and urinary N-acetyl-b-D-glucosaminidase (uNAG). These biomarkers were used to establish a model for predicting a reduced graft function (RGF) classified as either a delayed or slow graft function. RESULT: Our analysis suggest that out of four tested biomarkers, the serum TIMP-2 and uNAG levels of the donors had a predictive value for RGF; the area under the receiver operating characteristic curves (AUROC) of serum TIMP-2 and uNAG were 0.714 and 0.779, respectively. The combined best fitting prediction model of serum TIMP-2, uNAG, and creatinine levels was better in predicting RGF than the serum creatinine level alone. In addition, the recipient serum TIMP-2 level on the third day post-transplantation (D3) was associated with the estimated glomerular filtration rate (eGFR) on the seventh day post-transplantation (D7; OR 1.119, 95% CI 1.016-1.233, p = 0.022). Furthermore, the ROC curve value revealed that the AUROC of TIMP-2 on D3 was 0.99 (95% CI 0.97-1, p < 0.001), and this was the best predictive value of the renal function on D7. CONCLUSIONS: Donor serum TIMP-2 and uNAG levels are useful predictive biomarkers because they can provide the donor-based prediction for RGF.

Network pharmacology and molecular docking analysis on the mechanism of Baihe Zhimu decoction in the treatment of postpartum depression.

Baihe Zhimu decoction (BZD) has significant antidepressant properties and is widely used to treat mental diseases. However, the multitarget mechanism of BZD in postpartum depression (PPD) remains to be elucidated. Therefore, the aim of this study was to explore the molecular mechanisms of BDZ in treating PPD using network pharmacology and molecular docking. Active components and their target proteins were screened from the traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The PPD-related targets were obtained from the OMIM, CTD, and GeneCards databases. After overlap, the targets of BZD against PPD were collected. Protein-protein interaction (PPI) network and core target analyses were conducted using the STRING network platform and Cytoscape software. Moreover, molecular docking methods were used to confirm the high affinity between BZD and targets. Finally, the DAVID online tool was used to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of overlapping targets. The TCMSP database showed that BZD contained 23 active ingredients in PPD. KEGG analysis showed that overlapping genes were mainly enriched in HIF-1, dopaminergic synapses, estrogen, and serotonergic synaptic signalling pathways. Combining the PPI network and KEGG enrichment analysis, we found that ESR1, MAOA, NR3C1, VEGFA, and mTOR were the key targets of PPD. In addition, molecular docking confirmed the high affinity between BZD and the PPD target. Verified by a network pharmacology approach based on data mining and molecular docking methods, the multi-target drug BZD may serve as a promising therapeutic candidate for PPD, but further in vivo/in vitro experiments are needed.

Prostate Cancer Therapy Using Docetaxel and Formononetin Combination: Hyaluronic Acid and Epidermal Growth Factor Receptor Targeted Peptide Dual Ligands Modified Binary Nanoparticles to Facilitate the in vivo Anti-Tumor Activity.

Objective: To evaluate the prostate cancer therapy efficiency of the synergistic combination docetaxel (DTX) and formononetin (FMN) in one nano-sized drug delivery system. Hyaluronic acid (HA) and epidermal growth factor receptor-targeted peptide (GE11) dual ligands were applied to modify the nano-systems. Methods: In this study, GE11-modified nanoparticles (GE-NPs) were applied for the loading of DTX, and HA-decorated NPs (HA-NPs) were used to encapsulate FMN. HA and GE11 dual ligand-modified binary nanoparticles (HAGE-DTX/FMN-NPs) were constructed by the self-assembling of GE-NPs and HA-NPs. The anti-PCa ability of the system was evaluated in vitro on PC-3 human prostate carcinoma cells (PC3 cells) and in vivo on PC3 tumor-bearing mice in comparison with single NPs and free drugs formulations. Results: HA/GE-DTX/FMN-NPs were nano-sized particles with smaller particles coating on the inner core and achieved a size of 189.5 nm. HA/GE-DTX/FMN-NPs showed a cellular uptake efficiency of 59.6%, and a more efficient inhibition effect on PC3 cells compared with single ligand-modified NPs and free drugs. HA/GE-DTX/FMN-NPs showed significantly higher tumor inhibition efficiency than their single drug-loaded counterparts and free drugs. Conclusion: HA/GE-DTX/FMN-NPs have a synergistic anti-tumor effect and also could the reduce unexpected side effects during the cancer therapy. It could be used as a promising anti-PCa system.

miR-1293 Suppresses Tumor Malignancy by Targeting Hydrocyanic Oxidase 2: Therapeutic Potential of a miR-1293/Hydrocyanic Oxidase 2 Axis in Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is a common cancer, and extensive research suggests that microRNA may play an important role in the progression of RCC. The emphasis of this article was to reveal the function and mechanism of microRNA-1293(miR-1293) in the development of RCC tumors. First, the authors carried out bioinformatics analysis. The differential expression of miR-1293 in RCC tumor and normal cells was analyzed using the data from The Cancer Genome Atlas database, and Kaplan-Meier survival analysis was carried out to test the survival rate. Subsequently, the miR-1293 expression in RCC cell lines was examined by quantitative real-time PCR. Then Cell counting kit-8 and Transwell assays were executed to detect the function of miR-1293 in RCC. Bioinformatics prediction, western blotting, and dual-luciferase reporter assay were set to check the target gene of miR-1293. Finally, they conducted rescue experiments to verify whether the regulation of miR-1293 on the biological function of RCC cells was achieved by regulating hydrocyanic oxidase 2 (HAO2). Bioinformatics results showed that miR-1293 was highly expressed in RCC, and the miR-1293 high-expression group showed a lower survival rate than the miR-1293 low-expression group, which suggested that the high expression of miR-1293 was related to unfavorable prognosis in RCC. Subsequent assays evidenced that upregulation of miR-1293 expression significantly increased the cell viability and promoted cell migration and invasion in RCC. Silencing miR-1293 expression showed opposite results. Furthermore, HAO2 was confirmed to be a direct target gene of miR-1293 by dual-luciferase reporter assay, and miR-1293 negatively regulated the expression of HAO2. Moreover, rescue experiments evidenced that miR-1293 reduced the cell viability, invasion, and migration of RCC by regulating HAO2. In sum, miR-1293 can regulate the viability, invasion, and migration of RCC tumor cells by targeting HAO2, suggesting that miR-1293 can be used as a new biomarker for clinical treatment of RCC.

Co-delivery of docetaxel and curcumin prodrug via dual-targeted nanoparticles with synergistic antitumor activity against prostate cancer.

PURPOSE: Combination therapy is increasingly used as a primary cancer treatment regimen. In this report, we designed EGFR peptide decorated nanoparticles (NPs) to co-deliver docetaxel (DTX) and pH sensitive curcumin (CUR) prodrug for the treatment of prostate cancer. RESULTS: EGFR peptide (GE11) targeted, pH sensitive, DTX and CUR prodrug NPs (GE11-DTX-CUR NPs) had an average diameter of 167nm and a zeta potential of -37.5mV. The particle size of the NPs was adequately maintained in serum and a sustained drug release pattern was observed. Improved inhibition of cancer cell and tumor tissue growth was shown in the GE11-DTX-CUR NPs group compared to the other groups. CONCLUSION: It can be summarized that DTX and CUR prodrug could be delivered into tumor cells simultaneously by the GE 11 targeting and the EPR effect of NPs. The resulting GE11-DTX-CUR NPs is a promising system for the synergistic antitumor treatment of prostate cancer.