Apurinic/apyrimidinic endonuclease 1, the sensitive marker for DNA deterioration in dextran sulfate sodium-induced acute colitis

Abstract

Mutations in mismatch repair (MMR) genes are commonly associated with the development of colorectal cancer. Additionally, base excision repair, which involves apurinic/apyrimidinic endonuclease 1 (APE1), recognizes and eliminates oxidative DNA damage. Here, we investigated the possible roles of APE1 in dextran sulfate sodium (DSS)-induced acute colitis using the young rat model. Four-week-old Sprague-Dawley rats were administered 2% DSS in drinking water for 1 week. MMR and APE1 expression levels were assessed by western blotting and immunohistochemistry. Following DSS treatment, growth of young rats failed and the animals had loose stools. Together with the histological changes associated with acute colitis, APE1 and MSH2 levels increased significantly at 3 and 5 days after DSS treatment, respectively. The difference between APE1 and MSH2 expression was significant. DSS-induced DNA damage and subsequent repair activity were evaluated by staining for 8-hydroxy-deoxyguanosine (8-OHdG) and APE1, respectively; 8-OHdG immunoreactivity increased throughout the colonic mucosa, while APE1 levels in the surface epithelium increased at an earlier timepoint. Taken together, our data suggest that changes in APE1 expression after DSS treatment occurred earlier and were more widespread than changes in MMR expression, suggesting that APE1 is more sensitive for prediction of DNA deterioration in DSS-induced colitis.

Inhibition of APE1/Ref-1 Redox Signaling Alleviates Intestinal Dysfunction and Damage to Myenteric Neurons in a Mouse Model of Spontaneous Chronic Colitis

“…Our study provides novel findings on the presence of APE1/Ref-1 in enteric neurons and increased level of APE1/Ref-1 in both the mucosa and myenteric ganglia in the colons from Winnie mice. These results are consistent with findings in the colon tissues removed from IBD patients with active inflammation (Hofseth et al 2003) and in the colonic epithelium of an animal model of DSS-induced colitis (Chang et al 2013). Inflammation caused by pathogenic bacteria, ionising radiation, ROS and toxic agents transiently increase intracellular APE1/Ref-1 in gastric epithelial cells and sensory neurons (O'Hara et al 2006;Vasko et al 2011).…”

“…In our study, oxidative stress in myenteric neurons and surrounding cells was shown by the increased mitochondrial superoxide production in Winnie mice. Myenteric neurons in Winnie mice exhibit increased mitochondrial superoxide and oxidative stress-induced DNA damage, as seen in multiple studies that describe increase in oxidative DNA damage in the colonic mucosa of IBD patients (D'Incà et al 2006;Dincer et al 2007;Lih-Brody et al 1996) and chemically-induced colitis (Chang et al 2013). Our results demonstrate that APX3330 reduced oxidative stress via its redox inhibition of APE1/Ref-1 and oxidative DNA damage in chronic colitis.…”

“…Previous studies have demonstrated increased APE1/Ref-1 redox activity in tissues removed from IBD patients with active inflammation, indicating underlying oxidative stress within the GI tract (Hofseth et al 2003;Lih-Brody et al 1996). In addition, increased expression of APE1/Ref-1 was observed in colon sections from rats with dextran sodium sulfate (DSS)-induced colitis, which has been associated with an enhanced pro-inflammatory response (Chang et al 2013). Thus, APE1/Ref-1 is involved in the pathophysiology of GI inflammation.…”

APE1/Ref-1 – One Target with Multiple Indications: Emerging Aspects and New Directions

“…Several preclinical investigations demonstrate that APE1 is an effective target in treating IBD [32,67]. For instance, Chang et al induced IBD in rats with dextran sulfate sodium (DSS) administration, which initially induces colonic injury, and then further causes chronic colitis over the time.…”

“…For instance, Chang et al induced IBD in rats with dextran sulfate sodium (DSS) administration, which initially induces colonic injury, and then further causes chronic colitis over the time. They revealed that APE1 and MSH2 (mismatch repair gene) levels were significantly increased in a timedependent manner with DSS-treatment [68]. In addition, DNA damage marker 8-hydroxy-deoxyguanosine (8-OHdG) was increased in the colonic mucosa, whereas APE1 levels in the surface epithelium increased at an earlier timepoint, highlighting the fact that APE1 is a sensitive target for determining exacerbation of DNA damage in DSS-induced colitis [68].…”