In the process of liver fibrosis, stimulation of hepatocyte regeneration and inhibition of apoptosis is essential to treating hepatic fibrosis. In the present study, DAPT treatment was found not to inhibit hepatocyte proliferation. In contrast, DAPT was found likely to inhibit hepatocyte apoptosis to some degree in vivo. We also found that the expression of TGF-b1 was upregulated in the fibrotic livers, and some hepatocytes close to the fibrotic area expressed high levels of TGF-b1, which can induce apoptosis in hepatocytes and stimulate ECM deposition in hepatic fibrosis. We infer that one potential mechanism underlying the protecting effect of DAPT may involve the suppression of TGFb1 expression, which contributes to hepatocyte proliferation and protects hepatocytes from apoptosis. Inhibiting c-secretase can prevent the cleavage of the Notch receptor, blocking Notch signal transduction. The clinical trials with c-secretase inhibitors have revealed several adverse events, such as gastrointestinal toxicity. Other approaches that target the Notch signaling were recently evaluated and showed promising effects accompanied by a lack of intestinal toxicity in preclinical models. These studies shed light on the clinical implications of c-secretase inhibitor. In summary, the present investigation indicates that the Notch signaling pathways become activated in a rat model of liver fibrosis induced by CCl4 and that inhibition of Notch signaling LY2109761 exerts potent anti-fibrotic effects in preclinical models. Our study provides the first evidence for the striking suppressive effects of DAPT on hepatic fibrosis. These findings suggest that inhibition of Notch signaling might be a novel option for hepatic fibrosis therapy. Cells employ multiple mechanisms to repair or tolerate DNA lesions in order to maintain 
genomic integrity. Translesion DNA synthesis is one of the mechanisms used to tolerate unrepaired DNA lesions. DNA polymerase k is a TLS polymerase that has been shown to catalyze TLS past a variety of DNA lesions, being particularly proficient in the bypass of minor groove N2-dG lesions, including the acrolein-derived adducts c-HOPdG and its ring-opened reduced form, DNA- peptide cross-links, and DNA-DNA interstrand cross-links, as well as adducts induced by activated polycyclic aromatic hydrocarbons such as benzopyrene diolepoxide. Importantly, pol k has been demonstrated to be involved in the tolerance of ICLs induced by a chemotherapeutic agent, mitomycin C. In addition to its role in the bypass of N2-dG lesions, pol k has also been shown to play a role in the processing of various ultraviolet light-induced DNA lesions. Many clinically relevant chemotherapeutic agents, including mitomycin C, cisplatin, and nitrogen mustard, target tumor cells by virtue of their ability to covalently cross-link complementary DNA SJN 2511 446859-33-2 strands, introducing ICLs into the genome. These ICLinducing agents are powerful chemotherapeutic agents as the ICL interferes with vital cellular processes such as DNA replication, RNA transcription, and recombination by preventing transient DNA strand separation. Therefore, although TLS is an essential process for cells to survive genotoxic stress, the ability of pol k to bypass ICLs could limit the efficacy of these agents. Critical to this point are data demonstrating that the effectiveness of mitomycin C was increased when pol k expression was suppressed by siRNA. Germane to these observations, previous reports have suggested that pol k may play a role in glioma development and therefore serve as a potential target for novel routes of therapies.