In cholestasis, increases in bile acid levels result in the generation of reactive oxygen species and the induction of DNA damage and mutation. It is believed that bile acid accumulation is associated with liver tumorigenesis. However, the mechanism that underpins this phenomenon remains to be elucidated. Mcl-1, which is overexpressed in hepatic cells, is a pro-survival member of the Bcl-2 family. In this study, we observed that Mcl-1 potently suppresses the repair of bile acid-induced abasic (apurinic/apyrimidinic) sites in DNA lesions. Upon exposure of hepatic cells to glycochenodeoxycholate, one of the major conjugated human bile acids, we observed an increase in AP site accumulation along with induction of poly(ADP-ribose) polymerase and XRCC1 ( X-Ray Repair Cross Complementing 1). In addition, accumulation of Mcl-1 was observed in the nuclei of QGY-7703 cells in response to glycochenodeoxycholate stimulation. Knockdown of endogenous Mcl-1 by RNA interference significantly accelerated the repair of DNA lesions in glycochenodeoxycholate-treated cells. However, unlike XRCC1, poly(ADP-ribose) polymerase was induced following Mcl-1 knockdown. Conversely, poly(ADP-ribose) polymerase suppression was observed following glycochenodeoxycholate treatment of cells overexpressing Mcl-1. Moreover, AP-site counting analyses revealed that DNA repair activity was enhanced in cells overexpressing poly(ADP-ribose) polymerase under glycochenodeoxycholate stress conditions. It is well known that poly(ADP-ribose) polymerase plays a crucial role in the base excision repair pathway. Thus, our findings suggest that Mcl-1 suppresses base excision repair by inhibiting poly(ADP-ribose) polymerase induction following glycochenodeoxycholate-induced DNA damage. These results potentially explain how bile acid accumulation results in genetic instability and carcinogenesis.
Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. Lupus nephritis (LN) is an important cause of morbidity and even mortality in patients with SLE. Some evidences suggest that neutrophillymphocyte ratio (NLR) associated with different inflammatory malignancies, ischemic injury and cardiovascular disease. Few scholars have investigated the relationship between NLR and SLE. This study aims to evaluate the role of NLR in SLE without nephritis and LN patients. Methods: A total of 228 subjects were participated in this study. 79 diagnosed with SLE in patients group and 149 healthy age-and sex-matched in control group. In patient team, 20 of them were diagnosed with LN. Results: The SLE without nephritis group showed significantly higher NLR than control group (control= 2.00 +/- 0.76, SLE=4.26 +/- 3.38, P<0.001), and the NLR values of the patients with LN were higher than those of the patients without LN (SLE=4.26 +/- 3.38, LN=7.21 +/- 6.01, P<0.001). Receiver-operating characteristics analysis (ROC) of NLR to predict SLE showed that the area under the curve (AUC) was 0.757. The cutoff value using the ROC curve was 3.13 (sensitivity, 0.574; specificity, 0.926; 95% confidence interval (CI), 0.668-0.845; P<0.001). While ROC analysis of NLR to predict LN showed that the AUC was 0.828). Logistic regression analysis showed that SLE without nephritis and LN were independently related to NLR. Conclusion: NLR is independently associated with SLE, and it may be a promising marker that reflects renal involvement in patients with SLE.