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.