Disruption of mitochondrial redox homeostasis as a mechanism of antimony-induced reactive oxygen species and cytotoxicity.

Occupational and environmental Sb exposure has been associated with increased risk of respiratory diseases and lung cancer, but the toxicities and molecular mechanisms of Sb have been less investigated. In the present study, we first analyzed the Sb toxicity profile of lung adenocarcinoma A549 cells, and found that Sb dose-dependently decreased the cell viability and arrested cell cycle at G2/M but did not induce apoptosis. We next investigated the role of reactive oxygen species (ROS) involved in Sb-induced cytotoxicity. The results showed that Sb did not significantly induce cytosolic ROS production by NADPH oxidase (NOX) and the NOX inhibitors did not ameliorate the Sb-induced cell viability loss in A549 cells. However, the level of mitochondrial ROS (mtROS) was significantly increased in Sb-exposed cells and the mitochondria-targeted antioxidant significantly improved cell viability. These results suggested that mitochondria but not NOX is the major source of ROS production and mtROS plays a critical role in Sb-induced cytotoxicity. Furthermore, we found that Sb induced mitochondria dysfunction including the significant decrease of ATP level and mitochondrial membrane potential. Finally, Sb exposure decreased the activity of complex I and complex III, the level of -SH and GSH in mitochondria, and the activity of mitochondrial GR, GPx and TrxR, but increased the mitochondrial SOD activity, suggesting the disruption of mitochondrial redox homeostasis. Taken together, these findings suggested that Sb impaired mitochondrial redox homeostasis, resulting in formation of mtROS, thereby inhibited mitochondrial function and led to cytotoxicity.

Distinct effects of rs895819 on risk of different cancers: an update meta-analysis.

Previous studies have indicated an association between the genetic variant in pre-miR-27a rs895819 with A->G transition and cancer risk; however, the results remain inconsistent and somehow conflicting in different cancers. Therefore, to obtain a more reliable conclusion, we performed an update meta-analysis by searching PubMed database or other databases. Odds ratio (ORs) and 95% confidence interval (CIs) were calculated to evaluate cancer risk. A total of 34 case-control studies involving 15,388 cases and 18,704 controls were included. The results showed that rs895819 was associated with an increased cancer risk (GG vs. AA/AG: OR = 1.15, 95% CI = 1.02-1.29). Furthermore, stratification analyses revealed an association of rs895819 with increased cancer risk among Asians (GG vs. AA: OR = 1.17, 95% CI = 1.01-1.36; GG vs. AA/AG: OR = 1.18, 95% CI = 1.03-1.35), but not Caucasians. Interestingly, the [G] allele of rs895819 was significantly associated with decreased risk of breast cancer (G vs. A: OR = 0.91, 95% CI = 0.86-0.97). However, rs895819 was associated with increased risk of colorectal cancer (GG vs. AA: OR = 1.56, 95% CI = 1.31-1.85; GG vs. AA/AG: OR = 1.53, 95% CI = 1.30-1.79; G vs. A: OR = 1.19, 95% CI = 1.09-1.30) and lung cancer (GG vs. AA/AG: OR = 1.43, 95% CI = 1.00-2.04). In addition, no association was found between rs895819 and risk of gastric cancer or esophageal cancer. In conclusion, our findings suggest distinct effects of rs895819 on risk of different cancers, and future well-designed studies with large samples are required to further validate our results.

Transcriptional activation of follistatin by Nrf2 protects pulmonary epithelial cells against silica nanoparticle-induced oxidative stress.

Silica nanoparticles (SiO2 NPs) cause oxidative stress in respiratory system. Meanwhile, human cells launch adaptive responses to overcome SiO2 NP toxicity. However, besides a few examples, the regulation of SiO2 NP-responsive proteins and their functions in SiO2 NP response remain largely unknown. In this study, we demonstrated that SiO2 NP induced the expression of follistatin (FST), a stress responsive gene, in mouse lung tissue as well as in human lung epithelial cells (A549). The levels of Ac-H3(K9/18) and H3K4me2, two active gene markers, at FST promoter region were significantly increased during SiO2 NP treatment. The induction of FST transcription was mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2), as evidenced by the decreased FST expression in Nrf2-deficient cells and the direct binding of Nrf2 to FST promoter region. Down-regulation of FST promoted SiO2 NP-induced apoptosis both in cultured cells and in mouse lung tissue. Furthermore, knockdown of FST increased while overexpression of FST decreased the expression level of NADPH oxidase 1 (NOX1) and NOX5 as well as the production of cellular reactive oxygen species (ROS). Taken together, these findings demonstrated a protective role of FST in SiO2 NP-induced oxidative stress and shed light on the interaction between SiO2 NPs and biological systems.