Sun Yang's team in our hospital revealed the scientific connotation of the qi-tonifying medicine Astragalus "Fuzheng and anti-cancer"

Astragalus has a long history of medicinal use, first seen in the book "Fifty-two Sick Prescriptions" excavated in the Han tomb Mawangdui, and the "Shennong Materia Medica" also listed it as a top grade, which has the effects
of strengthening the spleen and tonifying the middle, lifting the sun, benefiting the health and fixing the table, and toxin and muscle.
Astragalus is praised by Li Shizhen as "the first important medicine for qi replenishment", and astragalus is contained in many anti-tumor prescriptions in Chinese medicine clinics, mainly playing its role of
"correcting and fighting cancer".
The active ingredient of astragalus is cycloastragenol (CAG), which is the glycoside of astragaloside IV, which has been shown to have anti-aging, antiviral, anti-inflammatory and other functions, but its anti-tumor effect and mechanism are unknown
.

Cycloastragalol as a health food

In order to investigate the anti-tumor effect of cycloastragalol (CAG), the researchers first conducted trials on MC38 and CT26 mouse colon cancer transplant models, and found that CAG can inhibit tumor growth well
。 Single-cell transcriptome sequencing (scRNA-seq) and single-cell chromatin accessibility sequencing (scATAC-seq) were then used to resolve the specific mechanism
of CAG anti-tumor action.
Through scRNA-seq analysis, it was found that the number of C05 tumor cells in the tumor of mice in the CAG administration group was significantly reduced, and the antigen presentation related pathway was significantly enriched
.
Subsequently, the researchers also found antigen-presenting genes H2-k1, B2m, Anxa1 and related genes in the CAG treatment group in tumor tissue CD74 expression levels were significantly higher than those in the control group
.
At the same time, scATAC-seq analysis also found that the CAG group regulated antigen presentation-related genes H2-k1, B2m, and Anxa1 and CD74 transcription factor expression levels were also significantly higher than those in the control group
.

Next, the researchers used the Target-Responsive Accessibility Optimization (TRAP) strategy to find the target protein of CAG and reveal the anti-tumor mechanism of CAG
。 This was followed by intracellular thermal migration, microthermophoresis and point mutation techniques to confirm that the key binding site between CAG and the target protein cathepsin B (CTSB) was A77 and G198
.

It has been reported that the degradation of MHC-I in lysosomes during tumor progression can lead to tumor immune escape
.
Therefore, the researchers wonder whether CAG can also block the degradation of MHC-I by regulating the target protein CTSB, thereby enhancing antigen presentation.
The researchers then found that CTSB was associated with MHC-I by knocking down and overexpressing CSTB in MC38 and HCT-116 cell lines is negatively correlated
.
Further, MHC-I aggregation on the cell membrane increased significantly after CAG treatment of MC38 cells, and CAG was found by Co-IP experiments It can inhibit the binding of CTSB and MHC-I, and at the same time, point mutation and other means also verify that CAG is mediated by inhibition of CTSB MHC-I degradation enhances antigen presentation
.

Finally, the researchers found that the combination of CAG and PD-1 antibodies obtained better anti-tumor effects, while the co-incubation experiment of colon cancer organoids and CD8 T cells in healthy human peripheral blood further suggested CAG It has clinical value
for the potential treatment of colorectal cancer.
The anti-tumor mode of CAG, the active molecule of traditional Chinese medicine, also suggested that blocking the combination of MHC-I degrading drugs and PD-1 antibodies had a better inhibitory effect
on tumors.
 

Cycloastragalol (CAG) directly targets cathepsin B (CTSB) to reduce MHC-I degradation on tumor cells and thereby enhance CD8T Cell-mediated anti-tumor immunity 

The results of the research were recently published in a long article entitled Targeting cathepsin B by cycloastragenol enhances antitumor immunity of CD8 T cells via inhibiting MHC-I degradation in the official journal of the European Society of Oncology and Immunology The Journal for ImmunoTherapy of Cancer was published to clarify that cycloastragalol, the active ingredient in the traditional Chinese medicine Astragalus, can directly target cathepsin B to reduce the degradation of MHC-I on tumor cells and thereby enhance CD8 T Cell-mediated anti-tumor immunity has revealed the scientific connotation
of the qi-tonifying drug Astragalus "Fuzheng and anti-cancer".

The study combines single-cell multi-omics with a research strategy for target confirmation (see APSB Review Tweet for details: New Opportunities and Challenges in Natural Product Research: When Target Confirmation Meets Single Cell Multiomics, https://mp.
weixin.
qq.
com/s/U7_w1sIedYTFqxRrVV0MLw This paper explains the scientific connotation of the active ingredient in the qi-tonifying drug Astragalus to enhance anti-tumor immunity, and also has reference significance
for the study of the mechanism of action of other compound or active ingredients of traditional Chinese medicine.

A new strategy for studying the mechanism of natural products based on target confirmation and organic combination of single-cell multi-omics 

Dr.
Deng Guoliang, Dr.
Lisha Zhou and Dr.
Binglin Wang (currently a lecturer at the School of Basic Medical Sciences, Henan University) are the co-first authors of the paper, and Professor Haibo Cheng and Professor Dongdong Sun of Nanjing University of Chinese Medicine and Professor Yang Sun of the School of Life Sciences, Nanjing University are the co-corresponding authors
of the paper.
The research was supported by the National Natural Science Foundation of China, the Basic Research Funds of Central Universities, the State Key Laboratory of Pharmaceutical Biotechnology, and the Institute of Chemistry and Biomedical Innovation
.
The study also received the help of Professor Ye Hui of China Pharmaceutical University in target identification, and I would like to express my gratitude
.

Original link: https://jitc.
bmj.
com/content/10/10/e004874