Introduction
Ulcerative colitis (UC), one of the main forms of inflammatory bowel disease (IBD), has the clinical severe symptoms like diarrhea, abdominal pain and mucus with bloody stools, which indicates the potential attack by cytokines and so on (Tripathi & Feuerstein, 2019; Ungaro, Mehandru, Allen, Peyrin-Biroulet & Colombel, 2017), but little is known about pathogenesis of UC. In recent years, many studies reported that genetic factors, environmental factors, microbial factors and intestinal immune system molecules have promoted the occurrence and development of UC (Ordás, Eckmann, Talamini, Baumgart & Sandborn, 2012). At present, the most used clinical drugs of IBD are aminosalicylic acid and glucocorticoids, however, they both show serious side effects, including the potential damages in liver and kidney (Patel, Barr & Jeejeebhoy, 2009; Zoubek et al., 2019). Therefore, it is urgent clinical needs to develop more effective therapeutic methods or agents and further investigate the underlying mechanisms of UC.
The intestinal epithelial barrier, composed of intestinal mucosa connecting epithelial cells and adjacent cells, is the first natural line of defense (Xu, Becker, Elizalde, Masclee & Jonkers, 2018). In recent years, a large number of evidences have indicated that the pathogenesis of IBD is associated with intestinal epithelial barrier injury (Antoni, Nuding, Wehkamp & Stange, 2014; Jäger, Stange & Wehkamp, 2013). Apical tight junction protein, a closed complex, is mainly formed by the interconnection of transmembrane proteins (Claudin, Occludin) and perimembrane protein (zonula occludens, ZO), which is vital in the control of epithelial barrier function and maintenance of paracellular permeability (Choi, Yeruva & Turner, 2017; France & Turner, 2017). Furthermore, some evidences were reported that inflammation and oxidative stress play critical roles in the pathogenesis of IBD. Reactive oxygen species (ROS) can induce intestinal tissue lipid peroxidation and disruption of intercellular junctions, as well as leukocyte and neutrophil infiltration, and promote the inflammatory process. The accumulation of ROS in the gut can cause death of mice and drosophila melanogaster (Dudzińska, Gryzinska, Ognik, Gil-Kulik & Kocki, 2018; Vaccaro et al., 2020). Therefore, preventing ROS and proinflammatory cytokine accumulation in the gut may be able to alleviate IBD.
In recent years, the relationship between disease and gut microbiotas have recently been intensively studied, which strongly indicate that gut microbiota play critical role in gut disorders, including IBD, obesity, liver disease and colorectal cancer (Hagymási, Bacsárdi, Egresi, Berta, Tulassay & Lengyel, 2018; Marchesi et al., 2016; Peng et al., 2019). Imbalance of gut microbiota can directly disorder tightly connected proteins, which results in decreasing integrity of intestinal mucosa epithelium and ultimately hurts the mucosal barrier (McNamara, Koutsouris, O’Connell, Nougayréde, Donnenberg & Hecht, 2001; Wang, Li & Ren, 2019). Moreover, gut microbiota can promote the differentiation of immune cells and the production of immune mediators, which regulate intestinal immune function (Li, Leonardi & Iliev, 2019). It is critical to look into the possible effect gut microbiota on IBD and seek the potential treatment.
Silent information regulator (Sirt1), a member of the sirtuin family that has been studied extensively and in-depth, plays a significant role in anti-aging, apoptosis, oxidative stress and DNA damage. The deacetylation of Sirt1 is an important component of the anti-intracellular inflammatory response. Previous studies have confirmed that Sirt1 interacts with NF-κB and inhibits the acetylation of NF-κB to inhibit transcription (Yeung et al., 2004). Sirt1 can also regulate the key transcription factor Nrf2 of oxidative stress, thereby affecting the redox state of cells(Do, Kim, Choi & Jeong, 2014). Xiaoling Li et al (Wellman et al., 2017) have revealed that Sirt1 prevented intestinal inflammation by regulating gut microbiota. Sirt1 regulated NF-κB and Nrf2 pathway and gut microbiota to maintain intestinal epithelial homeostasis as a transportation hub.
Circular RNA (circRNA), a covalently closed circular competitive internal RNA, participates in the regulation of circRNA-miRNA-mRNA network, and plays an important role in the regulation of various diseases, include colitis.(Ye, Yin, Hu, Zhang, Wu & Pang, 2019). Zusen Fan has demonstrated that CircKcnt2 inhibits ILC3 activation and alleviates the progression of colitis (Liu et al., 2020a). Intestinal immune cells promote self-renewal of intestinal stem cells through circPan3 (Zhu et al., 2019). Recent studies have shown that circ-Sirt1 inhibits vascular inflammation by regulating NF-κB acetylation and Sirt1 pathway (Kong et al., 2019). Therefore, upregulation of Circ-Sirt1 to increase Sirt1 signal may be a potential strategy to against DSS induced colitis.
Diosmetin (3’, 5, 7-trihydroxy-4 ’-methoxy flavone, C16H12O6), a natural flavonoid compound, is found in citrus species (Roowi & Crozier, 2011). A large number of pharmacological investigations have shown that diosmetin has anti-tumor, anti- acute kidney injury and anti-acute lung injury activities (Chen et al., 2019; Liu, Ci, Wen & Peng, 2018; Yang, Li, Yu, Yi & Huang, 2017). The previous studies also indicated that diosmetin can attenuate oxidative stress and decrease level of proinflammatory cytokine (Mo, He, Zhang, Lei & Luo, 2020; Zaragozá, Villaescusa, Monserrat, Zaragozá & Álvarez-Mon, 2020). In our experiment, we studied and reported the effects and potential molecular mechanisms of diosmetin treating IBD.