Comprehensive analysis of pain genes in prognosis of kidney renal clear cell carcinoma and tumor immunotherapy: A comprehensive bioinformatic study.

Background: The effect of pain genes (NAV1, EHMT2, SP1, SLC6A4, COMT, OPRM1, OPRD1, CYP2D6, and CYP3A4) have not been reported previously in kidney renal clear cell carcinoma (KIRC) patients and thus we made a comprehensive analysis of pain genes in the prognosis of KIRC and tumor immunotherapy. Methods: In this study, TCGA, Kaplan-Meier plotter, Metascape, STRING, Human Protein Atlas, Single Cell Expression Atlas database, LinkedOmics, cBioPortal, MethSurv, CancerSEA, COSMIC database and R package (ggplot2, version 3.3.3) were used for comprehensive analysis of pain genes in KIRC. Pearson and Spearman correlation coefficients were for co-expression analysis. Immunotherapy and TISIDB database were used for tumor Immunotherapy. Results: Representative pain genes (SP1, SLC6A4, COMT, OPRD1, CYP2D6, and CYP3A4) were statistically significant (p < 0.0001) in the prognosis of KIRC. Immunotherapy (anti-PD-1 therapy, anti-PD-L1 therapy, and anti-CTLA4 therapy) and immunomodulator (immunoinhibitor, immunostimulator, and MHC molecule) in KIRC were significant associated with pain genes (SP1, SLC6A4, COMT, OPRD1, CYP2D6, and CYP3A4), which were the important addition to clinical decision making for patients. Conclusions: Our study uncovered a mechanism for the effect of pain genes on KIRC outcome via the modulation of associated co-expression gene networks, gene variation, and tumor Immunotherapy.

Activated Hepatic Nuclear Factor-κB in Experimental Colitis Regulates CYP2A5 and Metronidazole Disposition.

Systemic exposure of metronidazole is increased in patients with inflammatory bowel diseases (IBDs), while the underlying mechanism remains unknown. Here, we aim to decipher the mechanisms by which experimental colitis regulates metronidazole disposition in mice. We first confirmed that the systemic exposure of metronidazole was elevated in dextran sulfate sodium (DSS)-induced experimental colitis. Hepatic microsomal incubation with metronidazole revealed that the production rate of 2-hydroxymetronidazole was inhibited, suggestive of a diminished hydroxylation reaction upon colitis. Remarkably, the hydroxylation reaction of metronidazole was selectively catalyzed by CYP2A5, which was downregulated in the liver of colitis mice. In addition, hepatic nuclear factor (NF)-κB (a prototypical and critical signaling pathway in inflammation) was activated in colitis mice. Luciferase reporter and chromatin immunoprecipitation assay indicated that NF-κB downregulated Cyp2a5 transcription through binding to an NF-κB binding site (-1711 to -1720 bp) in the promoter. We further verified that the regulatory effects of colitis on CYP2A5 depended on the disease itself rather than the DSS compound. First, one-day administration of DSS did not alter mRNA and protein levels of CYP2A5. Moreover, CYP2A5 was suppressed in the Il-10-/- spontaneously developing colitis model. Furthermore, Cyp2a5 expression was downregulated in both groups of mice with modest or severe colitis, whereas the expression change was much more significant in severe colitis as compared to modest colitis. Altogether, activated hepatic NF-κB in experimental colitis regulates CYP2A5 and metronidazole disposition, revealing the mechanism of pharmacokinetic instability under IBDs, and providing a theoretical foundation for rational drug use in the future.

Single-Cell Gene Expression Analysis in Patients with Medullary Sponge Kidney and a Retrospective Study.

Objective: To establish better diagnosis thinking and provide advanced understanding of MSK, the CT imaging features, clinical characteristics, and the expression of suspected genes in the kidney spatiotemporal immune zonation and fetal renal development were investigated. Methods: 17 patients with MSK hospitalized in our hospital were selected as our research subjects. Human Phenotype Ontology, MalaCards: The Human Disease Database, GeneCards: The Human Gene Database, Human Protein Atlas, and Single Cell Expression Atlas were used to analyze this disease. Results: In our 17 patients, the incidence of MSK tended to be the same in male and female, and the onset age of MSK was probably 31-50 years old. The top one related disease of MSK was nephrocalcinosis and the most frequent phenotype related to MSK was nephrolithiasis. In addition, the expression of HNF1B, CLCN5, GDNF, ATP6V0A4, ATP6V1B1, LAMA2, RET, ACAN, and ABCC8 has been implicated in both human kidney immune zonation and fetal kidney development. Conclusions: HNF1B, CLCN5, GDNF, ATP6V0A4, ATP6V1B1, LAMA2, RET, ACAN, and ABCC8 could be independent indicators for the diagnosis and preventive intervention of MSK patients, and abnormal kidney development due to mutations in key genes was the underlying cause of MSK.

Comprehensive Analysis of Transcriptional Expression of hsa-mir-21 Predicted Target Genes and Immune Characteristics in Kidney Renal Clear Cell Carcinoma.

