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