What is the clinical significance
TBⅡ could be a promising candidate reagent for the treatment or
prevention of intestinal inflammation.
Introduction
Ulcerative colitis (UC) is a
nonspecific inflammation of the intestinal tract, which is a chronic
disease of the digestive system (Zhou et al., 2022). The disease is
dominated by inflammation and ulcerative lesions of the rectum, colon
mucosa and submucosa (Pai et al., 2021). UC is a recurrent and has a
long course of disease. In severe cases, it usually leads to weight
loss, diarrhea, and even stool bleeding, making it a repeated illnesses
that might eventually increase the risk of cancer (Krausova et al.,
2021).
The occurrence and the development of UC are not caused by a single
factor, but is related to a variety of risks. The main factors
recognized are genetic factors, immune factors, environmental factors
and intestinal flora (Ramos & Papadakis, 2019). The above factors can
cause an excessive immune response to the intestinal mucosa, and
ultimately lead to inflammation and destruction of the intestine.
Studies showed that innate and adaptive cellular immunity play a crucial
role in the occurrence of UC (Texler et al., 2022). The typical symptoms
of UC are the increase of macrophages, neutrophils and T cells in the
colon (Zhang et al., 2021). When immune cells are activated, they
secrete a large number of inflammatory cytokines, such as IL-1β, TNF-α
and IL-18. To produce bio-active IL-1β, pro-IL-1β needs to be cleaved by
activated Caspase-1. The activated Caspase-1 depends on the activation
of the NLRP3 inflammasome (Elliott & Sutterwala, 2015). NLRP3
inflammasome is a macromolecular protein complex composed of NLRP3, a
member of the NOD receptor family, apoptosis associated speck-like
protein (ASC), and pro-Caspase-1 (Rathinam & Chan, 2018). The
activation of NLRP3 inflammasomes requires dual signals. The first
signal is the priming signal, which activates Toll-like receptors
through exogenous stimuli such as lipopolysaccharide (LPS), and
regulates the expression of NLRP3, pro-IL-1β and pro-IL-18 through the
NF-kB pathway (Peng et al., 2020). The second signal is an activation
signal, whose mechanisms includes mitochondrial damage, lysosome
rupture, and potassium outflow (Wang, Lin, Yuan, Li, Guo & Wu, 2018).
The activated NLRP3 will recruit ASC and pro-Caspase-1, and assemble
them into NLRP3 inflammasomes, causing promoting the activation of
cleaved-Caspase-1. Therefore, pro-IL-1β and pro-IL-18 can be cleaved
into mature IL-1β and IL-18 to the immune response (Fu & Wu, 2023).
NLRP3 inflammasome plays an important role in the occurrence and
development of immune diseases, and offers new targets for the treatment
of various immune diseases, also provides a new direction for the
research of related immune diseases (Wang et al., 2023). Studies have
shown that NF-κB and NLRP3 inflammasomes are a key parts of the
inflammatory processes, interacting with each other to aggravate the
condition of UC (Wang, Lin, Yuan, Li, Guo & Wu, 2018). In the acute UC
model induced by DSS, knockout of NLRP3 gene or drug inhibition of NLRP3
inflammasome activity could protect mice. Therefore, regulation of NLRP3
inflammasome activity represents a potential therapeutic strategy for UC
treatment, for it can both maintain the integrity of intestinal
epithelial cells and regulate intestinal inflammation (Dai et al.,
2021).
At present, the main drugs for the treatment of UC are aminosalicylic
acid preparations, glucocorticoids and immunosuppressive agents
(Ananthakrishnan & hepatology, 2015). However, long-term use of these
drugs may cause some adverse reactions, such as headache, vomiting, and
allergies (Kane & therapeutics, 2006). Therefore, the development of
new drugs for the treatment of UC with high efficiency and low toxicity
is imminent, making the search for new drugs for the treatment of UC has
become a research focus in the scientific and medical circles.
Timosaponin BⅡ (TBⅡ) is one of the
main active components of Anemarrhena asphodeloides, and it is a
steroidal saponin with various pharmacological activities such as
anti-oxidation, anti-inflammatory and anti-apoptosis (Wang et al.,
2021). Studies indicated that TBⅡ could reduce the inflammatory response
in LPS-induced INS-1 cells by inhibiting the expression of macrophage
inflammatory bodies (Zhang, et al., 2015), and reduce the secretion of
pro-inflammatory factors to alleviate neurodegenerative diseases induced
by LPS (Chen et al., 2020). Therefore, we speculate that TBⅡ may play a
preventive and therapeutic role in inhibiting UC. To verify this
hypothesis, we studied the protective effects of TBⅡ on DSS-induced
acute UC mice model.
Methods