Background: To uncover advanced prognosis biomarkers in patient with kidney renal clear cell carcinoma (KIRC), our study was the first to make a comprehensive analysis of hsa-mir-21 predicted target genes and explore the immune characteristics in KIRC. Methods: In this study, the comprehensive analysis of hsa-mir-21 predicted target genes and immune characteristics in KIRC were analyzed via TIMER2.0, UALCAN, Metascape, Kaplan-Meier plotter, Human Protein Atlas, CancerSEA, JASPAR, GEPIA, R package: GSVA package (version 1.34.0) & immune infiltration algorithm (ssGSEA) and R package: RMS package (version 6.2-0) & SURVIVAL package (version 3.2-10). Results: Up-transcriptional expressions of RP2, NFIA, SPRY1 were significantly associated with favorable prognosis in KIRC, whereas that of TGFBI was markedly significantly to unfavorable prognosis. Additionally, RP2, NFIA, SPRY1 and TGFBI were significantly relevant to the immune infiltration in KIRC. Finally, ZNF263 was a common predicted transcription factor of RP2, NFIA, SPRY1 and TGFBI, which can as an independent indicator for prognosis in KIRC patients. Conclusions: Hsa-mir-21 predicted target genes (RP2, NFIA, SPRY1 and TGFBI) and the common transcription factor ZNF263 could be the advanced prognosis biomarkers in KIRC patients.

Transcriptional expressions of hsa-mir-183 predicted target genes as independent indicators for prognosis in bladder urothelial carcinoma.

OBJECTIVE: To uncover novel prognostic and therapeutic targets for BLCA, our study is the first to investigate the role of hsa-mir-183 and its up-regulated predicted target genes in bladder urothelial carcinoma. METHODS: To address this issue, our study explored the roles of hsa-mir-183 predicted target genes in the prognosis of BLCA via UALCAN, Metascape, Kaplan-Meier plotter, Human Protein Atlas, TIMER2.0, cBioPortal and Genomics of Drug Sensitivity in Cancer databases. RESULTS: High transcriptional expressions of PDCD6, GNG5, PHF6 and MAL2 were markedly relevant to favorable OS in BLCA patients, whereas SLC25A15 and PTDSS1 had opposite expression significance. Additionally, high transcriptional expression of PDCD6, GNG5, PHF6, MAL2, SLC25A15 and PTDSS1 were significantly correlated with BLCA individual cancer stages and molecular subtypes. Furthermore, high mutation rate of PDCD6, MAL2, SLC25A15 and PTDSS1 were observed. Finally, TP53 mutation of PDCD6, GNG5, PHF6, MAL2, SLC25A15 and PTDSS1 has guiding significance for drug selection in BLCA. CONCLUSIONS: PDCD6, GNG5, PHF6, MAL2, SLC25A15 and PTDSS1 could be the advanced independent indicators for prognosis of BLCA patients, and TP53-mutation might be a biomarker for drug option in BLCA patients.

Investigation of Lymphocyte Subsets in Peripheral Blood of Patients with Benign Prostatic Hyperplasia.

OBJECTIVE: To investigate the immune profiles in benign prostatic hyperplasia, changes in the absolute number of lymphocyte subsets and the proportion of T lymphocyte subsets were detected. METHODS: Absolute value of lymphocyte subsets in peripheral blood (T, B and NK cells) and the proportion of T lymphocyte (native CD4+ T cell, memory CD4+ T cell, CD8+CD28+ T cell, CD8+CDDR+ T cells and CD8+CD38+ T cell) were measured by flow cytometry. RESULTS: The absolute values of CD3+ T cell (972.55±330.31 vs 1757.99±439.38), CD4+ T cell (656.43±252.39 vs 899.30±262.10), and CD8+ T cell (301.97±147.76 vs 728.45±230.34) in patients with benign prostatic hyperplasia were significantly reduced (all P<0.05). There was no significant difference in NK cell (285.58±182.84 vs 528.92±208.17) and B cell (186.66±86.62 vs 334.17±130.46). The proportion of naive CD4+ T cell (3.75±0.50 vs 8.54±1.61) in T lymphocyte subsets in patients with BPH was significantly reduced (P<0.05). There was no significant difference in memory CD4+ T cell (87.9±6.37 vs 92.63±5.94), CD8+CD28+ T cell (60.52±13.86 vs 64.32±12.78), CD8+CDDR+ T cell (36.58±12.87 vs 31.92±8.54) and CD8+CD38+ T cell (2.1±1.90 vs 2.55±2.01). CONCLUSION: Immune dysfunction raised the risk of viral infection, inflammatory stimulation, and tumor induction in prostate cells, leading to hyperplasia, and immune non-response was potentially a key factor in the transformation of BPH into prostate cancer.

Effects of low-dose X-ray irradiation on activated macrophages and their possible signal pathways.

Low-dose irradiation (LDI) has been used in clinics to treat human diseases, including chronic inflammation. This study assessed the effects of LDI on the inflammatory response of activated mouse primary peritoneal macrophages, and the underlying signal pathways. Primary peritoneal macrophages were isolated from mice and then incubated with lipopolysaccharide (LPS)-coated Ti microparticles (Ti-positive control) with or without brief exposure to LDI (X-ray, 0.5 Gy) 1 h later (Ti-LDI group) or left untreated in culture medium (Ti-negative control). The macrophages were then subjected to qRT-PCR, Western blot, cell viability CCK-8 assay, and ELISA. qRT-PCR analysis revealed the Ti-LDI group expressed significantly lower levels of IL-1ß, IL-6, and TNF-α mRNA than those of the Ti-positive control group, while the ELISA data showed that Ti-LDI group had significantly lower secretion of IL-1ß, IL-6, and TNF-α proteins. The most significant reduction associated with LDI was the secretion TNF-α protein, which barely increased from 13 to 25 h after treatment. Western blot data demonstrated that phosphorylation of p65 and ERK was much lower in the Ti-LDI group than in the controls. The data from the current study suggests that LDI of activated mouse macrophages was associated with significantly lower inflammation responses, compared with non-exposed activated macrophages, which was possibly through inhibition of the NF-κB and ERK pathways.