IL-1 receptor-associated kinase 1 participates in the modulation of the NLRP3 inflammasome by tumor-associated macrophages in hepatocellular carcinoma.

Background: Hepatocellular carcinomas (HCCs) occur frequently in the digestive system and are associated with high mortality. This current study examined the regulatory relationship between interleukin (IL)-1 receptor-associated kinase 1 (IRAK1), NLR family pyrin domain-containing 3 (NLRP3) inflammasomes, and tumor-associated macrophages (TAMs) in the growth and metastasis of HCC. Methods: The expression of IRAK1 and NLRP3 was assessed in tissues and cells via quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. Immunohistology was performed to detect the macrophage markers CD68, CD163, and CD168 in tumor tissues. Small interfering (si)RNA targeting IRAK1 (si-IRAK1) was designed to silence IRAK1 expression. Following si-IRAK1 transfection and/or co-culture with TAMs, HCC cell viability, proliferation, migration, and invasion, as well as the expression of NLRP3 and pro-inflammatory cytokines IL-1 ß, IL-18, and monocyte chemotactic protein 1 (MCP-1) were assessed. Results: HCC tissues showed elevated expression of IRAK1 and NLRP3, as well as increased expression of the macrophage markers CD68, CD163, and CD168, compared to adjacent healthy tissues. Silencing of IRAK1 expression in HepG2 and Huh7 cells resulted in suppression of cell proliferation, migration, and invasion, and also reduced expression of NLRP3 and the pro-inflammatory cytokines IL-1ß, IL-18, and MCP-1. Moreover, TAMs promoted HepG2 and Huh7 cell proliferation, migration, and invasion, and elevated the expression of NLRP3, IL-1ß, IL-18, and MCP-1. Furthermore, IRAK1 silencing reversed the effects of TAMs on HepG2 and Huh7 cells. Conclusions: The expression of IRAK1 was associated with HCC growth and metastasis, as well as NLRP3 inflammasome activation. The ability of TAMs to promote HCC growth and metastasis may be activated by NLRP3 inflammasomes and regulated by IRAK1.

Effect of Nano-Titanium Dioxide on Blood-Testis Barrier and MAPK Signaling Pathway in Male Mice.

Some studies have found that nano-sized titanium dioxide (nano-TiO2) has adverse effects on the male reproductive system. Blood-testis barrier (BTB), as one of the tightest blood-tissue restriction, is crucial to the male reproductive system. However, the potential effects on BTB and signaling pathway changes in testis tissue induced by nano-TiO2 remain poorly understood. Therefore, in this study, 60 Institute of Cancer Research mice were divided randomly into four groups (per group = 15). The mice of four groups were intragastrically administered with 0, 10, 50, and 100 mg/kg BW nano-TiO2 respectively for 30 days to analyze the changes of BTB structure, BTB-related proteins, and MAPK signal pathways. Besides, testosterone level, estradiol level, and sperm parameter (sperm count, sperm motility, and sperm malformation rate) changes were also studied in this research. The results indicated that nano-TiO2 could induce the BTB structural damage and accompanied by the BTB main protein (ZO-1, Claudin-11, and F-actin) elevation of irritability. Nano-TiO2 could also activate the MAPK signaling pathways (p38, JNK, and ERK) of mice testis tissue. The testosterone and estradiol levels in serum reduced. Besides when the mice were administered with nano-TiO2, we also found the sperm motility rate decreased, and sperm malformation increased. The above changes may be associated with BTB damage and the activation of MAPK signaling pathways, thereby causing male reproductive dysfunction.

Screening of a novel autophagy-related prognostic signature and therapeutic targets in hepatocellular carcinoma.

BACKGROUND: Many studies have indicated that autophagy plays an important role in multiple cancers, including hepatocellular carcinoma (HCC). This study aimed to establish a prognostic signature for HCC based on autophagy-related genes (ARGs) to predict the prognosis of patients. METHODS: The list of ARGs was derived from screening National Center for Biotechnology Information (NCBI)-Gene and Molecular Signatures Database (MSigDB) datasets. Differential analysis was conducted via the R limma package in HCC patients based on The Cancer Genome Atlas (TCGA) database. Univariate and multivariate Cox regression analysis were conducted to identify key prognostic ARGs via the survival package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed by clusterProfiler package. The Estimation of Stromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm was used to conduct immune analysis. Finally, the correlation between the prognostic model and clinical characteristics was also assessed, including age, tumor-node-metastasis (TNM) stages, and tumor grades. RESULTS: Firstly, 106 differential ARGs were identified and 10 candidates were further confirmed via Cox regression analysis, including BAMBI, HIF1A, SERPINE1, EZH2, SLC9A3R1, IGFBP3, HSPB8, DAB2, CXCL1 and PRNP. The receiver operating characteristic (ROC) curve analysis revealed that the ARGs risk model had a well diagnostic positive rate with 1-year area under the curve (AUC) =0.688 and 3-year AUC =0.674. Correlation analysis indicated that only advanced tumor stages were positively associated with high ARGs scores with P=0.0227. There were also significant differences in tumor purity (P=6.71e-05), infiltrating cell analysis (P=7.77e-05), immune analysis (P=7.9e-05), and stromal cells analysis (P=0.0015) in high- and low-risk ARGs samples. The genes HIF1A, IGFBP3, and DAB2 were found to have high frequent missense mutations in samples with high-risk ARGs scores. Lastly, we also established a nomogram to predict overall survival (OS) of HCC by integrating ARGs scores and other clinical parameters. CONCLUSIONS: Our study established an autophagy-related signature for predicting the prognosis of HCC patients, providing a thorough understanding of the underlying mechanisms of autophagy in HCC.

Oxidative Damage Induced by Nano-titanium Dioxide in Rats and Mice: a Systematic Review and Meta-analysis.

Nano-titanium dioxide is a kind of widely used nanomaterial that exhibits various adverse outcomes. However, the role of oxidative stress in this regard remains controversial. This study aimed to evaluate whether oxidative stress is one of the toxicity mechanisms induced by nano-titanium dioxide in rats and mice model. In this meta-analysis, 64 relevant publications were included through detailed database search. The pooled results showed that nano-titanium dioxide exposure could promote the expression of oxidants, such as malonaldehyde (MDA), 8-hydroxy-2-deoxyguanosine (8-OHdG), superoxide anion (O2-), and hydrogen peroxide (H2O2). Meanwhile, the levels of antioxidant-related enzymes and molecules, such as superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx), and catalase (CAT), were reduced. Subgroup analysis revealed that different intervention routes, exposure periods, exposure dosages, and sample sources could affect the oxidative stress when exposed to nano-titanium dioxide. It was worth noting that the levels of MDA, 8-OHdG, and GSH significantly increased (P < 0.05) when the particle size of nano-titanium dioxide was < 10 nm, whereas H2O2, SOD, and GPx showed the highest effect at 10-40 nm. This study indicated that nano-titanium dioxide could cause oxidative damage by affecting the levels of enzymes and molecules involved in oxidative stress in rats and mice. And these results could provide a reference for studies of the toxicity mechanism induced by nano-titanium dioxide in the future.