Docosahexaenoic Acid Reverses Epithelial-Mesenchymal Transition and Drug Resistance by Impairing the PI3K/AKT/ Nrf2/GPX4 Signalling Pathway in Docetaxel-Resistant PC3 Prostate Cancer Cells.

Drug resistance is a serious problem in cancer therapy. Growing evidence has shown that docosahexaenoic acid has anti-inflammatory and chemopreventive abilities. Studies have shown that autophagy inhibition and ferroptosis are promising therapeutic strategies for overcoming multidrug resistance. This study was aimed to examine whether docosahexaenoic acid (DHA) could reverse docetaxel resistance in prostate cancer cells. Cell survival was examined by MTT and colony formation. Protein expression was determined by Western blot. Reactive oxygen species (ROS) production was measured by flow cytometry. DHA displayed anti-cancer effects on proliferation, colony formation, migration, apoptosis, autophagy and epithelial mesenchymal transition. Glutathione-S-transferase π is an enzyme that plays an important role in drug resistance. DHA inhibited GSTπ protein expression and induced cytoprotective autophagy by regulating the PI3K/AKT signalling pathway in PC3R cells. DHA combined with PI3K inhibitor (LY294002) enhanced apoptosis by alleviating the expression of LC3B, (pro-) caspase- 3 and (uncleaved) PARP. DHA induced ferroptosis by attenuating the expression of glutathione peroxidase 4 (GPX4) and nuclear erythroid 2-related factor 2 (Nrf2). DHA-treated PC3R cells produced ROS. The ROS and cytotoxicity were reversed by treatment with ferrostatin-1. DHA combined with docetaxel inhibited EMT by regulating the expression of E-cadhein and N-cadherin. In summary, DHA reversed drug resistance and induced cytoprotective autophagy and ferroptosis by regulating the PI3K/AKT/Nrf2/GPX4 signalling pathway in PC3R cells. We propose that DHA could be developed as a chemosensitizer and that the PI3K/AKT /Nrf2/GPX4 signalling pathway might be a promising therapeutic target for overcoming cancer drug resistance.

Association of TNFSF4 rs1234315, rs2205960 polymorphisms and systemic lupus erythematosus susceptibility: a meta-analysis.

BACKGROUND: The aim of this study was to explore the association between tumor necrosis factor superfamily number 4 (TNFSF4) rs1234315, rs2205960 polymorphisms and systemic lupus erythematosus (SLE) susceptibility. METHODS: A meta-analysis was performed on the association between rs1234315 and rs2205960 polymorphisms and SLE by allelic contrast, additive model, recessive model and dominant model. RESULTS: Regarding rs1234315 polymorphism, a total of five studies were included (6575 cases, 14,798 controls). Meta-analysis showed significant associations between the T allele and SLE in overall subjects and Asians (OR = 1.310, 95%CI: 1.104-1.553, p = 0.002; OR = 1.458, 95%CI: 1.328-1.602, p < 0.001). With respect to the rs2205960 polymorphism, significant associations between the T allele and SLE were found in all subjects (OR = 1.333, 95%CI: 1.254-1.418, p < 0.001), Asians (OR = 1.407, 95%CI: 1.345-1.471, p < 0.001) and Europeans (OR = 1.254, 95%CI: 1.185-1.328, p < 0.001). Results also showed significant associations between the additive model and SLE in all subjects and Asians (OR = 1.934, 95%CI: 1.500-2.494, p < 0.001; OR = 1.882, 95%CI: 1.318-2.689, p = 0.001). Furthermore, we detected significant associations between the dominant model and SLE in all subjects and Asians (OR = 1.421, 95%CI: 1.239-1.629, p < 0.001; OR = 1.297, 95%CI: 1.083-1.555, p = 0.005). Significant associations were found between the recessive model and SLE in overall subjects and Asians (OR = 1.677, 95%CI: 1.312-2.144, p < 0.001; OR = 1.751, 95%CI: 1.235-2.483, p = 0.002). CONCLUSION: The present study suggested that TNFSF4 rs1234315 and rs2205960 polymorphisms were associated with SLE susceptibility.

Elevated levels of IL-24 in systemic lupus erythematosus patients.

OBJECTIVE: This study aimed to assess IL-24 levels and their association with clinical manifestations in patients with systemic lupus erythematosus (SLE). METHODS: There were 75 patients with SLE and 58 healthy controls recruited in this study. Serum levels of IL-24 were measured by enzyme-linked immunosorbent assays, and mRNA levels of IL-24 were tested by quantitative real-time polymerase chain reaction . The area under the curve of the receiver operating characteristic (ROC) curve was used for diagnostic ability of the inflammatory cytokine. RESULTS: Serum IL-24 levels were significantly higher in SLE patients than that in healthy controls. SLE patients with nephritis had higher IL-24 levels than those without nephritis. Active SLE patients showed higher expression of IL-24 as compared to less active disease patients. The mRNA levels of IL-24 were much higher in SLE patients. Correlation analysis showed significant correlation between serum IL-24 levels and SLE disease activity index. In addition, ROC analysis may suggest good ability of serum IL-24 in differentiating SLE. CONCLUSION: The inflammatory cytokine correlated with SLE disease activity, and may be involved in this disease pathogenesis.

[An analysis of latent tuberculosis infection among patients with rheumatic diseases].

OBJECTIVE: To investigate the incidence of latent tuberculosis infection (LTBI) in patients with rheumatic diseases in order to find evidence for the prevention of mycobacterium tuberculosis (MTB) in these patients. METHODS: From January 2013 to July 2015, 759 patients with rheumatic diseases and 38 health controls were enrolled. All of them underwent interferon-gamma release assays(T-SPOT.TB)to screen for LTBI. Incidence of MTB infection was evaluated in different groups and test was used for statistical analysis between groups. RESULTS: The incidences of LTBI in patients and health controls were 27.27%(207/759) and 10.53%(4/38), respectively. In 2013, 24.66%(73/296) (standardized infection rate 23.37%) patients with rheumatic diseases were positive for LTBI screening test. In 2014 and 2015, the percentages were 32.02%(73/296) (standardized infection rate was 32.15%) and 25.96%(73/228) (standardized infection rate was 28.46%), respectively, which was statistically significant in these 3 groups (P=0.004). the infection rate in 2014 tended to be higher than that in 2013 (P=0.001). There were 30.24%(88/291) male and 25.43%(119/468)female patients who were considered as LTBI. But the difference was not significant between genders. The infection rates between patients older than 60 years old and less was significantly different, which were 45.65%(42/92) and 24.74%(165/667), respectively (P=0.000). As far as diseases were concerned including rheumatoid arthritis, systemic lupus erythematosus, spondyloarthritis and other rheumatic diseases, the incidences were 33.93%(57/168), 22.06%(45/204), 25.73%(44/171) and 28.24%(61/216) respectively, without statistical significance. CONCLUSIONS: The incidence of LTBI is high in patients with rheumatic diseases. Attention should be paid especially to elderly patients and rheumatoid arthritis patients who have relatively higher rates of LTBI. Careful monitoring and prevention measures are suggested to take in these patients.