| The second-highest mortality rate of any cancer,colorectal cancer is the third-most prevalent malignancy of the digestive system worldwide.The incidence rate and mortality rate of colorectal cancer worldwide are rising even if there has been a major improvement in treatment.More than 2.2 million new cases are anticipated to be diagnosed by 2030,and 1.1 million people are anticipated to pass away.Patients with ulcerative colitis have a 3–20 times higher chance of developing colitis-associated cancer(CAC)than the general population.The primary mediators of ulcerative colitis supporting the development of CAC may be the release of inflammatory substances and the maintenance of inflammation.The standard treatments for CAC include radiation,chemotherapy,and endoscopic and local surgical excision.Strong side effects of these medical technologies include impaired gastrointestinal function,lowered immunity,and increasing pain following radiotherapy or chemotherapy,so that they are also associated with a poor prognosis and a low long-term survival rate after treatment.Investigating innovative,efficient CAC therapy options is urgent.Gene therapy,targeted therapy,immunotherapy,and natural product therapy are some of the novel methods for treating CAC.The traditional Chinese herb Bupleurum chinense contains Saikosaponin A(SSa),a glycosylated oleanolane-type saponin that has gained interest recently because of its many biological properties.Studies conducted both in vivo and in vitro have shown that SSa has anti-inflammatory,anti-tumor,antiviral,and liver-protective effects.However,there hasn’t been a consistent report of SSa’s inhibitory effect on CAC in animal Models.The growth of CAC tumors is accelerated by the carcinogen azomethane(AOM).Intestinal inflammation can be triggered by sodium dextran sulfate(DSS).AOM and DSS are used to create a mouse CAC Model that resembles human CAC in terms of symptoms,morphology,and histology.This approach is generally stable and well-established.In order to investigate the anti-CAC activity of SSa and its particular mechanism,the mouse CAC Model generated by AOM and DSS were used in this research.First,we created a mouse CAC Model using AOM/DSS and performed a preliminary assessment of SSa’s ability to limit CAC tumor growth and its safety.The mice were given free access to drinking water with 2%DSS for a week in order to develop the Model,and the animals significantly lost weight;The body weight of mice recovered significantly compared to the Model group after 42 days of SSa administration,however there was no discernible distinction between the Model group and the control group.The colon and various organs from the mice were removed,and statistical analysis was done on the length,index,and coefficient of the colorectal as well as the number of tumors.The outcomes of the experiment demonstrated that SSa treatment had some protective effects on the mouse colon and decreased tumor growth.According to the histological findings,treatment of SSa to mice had a good inhibitory impact on the inflammatory infiltration of cancer sites,and the amount of intestinal cancer tissue shrank.The mice’s liver,kidney,and heart structures did not change significantly,demonstrating the efficacy and safety of SSa in animals.SSa can also reverse the spleen index and repair spleen damage brought on by AOM/DSS,raising the possibility that SSa may prevent the growth of CAC by regulating the immune system.SSa is discovered to up-regulate the abundance of helpful bacteria like lactobacillus and bifidobacterium and down-regulate the number of detrimental bacteria at the general level through the research of intestinal microbiotics.The metabonomics detection of metabolites in serum found that the levels of various metabolites changed after the administration of SSa.Combined with the multi-omics analysis by establishing thermogram of metabolomic-microbiota interaction,L-glutamine has a positive correlation with Lactobacillus,D-proline and 3-phosphate glycerol.Glutamine has a protective effect on intestinal mucosa and can express its killing activity on tumor cells by improving the immune system response,thus proving that SSa can achieve its anti-CAC effect by regulating the metabolism of intestinal microbiota.Furthermore,to further investigate the mechanism of SSa immune activity surrounding T cell activation and CD4~+T cell differentiation,we employed cytokine detection,various immunohistochemical labeling,and Western blotting analysis.Two important cytokines that promote the differentiation of Th0 cells into Th1 cells are IL-12 and IFN-γ.They inhibit the development of a tumor microenvironment that is favorable for disease progression and play an anti-proliferative and pro-apoptotic function.At the same time,IL-12 or IFN-γmay adversely affect the differentiation of Th17 cells.TLR4/My D88/MAPK signaling pathway is the upstream pathway of Th activation and the release of immune-related mediators.The inhibition of MAPK contributes to the production of IL-12 and activates Th1 to initiate tumor immune response.The experiment shows that SSa can inhibit the growth of intestinal tumors by inhibiting TLR4/My D88/MAPK signal pathway,enriching Th1 cells and their related cytokines in CAC,and down-regulating the expression of Th17 cells and their related cytokines,while inhibiting Wnt/β-Catenin signal protects the intestine and inhibits the progress of CAC,thus inhibiting the growth of intestinal tumors in general.In conclusion,this study developed the AOM/DSS-induced CAC mice Model and discovered that SSa significantly inhibits the growth of CAC.The regulating influence of SSa on intestinal metabolism has been demonstrated by intestinal microbiotics and non-targeted metabolomics.Combined with the multi-omics analysis by establishing thermogram of metabolomic-microbiota interaction that have undergone significant modification point to a potential role for the immune system in the development of SSa’s anti-CAC tumor.It was established that SSa may achieve its anti-colorectal cancer activity by controlling the differentiation of helper T cells through the detection of Th1and Th17 cells and related cytokines,whose beneficial modifications are conducive to the therapy of CAC.The findings of this study demonstrate the potential benefit of SSa in lowering patients’risk for CAC. |
PDF Full Text Request